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Reducing bacterial resistance with IMPACT –
Interhospital Multi-disciplinary Programme on Antimicrobial
This guideline is available for download at: HKU Centre of Infection DH Centre for Health Protection IMPACT Third Edition (Version 3.0) Editors: PL Ho and SSY Wong Third Edition 2005 Second edition: 2001 (ver 2.0), 2002 (ver 2.1), 2003 (ver 2.2) First edition: 1999 All rights reserved. No part of this publication may be reproduced, stored in a retrieved system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, and recording or otherwise, without the prior approval from IMPACT We seek to improve the quality of this document. If you have comments or suggestion on this draft, please email to [email protected] or [email protected] This publication contains information relating to general principles of medical care, which should not be construed as specific instructions for individual patients. Manufacturers' product information and package inserts should be reviewed for the latest information, including contraindications, dosages and precautions. The editors, the working group and publisher are not responsible for errors or omissions or for any consequences from the application of the information in this document and make no warranty, express or implied, with respect to the currency, accuracy, or completeness of the contents of the publication. Application of this information in a particular situation remains the professional responsibility of the health care professionals. Readers are reminded that some products may not be available in their instutues. IMPACT Third Edition (Version 3.0) IMPACT Working Group

Dr. Raymond Wai Hung, Head, Infection Control Branch, Centre for Health Protection, Department of Health Dr. Dominic Ngai Chong, Consultant Microbiologist, Department of Clinical Pathology Queen Elizabeth Hospital Members (alphabetical
Dr. S Anandaciva Department of Anaesthesiology and Intensive Care Unit Tuen Mun Hospital Dr. Kin Sang, CHAN Chief of Service Department of Pulmonary Medicine Haven of Hope Hospital Dr. Wai Ming, CHAN Intensive Care Unit Department of Medicine Princess Margaret Hospital Dr. Wai Man, LAI Chief of Service Department of Microbiology Prince of Wales Hospital Dr. Patrick CK, LI Chief of Service Department of Medicine Dr. Wei Kwang, LUK Senior Medical Officer Department of Clinical Pathology Tseung Kwan O Hospital IMPACT Third Edition (Version 3.0) Dr. Tak Keung, NG Consultant Microbiologist Department of Clinical Pathology Princess Margaret Hospital Dr. Tak Lun, QUE Consultant Microbiologist Department of Clinical Pathology Tuen Mun Hospital Dr. Loletta KY, SO Senior Medical Officer Department of Medicine Pamela Youde Nethersole Eastern Hospital Dr. Wing Kin, TO Senior Medical Officer Department of Clinical Pathology Yan Chai Hospital Dr. Kwan Keung, WONG Chief of Service Department of Medicine North District Hospital Dr. Sai Hung, YEUNG Department of Orthopaedic Surgery Pamela Youde Nethersole Eastern Hospital Dr. Wai Chun, YIP Chief of Service Department of Surgery Kwong Wah Hospital Mr. Pak Wai, LEE Chief Pharmacist Hospital Authority Head Office IMPACT Third Edition (Version 3.0) Academic advisors
Professor Robert MT, CHAN Professor of Infectious Diseases Department of Medicine University of British Columbia Vancouver, Canada Dr. Pak Leung, HO Associate Professor and Honorary Consultant Division of Infectious Diseases, Department of Microbiology & Centre of Infection The University of Hong Kong Professor Margaret IP Department of Microbiology Chinese University of Hong Kong Professor Allan R. RONALD Distinguished Professor Emeritus (Internal Medicine, Medical Microbiology and Community Health Sciences) University of Manitoba Professor Kenneth WT, TSANG Professor and Honorary Consultant Department of Medicine Professor Kwok Yung, YUEN Chair Professor in Infectious Diseases Division of Infectious Diseases, Department of Microbiology & Centre of Infection The University of Hong Kong IMPACT Third Edition (Version 3.0) Secretaries
Dr. Cindy WS, TSE
Associate Consultant Department of Clinical Pathology Kwong Wah Hospital Medical Officer Department of Clinical Pathology Pamela Youde Nethersole Eastern Hospital Dr. Tak Chiu, WU Associate Consultant Department of Medicine Queen Elizabeth Hospital IMPACT Third Edition (Version 3.0) List of tables .9 Foreword .10 Preface.11 Part I: Antibiotic resistance- local scenario .12
Methicillin-resistant Staphylococcus aureus.16 Vancomycin-resistant enterococci .17 ESBL-producing Enterobacteriaceae .17 Enterobacter spp. 19 Part II: Antimicrobial stewardship programme .21
Antimicrobial stewardship program: summary .22 Classification of therapy.34 Part III: Guidelines for selected antimicrobials use.37
Vancomycin .38 Quinupristin/dalfopristin and linezolid .43 Ceftazidime.45 Imipienem/meropenem/ertapenem .48 Once daily aminoglycosides.50 Summary of selected antifungal agents .54 Part IV: Recommendation for the empirical therapy of common
infections .59
Musculoskeletal infections .60 Skin and soft tissue infections .61 Central nervous system infections.62 Intra-abdominal and GI system infections .63 Cardiovascular infections.64 Gynaecological infections .65 Head and neck infections .65 Urinary tract infections .65 Respiratory tract infections .66 Guidelines on the use and choice of antibiotics in severe acute pancreatitis .71 Management of community-acquired pneumonia .74 General considerations and principles.74 IMPACT Third Edition (Version 3.0) Part V: Guidelines for known pathogen therapy .81
Part VI: Guidelines for surgical prophylaxis.88
Antibiotic prophylaxis in clean operations .90 Antibiotic prophylaxis in clean-contaminated operations .92 Antibiotic prophylaxis in contaminated-infected operations .94 Part VII: Cost and recommended dosage of commonly-used
antimicrobial agents .95
Preparation and recommended dosing regimens for antibiotics .96 Cost comparison of selected IV antibiotics .100 Cost comparison of systemic antifungal agents.102 Dosage of antimicrobial agents for CNS infections .103 Intra-peritoneal antibiotic dosing recommendations for patients with CAPD peritonitis .104 Reference List .105 Abbreviations.123 IMPACT Third Edition (Version 3.0) List of tables

Table 1. Top ten isolates from clinical specimens in 2004 (data from a
regional hospital in Hong Kong). 14 Table 2. Intrinsic and associated resistance to antimicrobial agents among five nosocomial pathogens. 15 Table 3. Methods to implement antimicrobial control. 28 Table 4. Potential barriers to reaching the strategic goals . 29 Table 5. Summary of published data on antimicrobial strategies as an intervention to reduce ESBL resistance. 33 Table 6. Strategies for optimization of antimicrobial therapy. 36 Table 7. Dosage table for vancomycin. 41 Table 8. Calculation of vancomycin dose for morbidly obese patient. 42 Table 9. Comparison of linezolid and quinupristin/dalfopristin. 44 Table 10. Hartford Hospital once-daily aminoglycoside normogram for gentamicin and tobramycin . 53 Table 11. General patterns of antifungal susceptibility . 54 Table 12. Comparison of susceptibility of selected fungi to the azoles 55 Table 13. Mechanisms of antifungal action. 56 Table 14. Comparison of selected pharmacokinetic parameters for the azoles and caspofungin . 57 Table 15. A suggested scheme for systemic antifungal agents . 58 Table 16. Criteria for severity assessment of acute pancreatitis . 72 Table 17. Prophylactic use of antibiotic in acute pancreatitis . 73 Table 18. Comparative activities of commonly used beta-lactams against Streptococcus pneumoniae with different levels of penicillin susceptibility. 80 IMPACT Third Edition (Version 3.0) Foreword
Antibiotics are one of the essential armaments for management of infections. Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. It is becoming a global problem. Prevention of the emergence of resistance and the spread of resistant microorganisms will reduce these adverse effects and their attendant costs. Promoting appropriate use of antibiotic has shown to be an effective means to control antimicrobial resistance. In Hong Kong, our long-term battle against antibiotic resistance continues and antimicrobial guideline is an essential tool to promote rational use of antimicrobial agents with better application of existing knowledge and adherence to good practice. The IMPACT was developed in 1999 as a first step towards better control of the growing problem of antimicrobial resistance in Hong Kong. Developed with a multidisciplinary approach with inputs from different specialties and institutions, the IMPACT took into account the local data on prevalence of different pathogens and antimicrobial resistance patterns. Now into its third edition, the IMPACT has incorporated constructive comments from clinicians and other colleagues as part of an on-going effort to keep abreast of new antibiotics, changing resistance patterns and literature. This specifically developed guideline for practitioners in Hong Kong provides evidence-based principles focused on situations in which antimicrobial therapy could be curtailed without compromising patient care. The third edition of the IMPACT is a timely update to coincide with the launching of the Antibiotic Stewardship Programme by the Hospital Authority which includes optimal selection, dose and duration of treatment, as well as control of antibiotic use. The IMPACT constitutes an essential element along with other key elements of education, user-feedback, regular updates, clinical audits and process evaluation in this comprehensive Programme. I thank the many individuals and organizations who have contributed to the compilation of IMPACT and look forward to your continued support and partnership in our Antibiotic Stewardship Programme. Dr Cheung Wai-lun Director Professional Services and Operations Hospital Authority IMPACT Third Edition (Version 3.0) Preface

The "IMPACT" programme is a collaborative effort by recognized
authorities in the areas of clinical microbiology and infection,
infectious diseases, public health medicine, hospital epidemiology,
intensive care medicine, respirology, surgery, orthopaedics and
traumatology, and clinical pharmacology. The IMPACT working group
recognizes the challenges from drug-resistant organisms and believes
that the adverse impact of antimicrobial resistance could be reduced through a better and more judicial use of the existing agents. The document is intended to be of interest and value to colleagues who practise in institutional settings and prescribe or evaluate antimicrobial agents. This new edition updates and revises all the information in the previous edition. The document is now organized into eight parts. Part 1 and II covers the background information. Part III provides guidelines on the use of six classes of antibiotics. They are discussed separately because they represent new agents (linezolid, quinupristin-dalfopristin), agents in which usage has a strong link to development of multidrug-resistant organisms (glycopeptides, ceftazidime, and carbapenems) or that the dosing and monitoring are complicated (aminoglycosides). Several new sections have been added: antimicrobial stewardship programme, severe acute pancreatitis, antifungal agents, and antibiotic dosing for CAPD peritonitis. The font size and the print-out size have been increased to enhance readability. A full list of tables and a quick reference are added to facilitate the use of this book. The editors are grateful to the contributions by our experts in the working group. The secretaries are skillful and meticulous in their attention to the compilation of the document. On behalf of the working group, we thank the Infection Control Branch of the Centre for Health Protection for providing administrative support, the Chief Pharmacist Office in the Hospital Authority for the generous support in printing the hard copies and all colleagues who have provided us with their valuable opinions in the preparation of this document. PL Ho SSY Wong November 2005 IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario Part I: Antibiotic resistance- local scenario
IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario Background: the problem of antimicrobial resistance in
Hong Kong

1. The emergence of resistance has threatened the successful treatment of patient with infections (1-5). Antimicrobial resistance increases drug costs, length of stay and adversely affects patient's outcome (6). 3. Resistance to all classes of antibiotics has developed to various extents among the common and important nosocomial pathogens (Tables 1 and 2). IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario Table 1. Top ten isolates from clinical specimens in 2004 (data from a regional hospital in Hong

Blood Respiratory
specimens Urine
P. aeruginosa S. aureus Enterococci species staphylococci K. pneumoniae H. influenzae Klebsiella species Bacillus species Klebsiella Candida species S. aureus S. pneumoniae Proteus species Enterococcus species A. baumannii P. aeruginosa A. baumannii M. catarrhalis Coagulase negative staphylococci P. aeruginosa S. aureus B. fragilis group Enterobacter S. agalactiae (Lancefield gp B) P. mirabilis S. maltophilia M. marganii (Percentage omitted if number of isolates is less than 30) IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario Table 2. Intrinsic and associated resistance to antimicrobial
agents among five nosocomial pathogens.

