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Reducing bacterial resistance with IMPACT –

Interhospital Multi-disciplinary Programme on Antimicrobial ChemoTherapy

This guideline is available for download at:

HKU Centre of Infection

http://www.hku.hk/hkucoi/impact.pdf

DH Centre for Health Protection

http://www.chp.gov.hk/files/pdf/reducing_bacterial_resistance_with_impact.pdf

HA intranet

http://ha.home/ho/ps/impact.pdf

Editors: PL Ho and SSY Wong

Third Edition 2005

Version 3.0

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 plho@hkusua.hku.hk or hkumicro@hkucc.hku.hk

NOTICE

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 Working Group

Co-chairpersons Dr. Raymond Wai Hung, YUNG

Dr. Dominic Ngai Chong, TSANG

Members (alphabetical order)

Dr. S Anandaciva

Dr. Kin Sang, CHAN

Dr. Wai Ming, CHAN

Dr. Sik To, LAI

Dr. Wai Man, LAI

Dr. Patrick CK, LI

Dr. Wei Kwang, LUK

Head, Infection Control Branch, Centre for Health Protection, Department of Health

Consultant Microbiologist, Department of Clinical Pathology Queen Elizabeth Hospital

Consultant Department of Anaesthesiology and Intensive Care Unit Tuen Mun Hospital

Chief of Service Department of Pulmonary Medicine Haven of Hope Hospital

Consultant Intensive Care Unit Queen Mary Hospital

Consultant Department of Medicine Princess Margaret Hospital

Chief of Service Department of Microbiology Prince of Wales Hospital

Chief of Service Department of Medicine Queen Elizabeth Hospital

Senior Medical Officer Department of Clinical Pathology Tseung Kwan O Hospital

Dr. Tak Keung, NG

Dr. Tak Lun, QUE

Dr. Loletta KY, SO

Dr. Wing Kin, TO

Dr. Kwan Keung, WONG

Dr. Sai Hung, YEUNG

Dr. Wai Chun, YIP

Mr. Pak Wai, LEE

Consultant Microbiologist Department of Clinical Pathology Princess Margaret Hospital

Consultant Microbiologist Department of Clinical Pathology Tuen Mun Hospital

Senior Medical Officer Department of Medicine Pamela Youde Nethersole Eastern Hospital

Senior Medical Officer Department of Clinical Pathology Yan Chai Hospital

Chief of Service Department of Medicine North District Hospital

Consultant Department of Orthopaedic Surgery Pamela Youde Nethersole Eastern Hospital

Chief of Service Department of Surgery Kwong Wah Hospital

Chief Pharmacist Hospital Authority Head Office

Academic advisors

Professor Robert MT, CHAN

Dr. Pak Leung, HO

Professor Margaret IP

Professor Allan R. RONALD

Professor Kenneth WT, TSANG

Professor Kwok Yung, YUEN

Professor of Infectious Diseases Department of Medicine University of British Columbia Vancouver, Canada

Associate Professor and Honorary Consultant Division of Infectious Diseases, Department of Microbiology & Centre of Infection The University of Hong Kong

Professor Department of Microbiology Chinese University of Hong Kong

Distinguished Professor Emeritus (Internal Medicine, Medical Microbiology and Community Health Sciences) University of Manitoba Canada

Professor and Honorary Consultant Department of Medicine Queen Mary Hospital

Chair Professor in Infectious Diseases Division of Infectious Diseases, Department of Microbiology & Centre of Infection The University of Hong Kong

Secretaries

Dr. Cindy WS, TSE

Dr. Alan KL, WU

Dr. Tak Chiu, WU

Associate Consultant

Department of Clinical Pathology

Kwong Wah Hospital

Medical Officer

Department of Clinical Pathology

Pamela Youde Nethersole Eastern Hospital

Associate Consultant

Department of Medicine

Queen Elizabeth Hospital

Contents

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

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

Ceftazidime 45 Imipienem/meropenem/ertapenem 48 Once daily aminoglycosides 50

43

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

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

List of tables

Table 1. Top ten isolates from clinical specimens in 2004 (data from a regional hospital in Hong Table 2. Intrinsic and associated resistance to antimicrobial agents among five nosocomial Table 3. Methods to implement antimicrobial control Table 4. Potential barriers to reaching the strategic goals Table 5. Summary of published data on antimicrobial strategies as an

14

15

28

29

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

56

Table 14. Comparison of selected pharmacokinetic parameters for the

Table 13. Mechanisms of antifungal action

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

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.

and partnership in our Antibiotic Stewardship Programme. Dr Cheung Wai-lun Director Professional Services and

Dr Cheung Wai-lun Director Professional Services and Operations Hospital Authority

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

Part I: Antibiotic resistance – local scenario

Part I: Antibiotic resistance- local scenario

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).

2. 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).

14

Table 1. Top ten isolates from clinical specimens in 2004 (data from a regional hospital in Hong Kong).

Part I: Antibiotic resistance – local scenario

IMPACT Third Edition (Version 3.0)

(Percentage omitted if number of isolates is less than 30)

 

n=232

ICU rank

(%)

     

1 (32%)

   

7 (2