All beta-lactams, beta- Common: erythromycin, lactam/beta-lactamase inhibitor combinations aminoglycosides, cotrimoxazole, fluoroquinolones All cephalosporins, Common: ampicillin, imipenem, meropenem, vancomycin, high level All cephalosporins including fourth fluoroquinolones, (CTX-M, SHV-, TEM- cephalosporin (7), all penicillins, aztreonam Derepressed AmpC-type First, second and third mutant among E. fluoroquinolones, cloacae, C. freundii, S. cephalosporins, most marcescens lactamase inhibitor combinations, cefoxitin A. baumannii Ampicillin, first and Third generation second generation fluoroquinolones, aminoglycosides, (± imipenem, meropenem) (8) IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario Methicillin-resistant Staphylococcus aureus
On the basis of the patient history and epidemiological analysis,
Methicillin-Resistant Staphylococcus aureus (MRSA) may be
categorized into healthcare-associated or community-associated.
Healthcare-associated MRSA (HA-MRSA)
ƒ This type of MRSA is endemic in the local healthcare environment including hospitals, extended care facilities and old age homes since the mid-1980s (3;4;9). The HA-MRSA tends to be isolated in patients who are hospitalized for more than 48 hours. Since MRSA carriage may persist for many months after a previous acquisition, HA-MRSA also include those isolates that are found at admission (or within 48 hours) from patients who possess risk factors for their carriage including hospitalization in the previous 1 year, recent surgery, old age home residence, renal dialysis and exposure to invasive devices and employment in a healthcare institute (10;11). ƒ In Hong Kong, 30-50% of all hospital S. aureus isolates are currently resistant to methicillin. The proportion of MRSA increased to 70-80% among isolates from intensive care units (ICU). In 1999, a study involving ICUs in 11 public hospitals showed 12% of the patients were MRSA carriers at ICU admission and that new acquisition of MRSA occurred in about 12% of the patients who were non-carriers initially (12). ƒ Most HA-MRSA also encode a battery of other resistance genes, they are thus multiresistant to drugs in other antibiotic classes including aminoglycosides, macrolides, fluoroquinolones and clindamycin (3;12). Community-associated MRSA (CA-MRSA)
1. Patients infected with CA-MRSA do not have the usual risk factors associated with HA-MRSA. In overseas countries, CA-MRSA were found to be more common among certain populations: children with chronic skin condition, prisoners, military personnel, aboriginals, injection drug users, the homeless and contact sports athletes (13-16); but such associations have not been observed among the CA-MRSA cases in Hong Kong. IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario 2. This organism often remains susceptible to antibiotic classes other than beta-lactams, including clindamycin, aminoglycosides, tetracyclines and fluoroquinolones. 3. The genotypes of CA-MRSA are different from the local nosocomial strains. Most CA-MRSA strains in Hong Kong represent members in clonal cluster 30, similar to the situation in the Southwest Pacific region (17). 4. CA-MRSA possesses novel types of methicillin-resistance cassette elements: type SCCmec IV or V, which are rare among the HA-MRSA strains. 5. CA-MRSA is more likely to encode the virulence factor, Panton- Valentine leukocidin (PVL) toxin, which is associated with skin/soft tissue infections and severe necrotizing pneumonia (18). VRE here refers to E. faecium and E. faecalis with resistance to glycopeptides (vancomycin MIC ≥8 μg/mL or teicoplanin MIC ≥16 μg/mL). The incidence of VRE in Hong Kong is low at present. The first isolate of VRE (E. faecium) in Hong Kong was imported in 1997. In the subsequent 3 years, a few sporadic cases were identified in five hospitals including a small cluster recently in TMH. By the end of March 2001, about 10 cases of VRE have been detected, including both vancomycin-resistant E. faecium (vanA and vanB) and E. faecalis (vanA) (19). In a multicentre surveillance of 1600 consecutive patients hospitalized in >10 ICUs in 1999, the prevalence was found to be <0.1%.
ESBL-producing Enterobacteriaceae
Extended-Spectrum Beta-Lactamases (ESBLs) are any bacterial
enzymes that are capable of inactivation of third generation
cephalosporins. The term is most commonly used to refer to a group of bacterial enzymes that are derived from the classical beta-lactamases TEM-1, TEM-2 and SHV-1. In recent years, the "CTX-M" type of ESBL is also emerging in several Asian countries including China and Hong Kong SAR (20-22). IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario ESBL may lead to therapeutic failures despite apparent susceptiblity to some third generation cephalosporins in conventional antibiotic sensitivity testing methods. The ESBLs confer variable levels of resistance to cefotaxime, ceftazidime, other broad-spectrum cephalosporins, and to monobactams such as aztreonam, but had no detectable activity against the carbapenems (such as imipenem, ertapenem and meropenem). If antibiotic therapy is indicated (colonization do not need any treatment other than infection control), serious infections by ESBL-producers should be regarded as clinically resistant to all the cephalosporins (including cefepime). The ESBLs are usually encoded on genes in plasmids and because of the ready transmissibility of the responsible plasmids, dissemination of the resistance genes to other micro-organisms occur readily. Since genes encoding resistance to multiple antibiotics are often present in the same plasmid, co-transfer of multiple resistance to non-beta-lactam drugs, such as aminoglycosides, cotrimoxazole, chloramphenicol, and tetracycline is common. At present, the prevalence of ESBLs among Enterobacteriaceae isolated in many tertiary hospitals around the world is over 10-15%. In Hong Kong, a survey of four hospitals in 1997/98 (1200 non-duplicate clinical isolates) revealed rates of 6-23% for Klebsiella pneumoniae and 9 -14% for E. coli. (23). Numerous outbreaks due to ESBL-producing bacteria have been reported. Known risk factors for colonization and/or infection with organisms harbouring these enzymes include admission to an intensive care unit, recent surgery, instrumentation, prolonged hospital stay and antibiotic exposure, especially exposure to third generation cephalosporins. Incidence of ESBLs can decrease after changes in antibiotic policy (mainly reducing the use of third generation cephalosporins) and enforcement of barrier precautions (Table 5). Most CTX-M, TEM- and SHV-derived ESBLs are susceptible to inhibition by the beta-lactamase inhibitors and theoretically beta-lactam/beta-lactamase inhibitor combinations should be active against these isolates. It must be remembered that production of ESBL doesn't preclude other mechanisms of resistance. In a recent survey, it was found that 40-70% of the ESBL-producing IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario Enterobacteriaceae were resistant to amoxicillin-clavulanate, ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam and cefoperazone-sulbactam (20).
Enterobacter spp.
De-repression of AmpC beta-lactamase occurs most frequently among Enterobacter spp. De-repressed mutants are resistant to all the first, second and third generation cephalosporins. AmpC-mediated resistance usually cannot be reversed by the currently available beta-lactamase inhibitors. Hence, most de- repressed mutants are also resistant to ampicillin-sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam, ticarcillin-clavulanate, and cefoperazone-sulbactam. It should be noted that resistance may develop in 20-40% of serious Enterobacter infections during treatment with a second or third generation cephalosporin (refer to Part V for treatment recommendations). In Hong Kong, a recent study found AmpC de-repression in 23% of all Enterobacter spp. (21). It was also found that ESBL of the CTX-M type may be emerging in some Enterobacter spp., such as E. hormaechei. Therefore, laboratories should pay attention to speciation of Enterobacter and be alert to the possibility of ESBL production in this genus.
Multidrug-resistant Pseudomonas aeruginosa
1. Pseudomonas aeruginosa, a saprophyte widely distributed in nature and moist habitats (e.g. sinks, respiratory equipment, antiseptic or detergent solutions found in hospitals), is being increasingly recognized as a nosocomial pathogen, especially among critically ill or immunocompromised patients. Cross transmission or acquisition among patients likely occurs through hands of healthcare workers, or via contaminated fomites. 2. Under increasing antibiotic selection pressure, P. aeruginosa could acquire increasing drug resistance, leading to emergence of multi-drug-resistant phenotype (MRPA). By definition, MRPA isolates exhibit beta-lactam multiresistance (piperacillin, piperacillin- IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance – local scenario tazobactam, ceftazidime, cefepime, carbapenems), along with resistance to aminoglycosides and quinolones (24-26); underlying mechanisms include enhanced production and dissemination of novel beta-lactamases, decreased outer membrane permeability, and presence of drug efflux pumps (27;28). 3. During the past 10 years, there have been numerous reported outbreaks of MRPA worldwide (29-33). According to the recent global SENTRY surveillance conducted in 1997-1999, the rates of MRPA (defined as being resistant to piperacillin, ceftazidime, imipenem, and gentamicin) occurrence were as follows: Latin America, 8.2%; Europe, 4.7%; United States, 1.2%; Asia Pacific, 1.6%; and Canada, 0.9% (34). More recent reports indicate that the overall prevalence of MRPA continues to be on the rise, especially in tertiary care institutions (35;36). The exact prevalence of MRPA in Hong Kong is currently not known. 4. In patients suffering from chronic chest conditions (e.g. cystic fibrosis), MRPA infection occurs after chronic airway colonization (37); other patients appear to acquire the infection after hospitalization. MRPA is predominantly isolated from respiratory samples (35;38). Risk factors for nosocomial MRPA acquisition and infection included: old age; severe underlying disease and / or being bedridden (39); having maxillary sinusitis; high lung injury score and / or need for prolonged mechanical ventilation (40;41); various forms of instrumentation (e.g. urinary catheters and nasogastric feeding tubes (39;39), long dwelling central venous catheters (41). Prolonged use of antipseudomonal antibiotics such as beta-lactams, carbapenems, and fluoroquinolones is also important risk factor (38-41). 5. Treatment of MRPA infections is extremely difficult (42;43), because MRPA can be resistant to all the currently available anti- pseudomonal antibiotics, and may necessitate the use of unlicensed and potentially toxic drugs such as colistin and polymyxin B, or experimental combinations (44-46). Unfortunately, the new antibiotics (such as glycylcyclines and ketolides) in the pipeline are not active against MRPA. In view of this, MRPA infected or colonized patients should be nursed in single rooms whenever feasible and that all attending staff should practise hand hygiene for every patient contact and other necessary standard and contact precautions. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Part II: Antimicrobial stewardship programme
IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Antimicrobial stewardship program: summary
ƒ The present summary is based on an article in the Hong Kong Medical Journal (47). ƒ Antimicrobial drug resistance is now an important public health threat because it endangers our ability to effectively treat infections. A multi-faceted approach involving the continuous application of a package of interventions should be implemented at regional and international levels. In healthcare settings, the recommended measures include infection prevention, effective diagnosis and early treatment, using antimicrobials wisely and breaking the chain of transmission (Centers for Disease Control and Prevention, 2003). In the local settings, studies have found that there are rooms for optimization of antimicrobial prescriptions in the hospitals. Research conducted in the recent years further indicates that improvement in the pattern of prescriptions is feasible and can be implemented by means of antimicrobial stewardship programme (ASP) in a safe, scientific and professional manner. As antibiotic-resistant bacteria become more widespread, such initiatives will be assuming increasingly important roles. Therefore, the Scientific Committee on Infection Control in the Centre for Health Protection recently come up with a document on "Optimizing antimicrobial prescriptions in hospitals by antimicrobial stewardship programme in Hong Kong: consensus statement". The present text summarizes the document under six broad questions: 1. What is the definition for optimal antimicrobial use?
ƒ Optimal antimicrobial use (prudent prescribing) has been defined as "the cost-effective use of antimicrobials which maximizes their clinical therapeutic effect, while minimizing both drug-related toxicity and the development of antimicrobial resistance" (48;49). This implies usage in the most appropriate way for the treatment or prevention of human infectious diseases, having regard to the diagnosis, evidence of clinical effectiveness, likely benefits, safety, cost, and propensity for the emergence of resistance. Therefore, optimal antibiotic use means both "less" use (i.e. less unnecessary use), and "appropriate" use (i.e. not only the right antibiotic but also the right dose, route and duration to effect a cure while minimizing side effects and development of resistance according to the up-to- date knowledge). IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme 2. What is the rationale for optimizing antimicrobial use?
ƒ There are growing concerns about antimicrobial resistance. As antimicrobial resistance increases, many previously time-honored, first-line therapies are rapidly losing their efficacies and are becoming obsolete (49). Antimicrobial resistance adds substantially to our already rising healthcare costs, prolongs periods during which individuals are infectious, increases morbidity, increases length of hospital stay, and even mortality. ƒ In developed countries, studies have found that 30-40% of hospitalized patients were treated with antimicrobial agents. When antimicrobial usage was studied, there are large variations in the pattern of usage (50;51) and half of the usage could be classified as suboptimal using recommended quality indicators (52;53). It is clear that suboptimal use not only adversely affects patient outcome (54;55), but also increases the risk of developing antimicrobial resistance (52;53;56;57). ƒ Currently, the issue of antimicrobial resistance is complicated further by an insecure supply of new agents (58-60) and a dwindling number of companies investing in antimicrobial agents (61). Despite the dramatic rise of antimicrobial resistance in the past five years, only two new classes of antibiotics were approved since 2000: oxazolidinones (linezolid) and the cyclic lipopeptides (daptomycin). In 2004, there are few novel antibacterial agents in the pipeline. Thus, improving the use of existing antibiotics by all clinicians is imperative. 3. What is antimicrobial stewardship programme? Who are the
advocacies? (Table 3)
ƒ The term antimicrobial stewardship is defined as the optimal selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance (62). In practice, this involves prescribing antimicrobial therapy only when it is beneficial to the patient, targeting therapy to the desired pathogens and using the appropriate drug, dose, and duration. Thus, ASP should not be viewed simply as reduced use or a strategy for cost containment. Instead, by minimizing exposure to drugs, performing dose adjustments, reducing redundant therapy and targeting therapy to IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme the likely pathogens, such activities can be viewed as a strategy to enhance patient safety. ƒ ASP involves a multidisciplinary, programmatic, prospective, interventional approach to optimizing the use of antimicrobial agents. The multidisciplinary team typically includes clinical microbiologists, infectious diseases specialists, infection control practitioners, and clinical pharmacists. Having members from other medical specialties, such as surgery and paediatrics, is also recommended. Multiple approaches have been employed to enforce hospital policies to limit or control antimicrobial use (Table 3). Under the auspice of ASP, several behavioural methods have been used successfully to effect changes, including problem-based education, consensus guidelines, peer review, concurrent review, data feedback, computer-based reminders, financial incentives, and the use of opinion leaders (63;64). ƒ Many professional societies and public health guardians including the World Health Organization, Infectious Diseases Society of America (IDSA), Alliance for the Prudent Use of Antibiotics (APUA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH) are supportive of programmes that promote optimal antimicrobial use (65;66). A few have even gone a step forward with action plans (48;65-67). 4. Is there evidence that ASP is beneficial? How did people
document the benefits of the programme? Is there any evidence
that it leads to better and more optimal antibiotic use in the
hospital setting?

ƒ Most studies found this strategy effective in reducing the usage of targeted antibiotics and in controlling antimicrobial expenditures. In terms of its impact on antimicrobial resistance, programmatic interventions in hospitals have yielded mixed results (68;69). The reason for this is that the factors promoting resistance are complex and multiple. It is clear that strong relationship exists between certain antibiotic classes and multi-drug resistant pathogens such as vancomycin with VRE; third generation cephalosporins with ESBL; and fluoroquinolones with MRSA and MRPA. At an institutional level, programmes designed to limit utilization of agents that exert greater effect on the above were successful in reducing the specific resistance rates. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme ƒ Measurement and monitoring is an essential part of the programme. After an initial implementation of a restricted formulary and antimicrobial approval system as part of an antimicrobial control programme, the team should meet regularly to review and update the formulary, assess its effectiveness, provide and coordinate ongoing physician education, and analyze antimicrobial utilization data within the hospital. The programme should be dynamic, and continually reassessed, adding new components or deleting unsuccessful components over time. ƒ To allow for accurate intra- and inter-institutional comparison, confounding differences in expenditure related to acquisition costs and variations in the amount of individual antibiotic used for individual patients should be corrected by appropriate standardization using the defined daily dose (DDD) and rates calculated in terms of DDD per 1,000 admissions and DDD per 1,000 bed-days. 5. Is this the right time for Hong Kong to introduce ASP? Are we
too early, or are we too late, and why?

ƒ In Hong Kong, few would dispute the threat from antimicrobial resistance and the needless expenditures associated with excessive antimicrobial use (70). Recent surveys show that suboptimal antimicrobial prescriptions may be commonplace in our hospitals (71), and that they could be improved. In the two university hospitals, one prospective study in 2003 found that 76% of antibiotic prescriptions for patients hospitalized for exacerbation of chronic obstructive pulmonary disease were unjustified according to the prevailing Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (71). In 2004, real-time audit of "big gun" antibiotics in two hospitals have revealed that 20-25% of the prescriptions were not justified or suboptimal. The most common problems include treatment of colonization, narrower and equally effective alternative or less toxic alternatives not being used and inappropriate duration (Seto WH, personal communication). In another prospective study of antibiotic combinations over a six-month period, it was found that one of the agents was redundant in 80% of 200 prescription episodes (71). ƒ More actions are required in areas where the antimicrobial resistance problem is most serious. In Hong Kong, there is evidence that antibiotic resistance in some important nosocomial pathogens IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme is worse than in many other parts of the world (72). In the United States, a "Public health action plan to combat antimicrobial resistance-action plan" was developed in 1999. In the United Kingdom, significant progress has been made in optimizing the clinical use of antimicrobials since 2000 in terms of governmental directives, strategy and action plan (67;73). Recently, similar initiatives have been launched in Taiwan and South Korea at a national level. It is, therefore, definitely not premature to introduce such a "universal" and "continuous" programme to the public hospitals in Hong Kong. ƒ Many studies have found that optimization of antibiotics in hospitals was feasible, safe and effective. A diversity of approaches have been reported and the experience accumulated so far indicates a multi-faceted "stewardship" and "immediate concurrent feedback" approach has clear advantages (62;74-81). 6. What are the disadvantages for having ASP? What problems
have been reported? Are there any arguments against having ASP
in the literature? Is there a role for an alternative mechanism?
(Table 4)

ƒ ASP involves proactive monitoring and feedbacks. One alternative approach is "no control" (i.e. only by passive means). Such an approach relies heavily on the distribution of national guidelines. As discussed in detail in an international workshop, such a strategy has not worked in the past (82). Guidelines are seldom studied thoroughly by clinicians, and even if they are read, they rarely are incorporated into everyday practice. On the other hand, there are barriers and concerns to ASP that need to be addressed (Table 4). The perception of "threatened physician autonomy" can be a significant impediment to the effort. Previous studies and local experiences have indicated that this is often an "emotional" response that can be resolved by immediate concurrent feedback, consensus building, involvement of institutional opinion leaders, and attention to process measures (83-85). In fact, similar programmes have been launched successfully in some Hospital Authority hospitals for the other drugs, including the statins, calcium channel blockers and acid suppressive agents. ƒ Another impediment is the incorrect perception that
antimicrobial stewardship programmes are solely cost-driven
and that patient safety may be at risk.
In this regard, recent
IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme reports have emphasized the inclusion of quality indicators such as time to reception of appropriate empirical antibiotics. Other suggested indicators include: (a) clinical outcomes of bacteraemia due to Gram-negative organisms (86), (b) mortality for all patients, for those treated with antimicrobials, and for those suffering from infections, (c) duration of hospital stay for all patients and for those treated with antimicrobial drugs, and (d) re-hospitalization rate within 30 days after discharge for all patients and those treated with antimicrobial drugs (81). As in any quality improvement programme, a financial incentive is important to secure support by the hospital management. This is no exception for antimicrobial stewardship programme. Good leadership and effective communications are essential to keep members, prescribers and patients to the appropriate focus. This could be enhanced by having a multidisciplinary steering committee, and by regular use of data feedback on the patterns of usages, patient outcomes, and antimicrobial resistance data. In principle, member in the committee should have a strong sense of commitment and cooperation. The composition of the multidisciplinary steering committee may be unique to each institute. Conclusion
ƒ Considering the broader perspective, working targets are needed and the programmes should be regularly evaluated. For a start, each hospital will need to form a steering group and to lay down the institutional priorities. In the literature, programme models are available for optimizing the uses of aminoglycosides, vancomycin, broad-spectrum antibiotics, antibiotic combinations, and for switching therapy from intravenous to oral. It is clear that a multi-faceted approach incorporating immediate concurrent feedback is most likely to be successful. In order to safeguard health care quality, the use of quality indicators and timely feedback of data are essential. Our fight against antimicrobial resistance is going to continue. Hence, a major challenge will be how to keep the programmes viable and sustainable within our system in the longer terms. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Table 3. Methods to implement antimicrobial control
1. Written hospital guidelines.
2. Educational efforts aimed at changing prescribing practices of 3. Providing consultation from clinical microbiologist/infectious diseases specialist. 4. Restriction of hospital formulary through the Drug and Therapeutics Committee. 5. Utilization review with guidelines for rational and appropriate 6. Ongoing monitoring and analysis of antimicrobial agents 7. Ongoing surveillance of antimicrobial susceptibility. 8. Monitoring adherence to advice on choice of antimicrobial 9. Usage feedback to physicians. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Table 4. Potential barriers to reaching the strategic goals

Countermeasures and improvement
Ownership and accountability
1. Lack of ownership and 1. Designate responsibility and accountability for recognizing and accountability for the process. reporting trends. 2. Set up a multi-disciplinary team to 2. Failure to integrate work of develop a collaborative system and laboratory, infection control, monitor results. medical, nursing, and intensive care-unit staffs. Staff knowledge and practice
1. Lack of time for the laboratory 1. Ensure adequacy of laboratory and and/or infection control staff to infection-control staffing and prioritize generate and analyze data. activities of staff so that data can be 2. Lack of time for healthcare generated and analyzed. providers to examine and discuss 2. Report data in an easy-to read/interpret data and inconsistent or format and, when appropriate, include erroneous interpretation of data data interpretation in the report. Physician attitudes
1. Lack of trust in the hospital 1. Use a data-driven approach to cultivate trust; e.g. communicate regularly with physicians about trends in antimicrobial usage, cost, and resistance; feedback to individual physicians their performance Expertise
1. Lack of expertise in biostatistics 1. Ensure availability of consultants, (e.g. presenting trends and especially when designing analytic analyzing data). strategy and interpreting trend data. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme
State-of-the art: Limiting antimicrobial resistance
US surveys: 22-65% usage of antibiotics in the hospitals is Outbreaks of multi-resistant bacteria, including those that persist despite apparently adequate infection control measures, can be limited effectively by antibiotic programme directed at judicious use of antibiotics. While restriction of an individual antibiotic (such as cefotaxime or ceftazidime) has been reported to be useful in controlling outbreaks of drug-resistant bacteria, the general consensus is that the main focus should be directed at the rational use of all classes of antibiotics rather than merely restricting the use of individual drugs (6;86-96).
Over-prescription of third generation cephalosporins and

Experience from several overseas centres suggests that over-prescription of third generation cephalosporins and glycopeptides are closely associated with the selection and dissemination of ESBL-producing Enterobacteriaceae, de-repressed AmpC-type mutant among Enterobacter cloacae, Citrobacter freundii, Serretia marcescens, MRSA, Cephalosporin use has been identified as a risk factor for enterococcal colonization and superinfection, as well as for antibiotic-associated diarrhea, the main reason for oral vancomycin (97;98). Significant risk factors for colonization or infection with VRE were prior antibiotic use (p=0.04), the previous use of third-generation cephalosporins (p=0.03), and the previous use of parenteral vancomycin (p=0.002). This data was obtained from 7 hospitals including primary and tertiary care facilities (200-700 beds) (99). In the Cornell University Medical College, New York, it was found that the duration of hospitalization, intrahospital transfer between floors, use of antimicrobials (i.e. vancomycin and third generation cephalosporins), and duration of vancomycin use (≥7 IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme days) were independently associated with VRE infection or colonization (100). Ten weeks after the introduction of cefotaxime, resistant Enterobacter cloacae could be isolated from stool cultures in an increasing proportion of patients and septicaemia developed in 6 cases (101). In 6 US hospitals, previous administration of third-generation cephalosporins was more likely to be associated with multi-resistant Enterobacter isolates in an initial positive blood culture (69%) than was administration of antibiotics (20%) that did not include a third-generation cephalosporins (p<0.001) (102). Resistance to third generation cephalosporins among Enterobacter spp, Citrobacter freundii, Morganella morganii, Serratia marcescens and Providencia spp. has become widespread both locally within hospitals and nationally. This trend has been shown to correlate closely with the extent of usage of some third generation cephalosporins (1;103). Decreased antibiotic resistance after changes in
antibiotic use

No simple answer exists on the control of multi-drug resistant bacteria. The traditional approach slanted heavily on infection control measures, which are obviously important but can be difficult to implement. When audited, compliance with hand hygiene measures has been consistently low (<40%) (104). Outbreaks of multi-drug resistant bacteria have continued despite apparent adherence to "standard" hygienic measures. In recent years, there has been renewed interest on the strategic use of antibiotics as a measure for prevention or control of antimicrobial resistance (94). In fact, several studies have demonstrated that strategic use of antibiotics (so far, only class restriction of the cephalosporins have been evaluated to a significant extent) can lead to: Less multi-resistant de-repressed AmpC-type Enterobacter spp. An outbreak of infections by multi-resistant Enterobacter spp. disappeared after use of cefotaxime was discontinued in the unit. Less ESBL-producing Enterobacteriaceae. Literature on antimicrobial strategies as an intervention to reduce ESBL-producing K. pneumoniae was summarized in Table 5. In a case- IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme control study, the use of beta-lactam/beta-lactamase inhibitor combination was shown to be a protective factor (105). Less vancomycin-resistant enterococci. Two studies reported on the successful control of VRE outbreaks by changing antibiotic usage (92;106). In one medical centre (92) , the antibiotic formulary was altered by restricting the use of cefotaxime and vancomycin and adding beta-lactamase inhibitors to replace third-generation cephalosporins. After 6 months, the average monthly use of cefotaxime, ceftazidime, vancomycin, and clindamycin had decreased by 84%, 55%, 34% and 80% respectively (p<0.02). The point prevalence of faecal colonization with VRE decreased from 47-15% (p<0.001). In another haematologic unit (106), acquisition of VRE paralleled the use of ceftazidime as empirical therapy for neutropenic fever. Phase 1: ceftazidime as empirical therapy, VRE carriage rate was 57%. Phase 2: piperacillin-tazobactam replaced ceftazidime as empirical therapy, VRE carriage decreased to 8%. Phase 3: ceftazidime re-introduced as empirical therapy, VRE carriage increased to 36%. Those who are interested in the experimental data that might explained this observed relation between VRE, cephalosporins and BLBLI should refer to a recent review by Rice et al (107). IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Table 5. Summary of published data on antimicrobial strategies as an intervention to reduce
ESBL resistance.

Year period (Ref)
Setting (type of study) Intervention/result Other observations Epidemic rise in ESBL in K. Minimize use of ceftazidime ESBL rate remain pneumoniae from 6-28% within 1 (marked and sustained ↓); <10% next 4 years year in a medical centre addition of piperacillin- (intervention study) tazobactam to formulary (usage ↑) Spread of VRE in one institute Use of BLBLI emphasized and the Mean incidence of Cefotaxime-resistant continued despite infection control use of 3GCs, vancomycin and Acinetobacter ↑ by measures (intervention study). clindamycin restricted; addition of ampicillin-sulbactam and piperacillin-tazobactam to Outbreak of CRKP in one medical Ceftazidime was replaced by CRKP ↓ from >30% centre. Use of ceftazidime ↑ 600% in imipenem. the 2 years before outbreak (intervention study). A clonal outbreak of ESBL- Restriction of 3GC (usage ↓ by ESBL carriage ↓ from producing K. pneumoniae in an ICU 87% after intervention). 33 to 40% to 0%. (intervention study). An outbreak of ESBL-producing K. Class restriction of cephalosporins CRKP ESBL ↓ by Imipenem-resistant pneumoniae in a hospital since (usage ↓ by 80% after P. aeruginosa ↑ by 1990 (intervention study). intervention). Usage replaced by Clonal outbreak of CRKP in hospital Physician education on Hospital A: CRKP ↓ % KP resistant to A. Polyclonal outbreak of CRKP in association of ↓ ceftazidime use BLBLI also ↓ (36 to hospital B (intervention study). and ↓ CRKP. Use of ceftazidime ↓ Hospital B: CRKP ↓ by 71% (hospital A) and 27% 3GC, third generation cephalosporins; BLBLI, beta-lactam/beta-lactamase inhibitor; CRKP, ceftazidime-resistant K. pneumoniae. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Classification of therapy

Empirical therapy
In the clinical situation of "empirical use", the antimicrobial(s) is/are
used as initial therapy directed to eradicate the most likely pathogens.
Before initiation of antimicrobials, appropriate specimens for stains
and culture of microorganisms should be obtained. Results of
identification and susceptibility of microorganisms are likely to be
available in the following 48 to 72 hours. The use of broad-spectrum
antibiotics or combination therapy is usually necessary to cover the
different organisms capable of causing an infection. In general, the use
of agents in this situation should not extend beyond the time required
to obtain results of cultures and susceptibility.
Choice of agent(s): based upon adequate coverage of the potential
pathogens of the potential infection sites and the anticipated
antimicrobial susceptibility patterns of the bacterial isolates.
Recommendations of empirical therapy for some common infections
are outlined in Part IV.
Known-pathogen therapy
In the clinical situation of known pathogen use, the antimicrobial(s) is
/are used when the microbiology laboratory has identified the micro-
organism causing the infection and the susceptibility pattern is
known. If during empirical use, the patient is started on combination
therapy or broad spectrum antibiotics, the antimicrobial spectrum
should be narrowed to cover the micro-organisms identified as the
aetiologic agent. Streamlining from broad-spectrum to specific, narrow
spectrum antimicrobials helps to avoid colonization with resistant
organisms and superinfections. In the absence of allergy or other
contraindications, the agent (appropriate for the site and type of
infection) with the narrowest spectrum in a group or a list of candidate drugs should be used. It should be noted that the skin and mucous membrane surface of the hospitalized patient are often colonised with nosocomial bacteria (such as MRSA, E. coli, Klebsiella spp, etc.), systemic antimicrobial therapy (both IV and PO) should not be administered in an attempt to eradicate these micro-organisms. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme
Switch therapy-conversion from IV to PO
In the clinical situation of switch therapy use, PO antimicrobials
replace IV usage for completion of therapy. IV is almost always employed in serious infections to ensure maximal serum/tissue levels. With few exceptions such as meningitis, infective endocarditis, the majority of patients with infections do not require completion of the antimicrobial course with IV therapy. The following criteria have been developed for transition from IV to PO antimicrobial (114;115): 1. Patient with no clinical indication for IV therapy. 2. Patient is afebrile for at least 8 hours. 3. The WBC count is normalizing (falling towards or <10x109/L). 4. Signs & symptoms related to infection are improving. 5. Patient is not neutropenic (neutrophil count >2 x109/L). 6. Patient is able to take drugs by mouth (non-NPO). 7. Patient with no continuous nasogastric suctioning. 8. Patient with no severe nausea or vomiting, diarrhea, gastrointestinal obstruction, motility disorder. 9. Patient with no malabsorption syndrome. 10. Patient with no pancreatitis or active gastrointestinal bleeding or other conditions that contraindicated to the use of oral medications. IMPACT Third Edition (Version 3.0) Part II: Antimicrobial stewardship programme Table 6. Strategies for optimization of antimicrobial therapy
Stages in the management of infection

Strategies for optimization
Empirical therapy (ET)
• Document the presence of infection • Likely pathogens? • Collection and analysis of local • Likely susceptibility pattern • Community- or hospital-acquired • Pocket reference guide • Monotherapy or combination therapy? When culture and susceptibility results are available
Known-pathogen therapy (KPT)
• Narrowest spectrum according to • Cascade reporting of sensitivity laboratory results • Daily review of prescription of • Follow guidelines on the judicious use of "big gun" antibiotics by ASP ceftazidime, imipenem/ertapenem/ meropenem, vancomycin/teicoplanin/ • Daily reporting of deviations from guidelines to clinical microbiologist/ID physician • ASP team to give daily immediate concurrent feedback (ICF) to prescribers. Switch therapy (116;117)
• A switch from intravenous to oral therapy • Daily review of patients on IV • Criteria for switch therapy "big gun" antibiotics by ASP • Clinical diagnosis compatible with oral • Daily recommendation for • Patient has functioning gastrointestinal "switching" by ASP team • Patient is afebrile (for >24h) • Signs and symptoms related to infection are improving or resolved • The WBC count is normalizing
Stop therapy
• Type of infection • Clinical responses • Follow-up culture results where IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Part III: Guidelines for selected antimicrobials use
IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Vancomycin
Situations in which the use of vancomycin/teicoplanin is
Treatment of serious infections caused by beta-lactam resistant Gram-positive bacteria (e.g. MRSA, coagulase-negative staphylococci). Treatment of infections caused by Gram-positive bacteria in patients who have serious allergies to beta-lactam antimicrobial agents (e.g. anaphylactic reaction, Stevens-Johnson syndrome). When Clostridium difficile colitis fails to respond to metronidazole therapy or is severe and life-threatening. As prophylaxis for endocarditis following certain procedures in- patients at high risk for endocarditis; according to recommendation from the American Heart Association. (e.g. as prophylaxis for genitourinary or gastrointestinal procedures in moderate or high-risk patients allergic to ampicillin/amoxicillin). As prophylaxis for major surgical procedures involving the implantation of prosthetic material or devices in known carriers of MRSA. For elective procedures, daily washing of skin and hair with a suitable antiseptic soap (e.g. 4% chlorhexidine liquid soap) and topical treatment of the anterior nares with nasal mupirocin ointment (for 5 days) are recommended before the procedures. Vancomycin may be less effective in preventing surgical wound infection due to methicillin-sensitive staphylococci (118).
Situations in which the use of vancomycin/teicoplanin are not
Treatment of MRSA nasal carriage or colonization at other sites such as the isolation of MRSA from • Surface swab of superficial wounds • Surface swab of chronic ulcers • Surface swab of pressure ulcers Routine surgical prophylaxis other than in a patient who has serious allergy to beta-lactam antimicrobial agents. Routine empirical antimicrobial therapy for neutropenic fever (except as recommended by the IDSA 2002 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever). IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Treatment in response to a single blood culture positive for coagulase-negative staphylococci, if other blood cultures taken during the same time frame are negative. Continued empirical use of presumed infections in patients whose cultures (blood, joint fluid, peritoneal fluid, pus, etc), are negative for beta-lactam-resistant Gram-positive bacteria (e.g. MRSA). Systemic or local (e.g. antibiotic lock) prophylaxis against infection (or colonization) of indwelling (central or peripheral) intravascular catheters. As routine prophylaxis, before insertion of Hickman/Brovac catheter or Tenckhoff catheter. As part of the regimen for selective digestive tract decontamination. Primary treatment of Clostridium difficile colitis, except when it is severe and life-threatening. 10. Routine prophylaxis for patients on continuous ambulatory peritoneal dialysis or haemodialysis. 11. Treatment (e.g. chosen for dosing convenience) of infection caused by beta-lactam-sensitive Gram-positive bacteria in patients who have renal failure. 12. Use of vancomycin solution for topical application (e.g. to burn wound, ulcers) or irrigation (e.g. of T-tube, drains).
Vancomycin dosage in special situations and therapeutic drug
In adults, the standard recommended dose of vancomycin is 30 mg/kg/day (IV 1 g q12h or IV 0.5 g q6h in a normal 70 kg person). Therapeutic drug monitoring (TDM) Vancomycin exhibits time-dependent killing. Efficacy can usually be assumed if the trough concentration is sufficiently above the MIC of the infecting organism (i.e. best if vancomycin levels at site of infection are maintained above MIC throughout the dose interval). MIC of most susceptible organisms (e.g. MRSA) ranges 1-2 μg/mL. Routine TDM is not indicated in most patients because vancomycin pharmacokinetics are sufficiently predictable that safe and effective vancomycin dosage regimens (giving trough IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents levels 5-10 μg/mL and peak levels <40 mg/mL) can be constructed on the basis of patient's age, weight and estimated
renal function.
Indications for TDM
(a) Renal impairment (rapid change/unstable renal function
making it difficult to estimate dose) (b) ICU patients co-treated with dopamine and/or dobutamine (c) Severe burn (120) (d) Morbid obesity (121) (e) Spinal cord injury (122) When TDM is indicated, check only trough level. There is no solid data to support the widely referenced trough range of 5-10 μg/mL and accordingly, serum concentrations have been selected somewhat arbitrarily, based on pharmacology, retrospective studies, case reports and personal opinions. Due to the poor penetration of vancomycin to certain lung tissues, the 2005 ATS guideline recommend trough levels of 15−20 μg/mL for treatment of MRSA hospital-acquired pneumonia (123). Current literature does not support peak concentration measurement (124). Dosage table/nomogram in patients with impaired renal function (Table 7) • An initial single dose of 15 mg/kg should be given to achieve prompt therapeutic serum concentration. Subsequent daily maintenance dose is to be determined according to dosage • The dosage table/nomogram is not valid for functionally anephric patients on dialysis. For such patients, the dose required to maintain stable concentrations is 1.9 mg/kg/day ( 130 mg/day for a 70 kg person). • For patients with marked renal impairment, it may be more convenient to give maintenance doses of 0.25 g to 1 g every 3-7 days. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents
Table 7. Dosage table for vancomycin

Creatinine clearance ( mL/min)
Vancomycin dose (mg/24 h)
Adapted from vancomycin package insert July 2004 . morbidly obese patients (121;125) (Table 8)
• Serum clearance of vancomycin in morbidly obese patients was 2.3-2.5 times higher than that observed in non-obese subjects (121;126). • In a study of 24 morbidly obese patients, the mean (±SD) vancomycin dose required to achieve steady state peak 25-35 μg/mL and trough 5-10 μg/mL were 1.9 g (±0.5 g) q8h. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 8. Calculation of vancomycin dosage for morbidly obese

Scenario: Female/30yr,
body weight 200 kg,
height 1.8 m, serum
creatinine 80
Determine if the patient is TBW/IBW ratio: 0.8−1.25 = normal >1.25−1.9 = obese >1.9 = morbid obesity Determine dose of 30 mg/kg TBW/day 6 g per day if normal (administer as IV 2 g q8h; infuse each 2 g dose over at least 2 h) Estimate creatinine Cockcroft-Gault formula clearance (CrCl) not accurate in morbidly obese patients. The Salazar-Corcoran equation appears to give the least biased estimate of CrCl Monitor trough level Target trough at 5-10 Adjust dosing interval according to trough level Ideal body weight (IBW) • IBW for male = 50 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet) • IBW for female = 45.5kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet) Salazar-Corcoran equation (for estimate of creatinine clearance in morbidly obese patients): Male patient, calculate CrCl as follows: (137−age in years) × (TBW in kg × 0.285) + (12.1 × height in meter) 0.58 × serum creatinine in μmol/L Female patient, calculate CrCl as follows: (146−age in years) × (TBW in kg × 0.287) + (9.74 × height in meter) 0.68 × serum creatinine in μmol/L a TBW, total body weight IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Quinupristin/dalfopristin and linezolid
Indications for linezolid (Zyvox) or quinupristin/dalfopristin (Synercid): a. Infections by vancomycin-resistant enterococci (VRE) or S. aureus with reduced susceptibility to vancomycin (e.g. VISA) b. Infections by methicillin-resistant Staphylococcus aureus in the case of vancomycin failure (e.g. unexplained breakthrough bacteraemia) and/or serious allergy. In these complicated circumstances, the opinion of a specialist (microbiologist or ID physician) should be sought. Most VRE (n=11) identified in Hong Kong so far are susceptible to linezolid (both E. faecalis and E. faecium) at ≤4 μg/mL and quinupristin/dalfopristin (E. faecium only, at ≤1 μg/mL) (19). IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 9. Comparison of linezolid and quinupristin/dalfopristin
Yes/1999 (for serious infections associated with vancomycin-resistant E. faecium) IV/PO. Bioavailbility of PO linezolid is 100%. IV/PO 600 mg q12h IV 7.5 mg/kg q8h (infuse over 1 h in D5) catheter for administration Activity vs. VRE both vancomycin-resistant Only vancomycin−resistant E. E. faecalis and E. faecium faecium a Nil (No effect on 1A2, 2C9, Inhibit 3A4 isoenzyme strongly, cytochrome P450 2C19, 2D6, 2E1, 3A4) hence interactions with midazolam, nifedipine, astemizole, terfenadine, cyclosporin (must monitor level), tacrolimus Yes (a weak, reversible, Nil (No effect on MAO). nonselective MAO inhibitor), hence potential for interactions with adrenergic and serotonergic drugs. Thrombocytopenia (related Phlebitis (high incidence if to duration of treatment; administered via peripheral incidence 0.3-10%; need vein); arthralgia/myalgia (dose monitoring if treated for >7d) related; incidence 1.3-33%) Compatible with both D5 Form precipitate with saline. DO NOT flush with saline or heparin after quinupristin/ dalfopristin administration. No adjustment in dose No adjustment in dose required required in pt. with renal in pt. with renal impairment or impairment. Give dose after undergoing dialysis. Data from package insert of Zyvox and Synercid.
a All E. faecalis isolate (including vancomycin-resistant E. faecalis) are intrinsically
resistant to quinupristin/dalfopristin.
IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Ceftazidime
Indications for using ceftazidime (Fortum) (127)
Empirical therapy of neutropenic fever, either as monotherapy or in combination with an aminoglycoside (128). 2. Therapy of infection by Burkholderia pseudomallei infection (melioidosis). • Probable case (compatible chest X-ray plus a melioidosis titre of ≥ 1/640) or definite case (isolation of B. pseudomallei). Known pathogen therapy of documented infection by susceptible Pseudomonas aeruginosaa, such as: (a) Bacteraemia with isolation of Pseudomonas aeruginosa from (b) Deep-seated infection with isolation of Pseudomonas aeruginosa from normally sterile body site or fluid (CSF, peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc) a. (c) Nosocomial pneumonia, as defined by CDC guidelines (appendix), with isolation of Pseudomonas aeruginosa in a significant quantity, from a suitably obtained, good quality respiratory tract specimenb. Footnotes
a For serious P. aeruginosa infection, an anti-pseudomonal beta-lactam should be given in combination with an aminoglycoside such as gentamicin given once daily for the initial 3 to 5 days to achieve synergistic killing. For susceptible isolates; anti-pseudomonal beta-lactams in decreasing order of preference: piperacillin or piperacillin-tazobactam or ticarcillin-clavulanate > cefoperazone or cefoperazone- sulbactam or cefepime or ceftazidime > imipenem or meropenem. b Colonization of the respiratory tract by P. aeruginosa, especially in mechanically ventilated patients is common. Antimicrobial therapy of colonization is not indicated. Isolation of P. aeruginosa at the indicated quantity and specimen type is suggestive of infection rather than colonization (in descending order of clinical significance): 1. 102-103CFU/mL or moderate/heavy growth for protected specimen brush. 2. 103-104 CFU/mL or moderate/heavy growth for bronchoalveolar lavage. 3. Moderate/heavy growth for tracheal/endotracheal aspirate specimens with ++ to +++ white cells and absent/scanty epithelial cells. 4. Expectorated sputum (as defined by the American Society for Microbiology) with >25 WBC/low power field and <10 epithelial cells/low power field. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Situations/conditions in which ceftazidime is not advised
Treatment of colonization by Pseudomonas aeruginosa such as the isolation of these organisms from • Surface swab of superficial wounds • Surface swab of chronic ulcers • Surface swab of pressure ulcers Empirical or continued treatment of suspected or confirmed infection by S. pneumoniae including bacteraemia, pneumonia and meningitis. • Infection outside the central nervous system by both penicillin- susceptible and penicillin-non-susceptible (MIC <4 μg/mL), the drugs of choice are penicillin G (standard or high dose) or amoxicillin or cefotaxime or ceftriaxone (refer to known-pathogen therapy chart). Empirical or continued treatment of infection by Enterobacteriaceae such as E. coli and Klebsiella spp. susceptible to other antimicrobial agents. • For susceptible isolates the beta-lactam of choice in descending order of preference are as follows: ampicillin or amoxicillin > ampicillin-sulbactam or amoxicillin-clavulanate > cefuroxime > ceftriaxone or cefotaxime. Empirical therapy of community-acquired pneumonia, including patients hospitalized in the ICU for serious pneumonia and patients with structural disease of the lung (adapted from Infectious Disease Society of America 1998). • Other agents with activity vs. P. aeruginosa and S. pneumoniae preferred because ceftazidime (while active vs. P. aeruginosa) is not useful vs. penicillin-non-susceptible S. pneumoniae. Empirical or continued treatment of anaerobic or mixed infection in the head and neck, biliary, pancreatic, gastrointestinal, peritoneal, pelvic or peritoneal regions. • Ceftazidime has virtually no activity against most of the medically important anaerobes. Empirical or continued treatment of patients with colonization or infection by Enterobacteriaceae such as E. coli, Klebsiella spp. and Enterobacter spp. known to produce ESBL. • Applies irrespective of whether ceftazidime was tested or not and also irrespective of the apparent in vitro susceptibility of the isolate to ceftazidime. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Empirical or continued treatment of infection by S. aureus (both Empirical or continued treatment of infection by all enterococci such as E. faecalis and E. faecium. Empirical treatment for community-acquired meningitis. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Indications for using imipenem/meropenem/ertapenem
Therapy of infections attributed to ESBL-producing bacteria (such as E. coli or Klebsiella spp. ) such as: • Bacteraemia with isolation of ESBL-producing bacteria from • Deep-seated infection with isolation of ESBL-producing bacteria from normally sterile body site or fluid (CSF, peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc). • Nosocomial pneumonia, as defined by CDC guidelines, with isolation of ESBL-producing bacteria in a significant quantity, from a suitably obtained, good quality respiratory tract Empirical therapy of neutropenic fever in high risk patients. (As Ertapenem has no anti-pseudomonal activity, it should not be used as empirical therapy for neutropenic fevers or for treatment of presumed/confirmed infections by the non-fermenters such as Pseudomonas aeruginosa and Acinetobacter.) a Colonization of the respiratory tract by ESBL-producing bacteria, especially in mechanically ventilated patients is common. Antimicrobial therapy of colonization is not indicated. Isolation of ESBL-producing bacteria at the indicated quantity and specimen type is suggestive of infection rather than colonization (in descending order of clinical significance): 1. 102-103 CFU/mL or moderate/heavy growth for protected specimen brush. 2. 103-104 CFU/mL or moderate/heavy growth for bronchoalveolar lavage. 3. Moderate/heavy growth for tracheal/endotracheal aspirate specimens with ++ to +++ white cells and absent/scanty epithelial cells. Expectorated sputum (as defined by the American Society for Microbiology) with >25 WBC/low power field and <10 epithelial cells/low power field. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Situations/conditions in which imipenem/meropenem/ertapenem
is not advised
Treatment of colonization by ESBL-producing bacteria such as the isolation of these organisms from. • Surface swab of superficial wounds • Surface swab of chronic ulcers • Surface swab of pressure ulcers Empirical therapy of most community-acquired infections including pneumonia, appendicitis, cholecystitis, cholangitis, primary peritonitis, peritonitis secondary to perforation of stomach, duodenum or colon, skin/soft tissue infections, etc. As known-pathogen therapy for infections caused by organisms susceptible to other beta-lactams. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Once daily aminoglycosides
Once daily aminoglycoside (ODA) dosing is as effective as multiple-daily dosing in most clinical settings. The former dosing probably results in a lower risk of nephrotoxicity than the latter. With ODA, any differences in the relative nephrotoxicity of the aminoglycosides are likely to be small. Nonetheless, there is considerable confusion on the dose and how to monitor serum aminoglycoside levels when using ODA dosing. Dosing to be based on actual body weight unless the patient is
morbidly obese (i.e. 20% over ideal body weight, IBW).
Aminoglycoside dosing weight for morbidly obsess
= ideal body weight + 0.4 (actual body weight - IBW).
Formula for calculation of ideal body weight is as follows:
Ideal body weight for male = 50 kg + 0.9 kg for each cm
over 152 cm (2.3 kg for each inch over 5 feet)
Ideal body weight for female = 45.5 kg + 0.9 kg for each cm
over 152 cm (2.3 kg for each inch over 5 feet)
For patient with impaired renal function, give the first dose
according to body weight as above. Subsequent frequency of
administration (of the same dose) to be based on the estimated
creatinine clearance of the patient according to the following
Cockcroft-Gault formula
To estimate creatinine clearance, calculate as follows
Creatine clearance for male patient (mL/min) = (140-age) x
1.2 x ideal body weight (kg) /serum creatinine (μmol/L)
(Female: 0.85 × above value)
(Unit conversion for serum creatinine: mg/dL x 88.4 =
IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Initial dosing interval a
20-40 q48h <20 Follow serial levels to determine time of next dose (level <1 μg/mL)
a At present, the dosage of aminoglycoside to use in a ODA strategy
has not been clearly determined. Dosages for gentamicin, tobramycin and netilmicin have ranged from 3 to 7 mg/kg, and amikacin dosages have ranged from 11 to 30 mg/kg. On the basis of local experiences and a recent consensus meeting, the following doses are recommended for initial therapy in local Chinese: for gentamicin and tobramycin, 3.5 mg/kg; netilmicin, 4.4 mg/kg and amikacin, 15 mg/kg (129). 4. Therapeutic drug monitoring (TDM) (130-132) Routine TDM not indicated in patients under the following conditions: (a) Receiving 24-h dosing regimen, (b) Without concurrently administered nephrotoxic drugs (e.g. vancomycin, amphotericin B, cyclosporin), (c) Without exposure to contrast media, (d) Not quadriplegic or amputee, (e) Not in the ICU, (f) Younger than age 60 yr (g) Duration of planned therapy less than 5 to 7 days. IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents If Therapeutic drug monitoring is indicated (e.g. due to impaired renal function), check level and interpret the result as follows: a) For once daily (extended-interval) dosing, obtain a single blood sample after the first dose between 6-14 h after the start of the infusion. Do not check pre- and post-dose. b) Write down the time in number of hours after last dose in request form (e.g. 8 h post-dose). This is essential for result interpretation. c) When result becomes available, plot the value on the Hartford normogram (Table 10) and work out the appropriate dosing interval by the following table. With this method, the size of each dose need not be reduced. Post-dose level
Dosing interval
Level falls in the area Dose at an interval of every Level falls in the area Dose at an interval of every Level falls in the area Dose at an interval of every Level on the line Choose the longer interval Level off the normogram at Stop the scheduled therapy, the given time obtain serial levels to determine the appropriate time of the next dose IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 10. Hartford Hospital once-daily aminoglycoside normogram
for gentamicin and tobramycin
The Hartford normogram has not been validated in the following
category of patients: paediatrics, pregnancy, burns (>20%), ascites,
dialysis, Enterococcal endocarditis (51).
IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Summary of selected antifungal agents
Table 11. General patterns of antifungal susceptibility

Fluconazole Itraconazole 5-Flucytosine Amphotericin B Voriconazole C. albicans (MIC 0.5 μg/mL) C. tropicalis C. glabrata C. krusei C. lusitaniae (MIC 0.5 μg/mL) C. parapsilosis C. guillermondii Cryptococcus neoformans Trichosporon Pseudallescheria Asperigillus 0.1-0.15 μg/mL) S, susceptible; S-DD, susceptibility is dose-dependent; R, resistant IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 12. Comparison of susceptibility of selected fungi to the azoles
Organism (no. of

MIC that can
MIC that can
isolates tested) (133-
inhibit 50% of all inhibit 90% of all
tested isolates
tested isolates
C. glabrata (n=217)
Fluconazole 0.25−128 16 Itraconazole 0.06−8 1 Voriconazole 0.03−8 0.5 C. krusei (n=33)
Fluconazole 8−128 64 Itraconazole 0.12−2 1 Voriconazole 0.06−4 0.5 resistant C. albicans
Fluconazole 64−128 >128 Itraconazole 1−8 >8 >8 Voriconazole 0.25−8 >8 A. fumigatus (n=284)
resistant A.
fumagitus (n=15)
Itraconazole 0.25−0.5 0.25
Voriconazole 0.25−1 0.25 resistant A.
Voriconazole 0.25−1 0.5 IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 13. Mechanisms of antifungal action.
Primary mode of
Azoles: (fluconazole,
Inhibit ergosterol Fungal cytochrome P-450 dependent 14 α-sterol Caspofungin
Inhibit fungal cell wall Fungal β-1,3-glucan glucan synthesis Amphotericin B
Bind to and make Fungal cell membrane fungal cell membrane ‘leaky' IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 14. Comparison of selected pharmacokinetic parameters for the azoles and caspofungin

Trade name
>80% Capsule: Solution: 60-80% 0.2-0.4 mg/L after 2-4 h of 2 mg/L after 250 oral 10 mg/L end infusion Unknown (Very low) penetration Plasma half-life 22-35 9-11 (terminal half-life 40-50 Levels in body fluids/CSF Widely distributed into body Widely distributed; highest low; concentrations in lung, tissues & fluid including brain concentration in liver. liver & bone 2-3 times > including CSF. serum. High concentration in stratum corneum due to drug secretion in sebum. Principal route Renal Hepatic of elimination Active drug in urine (%) Dosage Adult, oral, 200-400 mg 12- i.v. infusion of 70 mg loading, [In life-threatening hourly for 24 h, then, 100-200 then 50 mg daily situations, a loading dose should be used whether i.v. 6mg/kg 12 hourly for 24 h, given oral capsule or IV, then 4 mg/kg 12 hourly e.g. 200mg PO tds for first 3 days] Usual dose. At CFR <10 No dose adjustment need with No dose adjustment needed. Not ml/min, some recommend oral voriconazole. Avoid iv removed by hemodialysis decrease dose 50% voriconazole in renal failure. Reduce dose to 35 mg daily (after the 70 mg loading dose) in moderate (Child-Pugh score 7-9). No data on usage in patient with severe hepatic failure IMPACT Third Edition (Version 3.0) Part III: Selected Antimicrobial agents Table 15. A suggested scheme for systemic antifungal agents

Neutropenic or critically Fluconazole or caspofungin Consider agent other than (if intolerant of caspofungin for serious infection due to C. guilliermondii & C. parapsilosis (136) Evidence is mainly for C. albicans. It also works for C. parapsilosis and C. tropicalis INVASIVE ASPERGILLOSIS
Amphotericin B (1-1.5 Efficacy of voriconazole is clear (documented invasive mg/kg) or caspofungin for for A. fumigatus. In the case of documented non-fumigatus non-fumigatus aspergillus, treatment response requires confirmation with a larger data set (137). Note: The diagnosis and treatment of systemic fungal infection is complicated. The newer anti-fungal agents (e.g. itraconazole, voriconazole, caspofungin) should be used at the specific advice of a specialist.
IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Part IV: Recommendation for the empirical therapy of
common infections
IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Usual organisms Preferred regimens
Special considerations /
[usual duration of treatment]
Septic arthritis,

S. aureus; IV cloxacillin + • Urgent diagnostic tapping Streptococci, N. for gram stain to guide gonorrhoeae • If smear reveal Gram- negative cocci or bacilli: ceftriaxone or cefotaxime to replace cloxacillin. • Factors suggest N. gonorrhoeae etiology: sexually active teenager/adult ± rash. S. aureus • Occasionally Salmonella • Often vertebral. • IVDU: S. aureus (vertebral); P. aeruginosa (ribs, sternoclavicular joint). IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Diabetic foot
(a) Previously
S. aureus, beta- sulbactam (138) or Streptococci amoxicillin-clavulanate PO levofloxacin/ Cultures from ulcers ciprofloxacin + PO Early radical debridement to obtain tissue for culture; to exclude nercotizing fasciitis and for cure. Ability to insert probe to bone suggest concomitant osteomyelitis. Skin and soft tissue
Erysipelas or

Groups A, B, C, G (IV penicillin or IV cellulitis
Streptococci S. ampicillin or PO amoxicillin) + IV/PO clavulanate or Necrotizing fasciitis Immediate
intervention essential. Aeromonas IV fluoroquinolone + Urgent consult clinical hydrophilia, A. caviae; Vibrio vulnificus 2. Following cuts and Group A IV penicillin G + IV Add high dose IVIG (1−2 g/kg abrasion; recent Streptococcus for 1 dose) for streptococcal chickenpox; IVDU; toxic shock syndrome (140) a
IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy 3. Following intra- Enterobacteriacea, clavulanate + IV gynaecological or streptococci, perineal surgery Bite wound (animal
Streptococci, S. • Risk of infection after cat aureus, anaerobes, clavulanate or Pasteurella • Monotherapy with multocida (cat), penicillin, cloxacillin or first Capnocytophaga generation cephalosporin Eikenella spp. (human) Central nervous
system infections
Brain abscess

• Urgent consult polymicrobial with metronidazole • Exclude primary focus in middle ear, mastoid, paranasal sinuses, dental and lung. Meningitis
S. suis, S. • If impaired cellular pneumoniae, N. immunity e.g. high dose meningitides, steroid, add ampicillin to cover Listeria spp. Streptococcus • If rapid test (e.g. Gram smear, antigen detection) or other clues suggest S. pneumoniae, add vancomycin until sensitivity data available. For pen-R S. pneumoniae (MIC ≥2), 77% and 5% are respectively intermediate and resistant to Ceftriaxone (56;144). IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Intra-abdominal and
GI system infections
Enterobacteriacea, Cefuroxime + • Surgical intervention peritonitis (PPU,
B. fragilis, other • BL/BLI cover anaerobes perforation, ruptured Enterococci including B. fragilis. • Adequate biliary drainage cholecystitis or
Enterococci, other biliary sepsis
Bacteroides (cefuroxime + • BL/BLIs covermost sulbactam (± an enterococci and anaerobes. Liver abscess
• For all cases: serology for E. (community-acquired) Bacteroides, histolytica. enterococci, • CT guided or open drainage Entamoeba for large abscess. histolytica metronidazole (for E. histolytica) Mild to moderate
Food poisoning (B. Routine antibiotic Fluid and electrolytes cereus, S. aureus, C. perfringens), Salmonella spp., E. coli, Campylobacter spp., Aeromonas spp. IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Moderate to severe Salmonella spp,
Campylobacter among Campylobacter (presume bacterial)in spp. increasing. If symptoms not improving or worsening when immunosuppresive diagnosis of campylobacter disease (e.g. for HIV gastroenteritis is made; stop +ve; high dose steroid fluoroquinolone and prescribe a course of oral macrolide for results not available) ≥6 unformed stool Add metronidazole if severe /day, fever gastroenteritis after recent (laboratory results ≥38.5°C; tenesmus; antibiotic therapy; replace blood or faecal fluid and electrolytes; avoid antimotility agents. infections
Subacute infective

S. viridans, IV Ampicillin 2 g Obtain at least 3 sets of blood endocarditis (CRHD, HACEK,
q4h + gentamicin 1 cultures by 3 different Enterococci venepuncture over 24 h (label congenital valvular "? IE" in laboratory form); then diseases) (145;146) start IV antibiotics (147). Acute infective
S. aureus IV Cloxacillin 2 g IV Cefazolin 2 g • Usually tricuspid valve endocarditis (IVDU)
q4h + gentamicin 1 infection ± metastatic lung mg/kg q8h for the • Blood culture q30min × 3 sets (label "? IE" in laboratory form); then start IV antibiotics immediately (147). IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy infections
Pelvic inflammatory N. gonorrhoeae, C. IV amoxicillin-
Coverage of anaerobes disease (or upper
trachomatis, 600−900 mg q8h important in tubo-ovarian genital tract infection) Enterobacteriacea, cefoxitin 1-2 g q6h abscess, co-existing bacterial vaginosis, HIV +ve (149). Breast abscess
Usually S. aureus IV/PO cloxacillin (+ I & D essential; send pus for (± anaerobes in PO metronidazole if amoxicillin- Gram smear and culture. anaerobes likely) ampicillin-sulbactam Head and neck
Odontogenic or

(IV Penicillin + PO neck infection
metronidazole) or IV/PO clindamycin Urinary tract

E. coli; S. PO Nitrofurantoin or PO Cephalexin or Encourage fluid intake saprophyticus, Streptococcus Enterobacteriacea, IV Amoxicillin- Blood culture and MSU Enterococcus, clavulanate or IV cultures, need to rule out (Pseudomonas in obstructive uropathy. catheter-related, sulbactam or PO/IV tazobactam if IV until afebrile 24−48h, then complete 14 days course with transplant) ceftriaxone 1−2g IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Respiratory tract infections
Acute bacterial
IV/PO amoxicillin- • Latest AACP/ACP-ASIM exacerbation of
viruses, S. recommendation: antibiotic COPD (AECB) (150-
pneumoniae, H. is only indicated when all 3 influenzae, M. cardinal symptoms are catarrhalis d
present: ↑ sputum Appropriate use of resistant S. purulence, ↑ sputum antibiotics in AECB is pneumoniae with volume, ↑ dyspnoea. imperative to help penicillin MIC >2 • Penicillin- control the emergence intermediate/resistant S. of multidrug resistant pneumoniae (MIC 0.1−2 μg/mL) can be treated by high dose PO amoxicillin or IV penicillin G (high dose Amoxicillin-clavulanate if co-infection by ampicillin- resistant H. influenzae) (152) Acute bacterial
P. aeruginosa PO Levofloxacin/ P. aeruginosa, exacerbation or
ciprofloxacin or IV fluoroquinolone should be pneumonia in
given at high dose (e.g. patient with
Levofloxacin PO 500-750 mg qd; ciprofloxacin 500-750mg tazobactam ± an Aspiration
(IV Penicillin G + PO Amoxicillin- pneumonia
Bacteroides, metronidazole) or Fusobacterium, S. IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy acquired pneumonia
1. CAP, not
S. pneumoniae, H. PO Amoxicillin- Meta-analysis of 127 studies influenzae, M. (n=33148): S. pneumoniae pneumoniae, C. (73%); H. influenzae (14%); S. pneumoniae, C. aureus (3%); Gram-negative psittaci (influenza rods (2%). In Hong Kong, A, M. tuberculosis) or macrolide/azalide, tetracycline PO amoxicillin + a or co-trimoxazole should not be used alone for empiric treatment of CAP. Locally, 50−70% pen-S and pen-R S. pneumoniae isolates (both community and hospital isolates) are multiply resistant to these agents (5;155;156) 2. CAP, hospitalized As above IV/PO Amoxicillin- Modifying factors: ceftriaxone ± a bronchiectasis: either macrolidesf
(ticarcillin-clavulanate or piperacillin-tazobactam or macrolidesf
cefepime) + a macrolide; or fluoroquinolone + an aminoglycoside 3. CAP, hospitalized As above + Ticarcillin-clavulanate and in ICU for serious Enterobacteriaceae tazobactam or ceftazidime are not useful vs penicillin-non-susceptible S. pneumoniae IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
pneumonia (HAP)
HAP, onset <4 days
S. pneumoniae, H. IV/PO Ampicillin- after admission + no influenzae, M. previous antibiotics catarrhalis, S. penicillin-allergy (non-type I hypersensitivity) HAP, onset ≥4 days • Refer also to guideline on after admission + had aeruginosa, use of vancomycin. antibiotics recently, Acinetobacter, OR onset ≥5 days Klebsiella spp., tazobactam ± an after admission OR Enterobacter spp. mechanical ventilation (158) IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Footnote
a Classification and definition of group A streptococcal toxic shock syndrome (159)
Definite case = criteria IA + IIA + IIB; probable case = criteria IB + IIA + II B
Criteria IA:
Isolation of group A streptococci (Streptococcus pyogenes) from a normally sterile site (e.g., blood, cerebrospinal, pleural, or peritoneal fluid, tissue biopsy, surgical wound). Isolation of group A streptococci (Streptococcus pyogenes) from a nonsterile site (e.g., throat, sputum, vagina, superficial skin lesion). Hypotension, systolic blood pressure ≤90 mm Hg in adults or <5th percentile for age in children, and; ≥2 of the following signs: Renal impairment: creatinine ≥177 µmol/L for adults or >2× the upper limit of normal for age. In patients with pre-existing renal disease, a ≥2-fold elevation over the baseline level. (b) Coagulopathy: ≤100,000/mm3 or DIC defined by prolonged clotting times, low fibrinogen level, and the presence of fibrin degradation products. Liver involvement: alanine aminotransferase (ALT), asparate aminotransferase (AST), or total bilirubin levels >2× the upper limit of normal for age. In patients with pre-existing liver disease a ≥2-fold elevation over the baseline level. (d) Adult respiratory distress syndrome defined by acute onset of diffuse pulmonary infiltrates and hypoxaemia in the absence of cardiac failure, or evidence of diffuse capillary leak manifested by acute onset of generalized oedema, or pleural or peritoneal effusions with hypoalbuminaemia. A generalized erythematous macular rash that may desquamate. Soft tissue necrosis, including necrotizing fasciitis or myositis, or gangrene. b Avoid in patient with G6PD deficiency.
c These agents preferred in patient with recent antimicrobial therapy.
IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy d Stratification schemes have been proposed to allow the physician to identify high risk patients for targeted
antimicrobial chemotherapy. One such scheme is as follows:
1. Acute tracheobronchitis No underlying structural disease 2. Simple chronic bronchitis FEV1>50%, ↑ sputum volume + H. influenzae, M. catarrhalis, S. pneumoniae 3. Complicated chronic As for group 2 + ≥1 of FEV1<50%, H. influenzae, M. catarrhalis, S. advanced age, significant co-morbidity pneumoniae 4. Chronic bronchial infection As for group 3 + continuous sputum Above + Enterobacteriaceae, P. aeruginosa e Caution required as unique groups of COPD patients appears to be the main reservoir of levofloxacin-resistant S. pneumoniae (32). Suboptimal dose of levofloxacin has been associated with levofloxacin-resistant S. pneumoniae (32). Ofloxacin and ciprofloxacin should not be used for treatment of pneumococcal infection. Levofloxacin is the L-isomer of the racemate, ofloxacin. The MICs of most pneumococci in Hong Kong are close to the breakpoint of levofloxacin. In patients with acute purulent exacerbation of chronic bronchitis, failures appeared to be common in those with pneumococci (failures in 65%, 13/20) (16). The recommended dose for levofloxacin is 500 mg QD that for moxifloxacin is
400 mg QD. Opinion from clinical microbiologist suggested if use of fluoroquinolone is contemplated.
f IV or PO erythromycin preferred. Alternatives for patients intolerant of erythromycin are clarithromycin and
IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Guidelines on the use and choice of antibiotics in severe
acute pancreatitis

1. Criteria for severity assessment of acute pancreatitis (Table 16).
Most acute pancreatitis is mild. Severe acute pancreatitis (SAP) occurs in about 5-13% of all patients. SAP is commonly defined as having any of the following 4 criteria: (a) organ failure; (b) local complication such as necrosis, pseudocyst, or abscess; (c) Ranson score ≥3; or (d) at least 8 of the APACHE II criteria (160). Of all markers available, CRP is the single most useful parameter in predicting the severity of acute pancreatitis (161). 2. Infection risk. Pancreatic or peripancreatic infection occurs in 30-
40% patients who have >30% pancreatic necrosis in CT staging. Infection usually occurs at least 10 days after the onset of SAP. In patients with severe acute pancreatitis, the data suggests that prophylactic antibiotic reduce infection and mortality (162-166). 3. Choice of antibiotics (Table 17): the agents should be able to
penetrate into pancreatic tissue. Good pancreatic tissue concentrations have been documented for cefotaxime, piperacillin, imipenem and metronidazole (167). In terms of activity, it seems reasonable to provide coverage for the enteric Gram-negative bacilli and anaerobes. Carbepenem group of antibiotic should be reserved for the most severe form of disease (i.e. SAP with highly suspected or documented pancreatic necrosis) 4. Duration of prophylactic antibiotics: 5 to 14 days depending on
disease severity and patient progress (162-169). Excessive and prolonged antibiotic use in this setting is known to cause fungal super-infection and emergence of antibiotic-resistant bacteria, and should be avoided (170;171). 5. Work-up. Consider CT or USS guided-FNA of necrotic area for
culture if secondary pancreatic infection is suspected and if fever or leukocytosis persist or develops beyond 7-10 days. IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Table 16. Criteria for severity assessment of acute pancreatitis
One point for each of: ƒ CVS: shock (SBP <90mmHg At admission
or mean arterial pressure • Age > 55 yr <70mmHg or inotropic • WBC >16,000/μL • Glucose >11.1 mmol/L (>200 ƒ Resp: PaO2 <60 mmHg or ventilator dependent • LDH >350 IU/L ƒ Renal: Urea >7.4 mmol/L or • AST >250 IU/L Creatinine >250 μmol/L or During initial 48 hours
requiring renal replacement • Haematocrit decrease >10% ƒ Gastrointestinal: bleeding >500mL in 24 hours BUN increase >1.8 mmol/L • Calcium <2 mmol/L (<8 • PaO2 <60 mm Hg • Base deficit >4 mEq/L • Fluid sequestration >6 L IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Table 17. Prophylactic use of antibiotic in acute pancreatitis

Acute pancreatitis
(Box 1 & 2)
Moderately severe
Very severe
Only Ranson ≥3 but no organ failure and CRP ≥150 mg/L; CRP <150 mg/L CT proven pancreatic necrosis IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Management of community-acquired pneumonia
General considerations and principles

1. A number of guidelines on the management of community-
acquired pneumonia (CAP) were released or updated recently. While these guidelines were drawn on the basis of the same set of literature, patient stratification and specific suggestions still vary quite a bit (157;172;173). All agreed that S. pneumoniae is the most common pathogen in CAP including those without an identifiable etiology. Hence, the choice of agents for empirical therapy should consider the regional data on prevalence and risk factors for drug-resistant S. pneumoniae (DRSP). 3. Appropriate antimicrobial therapy should be initiated within 8 hours of hospitalization. Prior studies indicated that compliance with this recommendation is associated with a significant reduction in mortality (174). Factors to be considered in choosing empirical therapy for

(a) Place of therapy (outpatient, inpatient ward, or intensive
(b) Role of atypical pathogens (e.g. Chlamydia pneumoniae,
Mycoplasma pneumoniae and Legionella spp.) is increasingly being recognized. ATS guidelines even suggested that all patients should be treated for the possibility of atypical pathogen infections (173). (c) Presence of modifying factors including risk factors for
DRSP (e.g. age >65 yr., beta-lactam therapy within past 3 months, alcoholism, multiple medical comorbidities, exposure to a child in a day care centre), enteric Gram- negatives (residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbidities, recent antibiotic therapy), and P. aeruginosa (e.g. bronchiectasis). 5. Several antibiotics active against P. aeruginosa, including cefepime, imipenem, meropenem, piperacillin, and piperacillin-tazobactam are also highly active against DRSP. They can be used for patients having specific risk factors for P. aeruginosa. 6. If a macrolide is relied upon for coverage of H. influenzae, the newer macrolides (e.g. clarithromycin or azithromycin) should be used instead of erythromycin. IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy For most patients, appropriately chosen initial antibiotic therapy should not be changed in the first 72 h, unless there is marked clinical deterioration. 8. Most patients with CAP will have an adequate clinical response within 72 h. After the patient has met appropriate criteria, switch from iv to oral therapy can be made. IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Management of community-acquired pneumonia in the
era of pneumococcal resistance: conclusions from the
CDC working group
1. The current CLSI (NCCLS) categories for defining susceptibility
concentrations (i.e. penicillin G: sensitive for ≤0.06 μg/mL; intermediate for 0.1-1 μg/mL and resistant for ≥2 μg/mL) are not clinically useful for treatment of patients with pneumococcal pneumonia. Comparative studies of adults and children have reported that pneumonia due to penicillin-nonsusceptible pneumococci (most had MIC >0.1-1 μg/mL) does not influence the outcome of pneumonia treatment (175;176). At higher level of resistance (penicillin MIC 2-4 μg/mL), recent evidence suggests that risk of mortality or suppurative complications were increased (177;178). In one study (179), the observed increase in mortality was confined to patients with pneumococcal isolates with penicillin MIC of ≥4 μg/mL. S. pneumoniae causing pneumonia (but not otitis media and meningitis), the following revised categorization was suggested: ≤1 μg/mL, sensitive; 2 μg/mL, intermediate; ≥4 μg/mL resistant. By modifying the breakpoints, it is hope that there will be decreased use of broad-spectrum antimicrobial therapy in favour of more narrow-spectrum therapy. Patients with pneumococcal pneumonia caused by strains with penicillin MIC ≤1 μg/mL can be treated appropriately with optimal dosage of IV penicillin and selected other PO/IV beta-lactams. Comparative anti-pneumococcal activities of commonly used beta-lactams is shown in Table 18. Vancomycin is not routinely indicated for treatment of CAP or for pneumonia caused by DRSP. 4. The CDC working group does not advocate the use of newer fluoroquinolones for first line treatment of CAP. The reasons are: (a) Most S. pneumoniae pneumonia can be appropriately treated with a beta-lactam with good anti-pneumococcal activity at optimal dosage. (b) Concerns that resistance among pneumococci will rapidly emerge after widespread use of this class of antibiotics. (c) Their activity against pneumococci with high level penicillin resistance (MIC ≥4 μg/mL) makes it important that they be reserved for selected patients with CAP. Indications for use of fluoroquinolones in CAP IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy (a) Adults for whom one of the first line regimen has already failed. (b) Allergic to alternative agents. (c) Documented infection due to pneumococci with high level penicillin resistance (penicillin MIC ≥4 μg/mL). IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy
Regional considerations for S. pneumoniae

In Hong Kong, reduced susceptibility to penicillin and resistance to macrolides were high in both hospital (56;155) and community settings (180;181) (50-70% and >70%, respectively). 2. Erythromycin resistant isolates are also resistant to the newer macrolides/azalides such as clarithromycin and azithromycin (183). Globally, resistance to fluoroquinolones among the pneumococci is low (<1-2%). Hong Kong is one of the rare exceptions in which fluoroquinolone resistance (levofloxacin MIC ≥8 μg/mL) is rapidly emerging among the S. pneumoniae (56). The findings of two recent multi-hospital studies were summarized below. Similar findings have been reported from several recent international surveillance studies (e.g. Alexander project). In local strains of S. pneumoniae, fluoroquinolone resistance is associated with resistance to penicillin and is a result of double mutations in both targets (parC and gyrA) (156). Percentage resistant to levofloxacin (MIC Year Penicillin- In view of the above, adherence to the CDC guidelines on the use
of the fluoroquinolones seems appropriate. Moreover,
tuberculosis is prevalent in Hong Kong and was reported to
account for 10% of CAP in the elderly. Excess use of
fluoroquinolones in CAP may lead to: (1) delay in diagnosis of
tuberculosis; (2) increased fluororoquinolone resistance among
Mycobacterium tuberculosis (184;185). Hence, this class of
agents is not recommended as first line (or routine) therapy
in Hong Kong for CAP.
In this regard, extra-care need to be
exercised in using fluoroquinolones in patients with risk factors
for fluoroquinolone-resistant S. pneumoniae (186):
• presence of COPD;
IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy • nosocomial pneumococcal infection; • residence in old age home; and • past exposure to fluoroquinolones. Ciprofloxacin and ofloxacin should not be used to treat pneumococcal infection. Use of a suboptimal dose of fluoroquinolone should be avoided (e.g. the dose/frequency approved by FDA for levofloxacin in CAP is 500 mg qd). Use of <500 mg and in divided doses should be avoided as these have been showed to be associated with the emergence of fluoroquinolone-resistant S. pneumoniae (156). If a respiratory fluoroquinolone is indicated, there is evidence to suggest that the more potent ones (e.g. gemifloxacin, moxifloxacin, gatifloxacin) are less likely to lead to development of resistance. 5. Penicillin G (IV) or ampicillin (PO/IV) or amoxicillin (PO/IV) are generally viewed as the beta-lactam drugs of choice for treating infections with penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae. The following beta-lactams are not recommended because of poor intrinsic activities against S. pneumoniae: penicillin V, all first generation cephalosporins, cefaclor, cefixime, ceftibuten, and loracarbef. Lung infections involving strains with intermediate susceptibility to penicillin (MIC 0.1-1 μg/mL) may be treated with IV penicillin G or oral amoxicillin (high dose). 7. Penicillins combined with beta-lactamase inhibitors (ampicillin- sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam) are active against beta-lactamase-producing organisms including H. influenzae, M. catarrhalis, and methicillin-sensitive S. aureus. Except in-patients with mixed infection, these drugs offer no advantage over penicillin G or amoxicillin for the treatment of S. pneumoniae pneumonia, including those due to penicillin-resistant strains because beta-lactamase is not produced by S. pneumoniae. The MIC of ampicillin, amoxicillin, piperacillin for most local strains were similar to that of penicillin. However, the MIC of ticarcillin is increased disproportionately among penicillin non-susceptible strains. Amoxicillin capsules taken together with standard Augmentin (375 mg tablet) may be an acceptable alternative to high dose Augmentin (1 g preparation) in some clinical situations. An example of dosing for combinational use would be amoxicillin (Amoxil) 250 mg tds + Augmentin 375 mg tds. While they are expected to produce similar pharmacodynamic targets (T>MIC) (187), no specific pharmacokinetic studies have been conducted to demonstrate their bioequivalence. IMPACT Third Edition (Version 3.0) Part IV: Empirical therapy Table 18. Comparative activities of commonly used beta-lactams
against Streptococcus pneumoniae
with different levels of
penicillin susceptibility

0.12−1 μg/mL 2 μg/mL ≥4 μg/mL Year/type of study (ref.)
2000/hospital (56) 2000/community (181) Imipenem/meropenem +++ +++ ± a interpreted according to current CLSI (NCCLS) recommendation (188). IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy Part V: Guidelines for known pathogen therapy
IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy Guidelines for Known-Pathogen Therapy
Acinetobacter IV Ampicillin-
ƒ Cefoperazone-sulbactam + an ƒ Sulbactam is highly active aminoglyoside (mixed infection against Acinetobacter, with P. aeruginosa) gentamicin added to prevent ƒ Fluoroquinolone + an resistance and for synergy. aminoglyoside (if allergic to ƒ The entry site for at least 50% of the Acinetobacter bacteraemia in our hospitals is infected intravascular catheter. Removal of the catheter ± a short course of antibiotic is usually adequate treatment. Combination therapy recommended for all serious infection except for uncomplicated catheter-related bacteraemia. PO metronidazole PO vancomycin (if metronidazole • Clinical efficacy: fails as documented metronidazole = PO microbiologically) vancomycin. Relapse rate: metronidazole = PO vancomycin • Metronidazole remains the drug of choice for relapse. IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy DRUG OF CHOICE
Enterobacter • PO/IV
• Carbapenem (for severe • Cefepime is highly active in infection and/or ESBL- vitro against almost all ciprofloxacin for producing strain) Enterobacter isolates. • Emergence of AmpC derepressed mutants emerge • IV cefepime ( ± an in 20-40% of infections treated with the second or third generation cephalosporins. Use of these agents (even in combinations) for serious infections (other than UTI) is not recommended. • One study in Hong Kong found high prevalence of ESBL production among E. hormaechei (a member of the E. cloacae complex) (21) E coli
• PO/IV ampicillin- • Cefuroxime (if resistant to (ESBL -ve)
amoxicillin-clavulanate), add metronidazole (if mixed clavulanate (add infection with anaerobes likely). an aminoglyoside • Piperacillin-tazobactam + an aminoglyoside (if P. aeruginosa bactericidal action or Acinetobacter are co- clinical grounds) IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy DRUG OF CHOICE
Haemophilus • PO amoxicillin or • Fluorouinolones (if allergic to
• Amoxicillin-clavulanate also PO/IV ampicillin- provides good coverage for M. catarrhalis and S. pneumoniae. • PO/IV ampicillin- • Cefuroxime (if resistant to • Ampicillin-sulbactam less amoxicillin-clavulanate), add satisfactory because of poor (ESBL -ve)
metronidazole (if mixed inhibitory activity of clavulanate (add infection with anaerobes likely). sulbactam for SHV-1 beta- an aminoglyoside • Piperacillin-tazobactam + an aminoglyoside (if P. aeruginosa bactericidal action or Acinetobacter are co- clinical grounds) E. coli / K.
• PO cotrimoxazole • Fluoroquinolone (add an • Carbapenem has been aminoglyoside for serious shown to be effective (ESBL +ve)
clavulanate or PO infection and also if rapid clinically and is currently nitrofurantoin or bactericidal effect is desirable the beta-lactam agent of PO levofloxacin or choice for serious infection ciprofloxacin for • Piperacillin-tazobactam + an by ESBL+ve E. coli / Klebseilla spp. Data for beta- lactam/beta-lactamase • Carbapenem for inhibitor combinations limited and should be used IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy DRUG OF CHOICE
Pseudomonas IV Piperacillin or
ƒ Cefoperazone-sulbactam + an ƒ Combination therapy aminoglyoside (mixed infection recommended (for with Acinetobacter). synergism) for all serious ƒ Levofloxacin/ciprofloxacin + an infection except for aminoglyoside (if allergic to uncomplicated catheter- related bacteraemia. ƒ Piperacillin-tazobactam used instead of ceftazidime due to rapid rise in AmpC type and ESBL-producers in Enterobacteriaceae. ƒ In a parallel evaluation of 7000 P. aeruginosa isolates, no difference was found in the susceptibility between piperacillin-tazobactam and piperacillin i.e. 93.9% vs 93% IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy DRUG OF CHOICE
PO/IV cloxacillin or • Cefazolin (if allergic to sensitive S.
penicillin, but limited to those with minor allergy such as sulbactam or first • Clindamycin (if allergic to • Linezolid or teicoplanin (if • Cotrimoxazole, fusidic acid resistant S.
extensive rash, other than red- or rifampicin are useful man syndrome develop after adjuncts for deep-seated infections (e.g. osteomyelitis) but these agents should not be administered as monotherapy. ƒ Cotrimoxazole + ƒ Cotrimoxazole + ticarcillin- Cotrimoxazole + IV clavulanate is synergistic in vitro. Cotrimoxazole is a key component in therapy. ƒ Combination therapy recommended for synergy and to prevent resistance. IMPACT Third Edition (Version 3.0) Part V: Known pathogen therapy DRUG OF CHOICE
Streptococcus For infections
• Beta-lactam/beta-lactamase • For pure pneumococcal outside the central inhibitor combination with the infection, penicillin G exception of cefoperazone- instead of amoxicillin- sulbactam (for mixed clavulanate is preferred, switch therefore penicillin G (4 to • Erythromycin or clindamycin 8 MU / day, q6h) (if allergic to penicillin). • >70% resistant to erythromycin. Cross- intermediate: IV resistance to clindamycin penicillin G (high • Resistance to erythromycin MU/d; q4h)a
= resistance to other newer macrolides (clarithromycin, a CLSI (NCCLS) MIC (μg/mL) breakpoints for penicillin G: sensitive, ≤0.06; intermediate 0.12-1; resistant ≥2. These breakpoints were decided mainly for the relevance on meningitis. For pneumococcal pneumonia, pharmacokinetic/dynamic data indicates that isolates with MIC of up to 1−2 μg/mL should be considered "sensitive" to appropriate dose of penicillin, ampicillin and amoxicillin. IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis Part VI: Guidelines for surgical prophylaxis
IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis
General principles in surgical prophylaxis
1. Duration of prophylaxis: There is wide consensus that only a
single dose of intravenous antibiotic is needed for surgical prophylaxis in the great majority of cases. Published evidence showed that antibiotic prophylaxis after wound closure is unnecessary and could lead to emergence of resistant bacteria. Most studies comparing single- with multiple-dose prophylaxis have not shown benefit of additional doses (189). 2. Timing: Antibiotic should be given in a sufficient dose within 30
minutes before incision. This can be facilitated by having the anesthesiologist administer the drug in the operating room at induction. The goal is to archieve a high antibiotic level at the time of incision. 3. Antimicrobial dosing: The dose should be adequate based on the
patient's body weight. An additional dose of antibiotic should be given (intra-operatively) if the operation is still continuing after two half-lives of the initial dose, as follows:
Suggested initial dose and time to re-dose for selected antibiotics
used for surgical prophylaxis

intravenous dose redosing interval (hr)
Amoxycillin-clavulanate 1.2 Ampicillin-sulbactam Metronidazole 500 References for this section (189-192) IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis Antibiotic prophylaxis in clean operations
Recommended drugs
• Prosthetic valve • Cefazolin 1-2 g • Coronary artery Thoracica
• Cefazolin 1-2 g; or • (Amoxicillin- clavulanate 1.2 g or thoracostomy for ampicillin-sulbactam • Abdominal aortic • Cefazolin 1-2 g • Prosthesis • Groin incision • Lower extremity amputation for ischaemia • Cefazolin 1 g or • Cotrimoxazole 960 Orthopaedic a
ƒ Cefazolin 1-2 g (complete infusion of • Internal fixation antibiotic before • Multiple drops topically over 2 to 24 hours gentamicin or • Tobramycin or • Neomycin- gramicidin-polymyxins and IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis • Cefazolin 100 mg subconjunctivally at the end of the procedure a For hospitals or units with a high incidence of postoperative wound
infections by MRSA or MRSE, screening for MRSA may be indicated to
identify patients for additional preoperative measures such as
chlorhexidine bath, 2% mupirocin nasal ointment [Bactroban Nasal]
and/or the use of vancomycin as preoperative prophylaxis (see also
"Guidelines for prescribing vancomycin" section)(193).
b For patients allergic to cefazolin or patients with high risk of MRSA /
MRSE infections, vancomycin 1 g infused over at least 1 h should be
given after premedication with an antihistamine. Rapid IV
administration may cause hypotension, which could be especially
dangerous during induction of anaesthesia. IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis Antibiotic prophylaxis in clean-contaminated operations
Type of operation
Entering oral cavity or • Cefazolin 1-2 g • (Amoxicillin- clavulanate 1.2 g or ampicillin-sulbactam 1.5 g or clindamycin 600-900 mg) tympanostomy tube (to decrease incidence of purulent otorrhoea) Gastroduodenal High • Cefazolin 1 g • Obstruction • Haemorrhage • Gastric ulcer • Malignancy • H2 blocker • Proton pump • Morbid obesity • Gastric bypass • Percutaneous endoscopic gastrostomy • Cefuroxime 1.5 g • Age more than 70 • Acute cholecystitis • Obstructive jaundice • Common bile duct • Morbid obesity IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis Type of operation
Parenteral parenteral ± oral • (Cefuroxime 1.5 g + metronidazole 0.5 g) Oral • Neomycin and erythromycin base 1 g each P.O. tds the day before operation Both elective and • Cefuroxime 1.5 g + emergency procedures metronidazole 0.5 • Therapy should be continued postoperatively for ruptured and gangrenous appendix Vaginal or abdominal Both elective and • Cefazolin 1-2 g, emergency procedures or • Cefuroxime 1.5 g Significant bacteriuria • Treat according to IMPACT Third Edition (Version 3.0) Part VI: Surgical prophylaxis Antibiotic prophylaxis in contaminated-infected

Type of operation
Recommended drugs
For treatment of • Cefuroxime 0.75 to established infection 1.5 g q8h and metronidazole 0.5 g q8h For treatment of • Cefazolin 1-2 g q8h established infection • (Ampicillin 0.5 g q6h + cloxacillin 0.5 g q6h) For treatment of • IV/PO Amoxicillin- established infection ampicillin-sulbactam IMPACT Third Edition (Version 3.0) Part VII: Cost and recommended dosage of commonly-
used antimicrobial agents
IMPACT Third Edition (Version 3.0) Preparation and recommended dosing regimens for antibiotics
Trade name
Dosage form
Usual adult regimen
(unit cost, HK$)
(daily dose, route,
dosing interval) a
Amikacin (129) Amikin 0.1 g vial ($18) IV 15 mg/kg q24h 0.25 g vial ($38) (750 mg q24h)b or 7.5 mg/kg q12h 0.5 g vial ($59) 250 mg cap. ($0.14) 125 mg/5 mL syr. ($0.13/mL) 0.6 g vial ($14.14) 1.2 g vials ($28.3) 375 mg tab ($0.90) PO 375-750 mg tds 1 g tab ($ 2.49) 156 mg/5 mL syr. PO 312 mg (10 mL) 457 mg/5ml "BD syr" PO 914 mg (10 mL) bd 500 mg vial ($1.98) 250 mg cap ($0.16) PO 250−500 mg qid 500 mg cap ($0.32) 125 mg/5 mL syrup ($0.20/mL) 750 mg vial ($25) IV 1.5−3 g q6h 375 mg tab ($5.45) 250 mg/5mL syrup ($0.93/mL) 500 mg vial ($141) 250 mg tab ($13) PO 500 mg on first 200 mg/5ml syrup day then 250 mg q24h 1 g vial ($95.45) 2 g vial ($190.91) IMPACT Third Edition (Version 3.0) Trade name
Dosage form
Usual adult regimen
(unit cost, HK$)
(daily dose, route,
dosing interval) a

Cefoperazone+ Sulperazon 1 g vial ($89.50) 1 g vial ($79.9) 2 g vial ($160.8) 1 g vial ($54.6) IV 1g q6−8h (max 12 g/day) IM/IV 1−2 g/day 1 g vial IV( $31.20) q12−24h (max 4 0.75 g vial ($8.70) IV 0.75−1.5 g q8h 1.5 g vial ($16.5) 125 mg tab ($3.8) PO 250−500 mg bd 250 mg tab($7.39) 125 mg/5 mL suspension ($1.07/mL) PO 250−500 mg qid 500 cap ($0.68) 250mg/5mL syrup ($0.18/ml) 200 mg vial ($155) IV 200−400 mg q12h 400 mg vial ($260) 250 mg tab ($1.77) PO 500−750 mg bd 500 mg tab ($8.60) Clarithromycin Klacid 500 mg vial ($50) 250 mg tab ($7.23) PO 250−500 mg bd 500 mg tab ($14.55) 125 mg/5 mL syrup IMPACT Third Edition (Version 3.0) Trade name
Dosage form
Usual adult regimen
(unit cost, HK$)
(daily dose, route,
dosing interval) a

150 mg/mL in 2ml vials IV 600 mg q8h (max ($17.7/mL) 150 mg cap ($2.82) PO 150−300 mg qid 300 mg cap ($5.03) 500 mg vial ($2.04) IV 0.5−1 g q6h (max 250 mg cap ($0.33) 500 mg cap ($0.44) 100 mg tab ($0.25) 500 mg vial ($30.8) 250 mg tab ($0.39) PO 250−500 mg qid 125 mg/5 ml elixir PO 250−500 mg qid 20 mg/2 mL ($12) IV 3.6 mg/kg/day 80 mg/2 mL ($1.85) q24h (180 mg q24h) b or 1.2 mg/kg/dose q8h 500 mg vial ($114.5) 500 mg vial ($248.9) 100 mg tab ($3.81) 600 mg vial ($400) IV/PO 600 mg q12h 600 mg tab ($360) 20 mg/mL syrup ($12/ml) 500 mg vial ($126) 1g vial ($193.4) 500 vial ($4.50) 200 mg tab (0.17) 400 mg vial ($250) 400 mg tab ($14) IMPACT Third Edition (Version 3.0) Trade name
Dosage form
Usual adult regimen
(unit cost, HK$)
(daily dose, route,
dosing interval) a

50 mg vial ($18.5) IV 4.4 mg/kg q24h 300 mg vial ($33.6) (200 mg q24h) b or IV 1 MU vial ($2.80) IV 1−2 million unit q4−6h (max 24 million 4.5 g vial ($108) IV 4.5 g q6−8h tazobactam Teicoplanin 200 mg vial ($314.6) then 200 mg q24h 3.2 g vial ($52) IV 3.2 g q4−6h clavulanate Tobramycin 40 mg/mL 2 ml vial IV 3.6 mg/kg q24h (180 mg q24h) b or 1.2 mg/kg q8h 500 mg vial ($16.39) IV 1 g q12h or IV 500 mg q6h (i.e. 30 mg/kg/day) PO 125 mg qid (for refractory C. difficile colitis) Note: Approximate cost updated as of October 2005 in the public service. a Typical dosages in a 70 kg person with normal renal function. Dosage modification may be necessary for (i) the elderly; (ii) the very obese individuals (in whom the distribution volume of water-soluble drugs may be smaller than expected from body mass); (iii) those with renal failure and/or IV) liver failure. b Dosage for a typical 50 kg person given. Once daily administration of aminoglycoside is appropriate for most infections with the possible exceptions of neutropenic fever, infective endocarditis and in the presence of severe renal failure. IMPACT Third Edition (Version 3.0) Cost comparison of selected IV antibiotics

Usual dosage
IV Gentamicin* (3.5 mg/kg/day) 180 IV Netilmicin* (4.4 mg/kg/day) IV Tobramycin* (3.5 mg/kg/day) IV Amikacin* (15 mg/kg/day) Penicillins
IV Amoxillin-clavulanate (augmentin) IV Ampicillin-sulbactam IV Ticarcillin-clavulanate IV Piperacillin-tazobactam IV Cefoperazone-sulbactam Carbapenems
IMPACT Third Edition (Version 3.0)
IV Ciprofloxacin PO Ciprofloxacin Macrolides
IV Clarithromycin IV Metronidazole Note: Approximate cost updated as of October 2005 in the public service. *Dosage for a typical 50 kg person IMPACT Third Edition (Version 3.0) Cost comparison of systemic antifungal agents
Antifungal agent

Usual dosage

Loading 70 mg Day 1 Maintenance 50 mg qd IV Amphotercin B (1 mg/kg/day) * IV Liposomal amphotericin B (3 Note: Approximate cost updated as of October 2005 in the public *Dosage for a typical 50 kg person IMPACT Third Edition (Version 3.0) Dosage of antimicrobial agents for CNS infections
Recommended doses
Cost (HK$/day)
IV Metronidazole Note: * Dosage for a typical body weight ≥70 kg and normal renal ** Rifampicin should only be used in combination with another antibiotic for meningitis by certain bacteria (e.g. multi-resistant Streptococcus pneumoniae or MRSA) with documented sensitivity in susceptibility testing. IMPACT Third Edition (Version 3.0) Intra-peritoneal antibiotic dosing recommendations for
patients with CAPD peritonitis

Intermittent dosing (once daily) *
(Add drug into 1 bag/day unless
otherwise specified) (194)
Ceftazidime 1-1.5 Ampicillin/sulbactam * In patients with residual renal function, the drug dose should be empirically increased by 25%. IMPACT Third Edition (Version 3.0) (1) Ballow CH, Schentag JJ. Trends in antibiotic utilization and bacterial resistance. Report of the National Nosocomial Resistance Surveillance Group. Diagn Microbiol Infect Dis 1992; 15(2 Suppl):37S-42S. Cheng AF, French GL. Methicillin-resistant Staphylococcus aureus bacteraemia in Hong Kong. J HOSP INFECT 1988; 12(2):91- (3) French GL, Ling J, Ling T, Hui JW. Susceptibility of Hong Kong isolates of methicillin-resistant Staphylococcus aureus to antimicrobial agents. J Antimicrob Chemother 1988; 21(5):581-588. (4) Ho PL, Yuen KY, Yam WC, Wong SSY, Luk WK. Changing patterns of susceptibilities of blood, urinary and respiratory pathogens in Hong Kong. Journal of Hospital Infection 1995; 31(4):305-317. (5) Kam KM, Luey KY, Fung SM, Yiu PP, Harden TJ, Cheung MM. Emergence of multiple-antibiotic-resistant Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1995; 39:12-70. (6) Hierholzer-WJ J, Garner JS, Adams AB, Craven DE, Fleming DW, Forlenza SW et al. Recommendations for preventing the spread of vancomycin resistance: Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). Am J Infect Control 1995; 23(2):87-94. (7) Song W, Moland ES, Hanson ND, Lewis JS, Jorgensen JH, Thomson KS. Failure of cefepime therapy in treatment of Klebsiella pneumoniae bacteremia. J Clin Microbiol 2005; 43(9):4891-4894. (8) Chu YW, Afzal-Shah M, Houang ET, Palepou MI, Lyon DJ, Woodford N et al. IMP-4, a novel metallo-beta-lactamase from nosocomial Acinetobacter spp. collected in Hong Kong between 1994 and 1998. Antimicrob Agents Chemother 2001; 45(3):710-714. (9) Adeyemi-Doro FA, Scheel O, Lyon DJ, Cheng AF. Living with methicillin-resistant Staphylococcus aureus: a 7-year experience with endemic MRSA in a university hospital. Infect Control Hosp Epidemiol 1997; 18(11):765-767. (10) Ip M, Lyon DJ, Chio F, Enright MC, Cheng AF. Characterization of isolates of methicillin-resistant Staphylococcus aureus from Hong Kong by phage typing, pulsed-field gel electrophoresis, and fluorescent IMPACT Third Edition (Version 3.0) amplified-fragment length polymorphism analysis. J CLIN MICROBIOL 2003; 41(11):4980-4985. (11) Ip M, Lyon DJ, Chio F, Cheng AF. A longitudinal analysis of methicillin-resistant Staphylococcus aureus in a Hong Kong teaching hospital. Infect Control Hosp Epidemiol 2004; 25(2):126-129. (12) Ho PL. Carriage of methicillin resistant Staphylococcus aureus, ceftazidime resistant Gram negative bacilli and vancomycin resistant enterococci before and after intensive care units admission. Crit Care Med (in press) 2003. (13) Zetola N, Francis JS, Nuermberger EL, Bishai WR. Community-acquired meticillin-resistant Staphylococcus aureus: an emerging threat. Lancet Infect Dis 2005; 5(5):275-286. Palavecino E. Community-acquired methicillin-resistant Staphylococcus aureus infections. Clin Lab Med 2004; 24(2):403-418. (15) Hidron AI, Kourbatova EV, Halvosa JS, Terrell BJ, McDougal LK, Tenover FC et al. Risk factors for colonization with methicillin-resistant Staphylococcus aureus (MRSA) in patients admitted to an urban hospital: emergence of community-associated MRSA nasal carriage. Clin Infect Dis 2005; 41(2):159-166. Weber JT. Community-associated methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2005; 41 Suppl 4:S269-S272. (17) Ho PL, Tse CW, Mak GC, Chow KH, Ng TK. Community-acquired methicillin-resistant Staphylococcus aureus arrives in Hong Kong. J Antimicrob Chemother 2004; 54(4):845-846. (18) Said-Salim B, Mathema B, Braughton K, Davis S, Sinsimer D, Eisner W et al. Differential distribution and expression of Panton-Valentine leucocidin among community-acquired methicillin-resistant Staphylococcus aureus strains. J CLIN MICROBIOL 2005; 43(7):3373-3379. (19) Ho PL, Ng TK, Yung RW, Que TL, Yip EK, Tse CW et al. Activity of linezolid against levofloxacin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus and vancomycin- resistant enterococci in Hong Kong. J Antimicrob Chemother 2001; 48(4):590-592. (20) Ho PL, Chan WM, Tsang KWT, Wong SSY, Young K. Bacteremia caused by Escherichia coli producing extended-spectrum beta- lactamase: a case-control study of risk factors and outcomes. Scandinavian Journal of Infectious Diseases 2002; 34(8):567-573. IMPACT Third Edition (Version 3.0) (21) Ho PL, Shek RH, Chow KH, Duan RS, Mak GC, Lai EL et al. Detection and characterization of extended-spectrum beta-lactamases among bloodstream isolates of Enterobacter spp. in Hong Kong, 2000-2002. J Antimicrob Chemother 2005; 55(3):326-332. (22) Ho PL, Ho AY, Chow KH, Wong RC, Duan RS, Ho WL et al. Occurrence and molecular analysis of extended-spectrum {beta}-lactamase-producing Proteus mirabilis in Hong Kong, 1999-2002. J Antimicrob Chemother 2005; 55(6):840-845. (23) Ho PL, Tsang DN, Que TL, Ho M, Yuen KY. Comparison of screening methods for detection of extended-spectrum beta- lactamases and their prevalence among Escherichia coli and Klebsiella species in Hong Kong. APMIS 2000; 108(3):237-240. (24) Goossens H. Susceptibility of multi-drug-resistant Pseudomonas aeruginosa in intensive care units: results from the European MYSTIC study group. Clin Microbiol Infect 2003; 9(9):980-983. (25) Jones RN, Kirby JT, Beach ML, Biedenbach DJ, Pfaller MA. Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program (1997-2000). Diagn Microbiol Infect Dis 2002; 43(3):239-243. (26) Fluit AC, Jones ME, Schmitz FJ, Acar J, Gupta R, Verhoef J. Antimicrobial resistance among urinary tract infection (UTI) isolates in Europe: results from the SENTRY Antimicrobial Surveillance Program 1997. Antonie Van Leeuwenhoek 2000; 77(2):147-152. Livermore DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother 2001; 47(3):247-250. (28) Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 2002; 34(5):634-640. (29) Bert F, Maubec E, Bruneau B, Berry P, Lambert-Zechovsky N. Multi-resistant Pseudomonas aeruginosa outbreak associated with contaminated tap water in a neurosurgery intensive care unit. J Hosp Infect 1998; 39(1):53-62. (30) Douglas MW, Mulholland K, Denyer V, Gottlieb T. Multi-drug resistant Pseudomonas aeruginosa outbreak in a burns unit--an infection control study. Burns 2001; 27(2):131-135. (31) Luzzaro F, Mantengoli E, Perilli M, Lombardi G, Orlandi V, Orsatti A et al. Dynamics of a nosocomial outbreak of multidrug- IMPACT Third Edition (Version 3.0) resistant Pseudomonas aeruginosa producing the PER-1 extended-spectrum beta-lactamase. J Clin Microbiol 2001; 39(5):1865-1870. (32) Panzig B, Schroder G, Pitten FA, Grundling M. A large outbreak of multiresistant Pseudomonas aeruginosa strains in north-eastern Germany. J Antimicrob Chemother 1999; 43(3):415-418. (33) Pellegrino FL, Teixeira LM, Carvalho Md MG, Aranha NS, Pinto DO, Mello Sampaio JL et al. Occurrence of a multidrug-resistant Pseudomonas aeruginosa clone in different hospitals in Rio de Janeiro, Brazil. J Clin Microbiol 2002; 40(7):2420-2424. (34) Gales AC, Jones RN, Turnidge J, Rennie R, Ramphal R. Characterization of Pseudomonas aeruginosa isolates: occurrence rates, antimicrobial susceptibility patterns, and molecular typing in the global SENTRY Antimicrobial Surveillance Program, 1997-1999. Clin Infect Dis 2001; 32 Suppl 2:S146-S155. Andrade SS, Jones RN, Gales AC, Sader HS. Increasing prevalence of antimicrobial resistance among Pseudomonas aeruginosa isolates in Latin American medical centres: 5 year report of the SENTRY Antimicrobial Surveillance Program (1997-2001). J Antimicrob Chemother 2003; 52(1):140-141. Obritsch MD, Fish DN, MacLaren R, Jung R. National surveillance of antimicrobial resistance in Pseudomonas aeruginosa isolates obtained from intensive care unit patients from 1993 to 2002. Antimicrob Agents Chemother 2004; 48(12):4606-4610. (37) Saiman L, Mehar F, Niu WW, Neu HC, Shaw KJ, Miller G et al. Antibiotic susceptibility of multiply resistant Pseudomonas aeruginosa isolated from patients with cystic fibrosis, including candidates for transplantation. Clin Infect Dis 1996; 23(3):532-537. (38) Paramythiotou E, Lucet JC, Timsit JF, Vanjak D, Paugam-Burtz C, Trouillet JL et al. Acquisition of multidrug-resistant Pseudomonas aeruginosa in patients in intensive care units: role of antibiotics with antipseudomonal activity. Clin Infect Dis 2004; 38(5):670-677. (39) Defez C, Fabbro-Peray P, Bouziges N, Gouby A, Mahamat A, Daures JP et al. Risk factors for multidrug-resistant Pseudomonas aeruginosa nosocomial infection. J Hosp Infect 2004; 57(3):209-216. (40) Cao B, Wang H, Sun H, Zhu Y, Chen M. Risk factors and clinical outcomes of nosocomial multi-drug resistant Pseudomonas aeruginosa infections. J Hosp Infect 2004; 57(2):112-118. IMPACT Third Edition (Version 3.0) (41) Ortega B, Groeneveld AB, Schultsz C. Endemic multidrug- resistant Pseudomonas aeruginosa in critically ill patients. Infect Control Hosp Epidemiol 2004; 25(10):825-831. (42) Oie S, Uematsu T, Sawa A, Mizuno H, Tomita M, Ishida S et al. In vitro effects of combinations of antipseudomonal agents against seven strains of multidrug-resistant Pseudomonas aeruginosa. J Antimicrob Chemother 2003; 52(6):911-914. Hamer DH. Treatment of nosocomial pneumonia and tracheobronchitis caused by multidrug-resistant Pseudomonas aeruginosa with aerosolized colistin. Am J Respir Crit Care Med 2000; 162(1):328-330. (44) Bratu S, Quale J, Cebular S, Heddurshetti R, Landman D. Multidrug-resistant Pseudomonas aeruginosa in Brooklyn, New York: molecular epidemiology and in vitro activity of polymyxin B. Eur J Clin Microbiol Infect Dis 2005; 24(3):196-201. (45) Falagas ME, Kasiakou SK. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005; 40(9):1333-1341. (46) Tascini C, Gemignani G, Ferranti S, Tagliaferri E, Leonildi A, Lucarini A et al. Microbiological activity and clinical efficacy of a colistin and rifampin combination in multidrug-resistant Pseudomonas aeruginosa infections. J Chemother 2004; 16(3):282-287. (47) Ho PL, Cheng JCF, Ching PTY, Kwan JKC, Lim WWL, Tong WCY et al. 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IMPACT Third Edition (Version 3.0) Third generation cephalosporins American Association of Colleges of Pharmacy American College of Physicians- American Society of Internal Medicine Acute exacerbation of chronic bronchitis Alliance for the Prudent Use of Antibiotics Antimicrobial stewardship programme BLBLI Beta-lactam/beta-lactamase inhibitor CA-MRSA Community acquired methicillin resistant Staphylococcal aureus cap/caps Capsule/capsules CDC Centers for Disease Control and Prevention Clinical and Labortory Standards Institute Chronic obstructive pulmonary disease Chronic rheumatic heart disease Ceftazidime-resistant Klebsiella pneumoniae 5% dextrose solution Defined daily dose Drug resistant Streptococcus pneumoniae Extended-spectrum beta lactamase Empirical therapy Food and Drug Administration Fine needle aspiration Healthcare associated methicillin resistant Staphylococcus aureu Hemophilus parainfluenzae, H. aphropilus, Actinobacillus, Cardiobacterium, Eikenella, IMPACT Third Edition (Version 3.0) Ideal body weight Infectious Diseases Society of America IM Intramuscular IV Intravenous IVDA Intravenous drug abuser KPT Known-pathogen MRPA Multiply-resistant Pseudomonas aeruginosa Methicillin resistant Staphylococcus aureus Methicillin sensitive Staphylococcus aureus for Laboratory Standards National Institues of Health PO Oral PPU Perforated PVL Panton-Valentine Four times per day syr Syrup tab/tabs Tablet/tablets TBW Total Therapeutic drug monitoring Three times per day Vancomycin resistant Enterococcus World Health Organisation IMPACT Third Edition (Version 3.0) Part I: Antibiotic resistance-local scenario
Part II: Antimicrobial stewardship programme
Part III: Guidelines for selected antimicrobial use
Part IV: Empirical therapy of common infections
Part V: Known-pathogen therapy
Part VI: Guidelines for surgical prophylaxis
Part VII: Cost and dosage of antimicrobial agents
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Practice Management and Human Relations Ethical decision-making for multiple prescription dentistryKevin Huff, DDS, MAGD  n  Marlene Huff, PhD, RN  n  Constantin Farah, DDS, MSD Technology provides a selection of treatment choices for dental This article presents four case studies that illustrate the process of problems. Dental ethics must be applied to the development of a

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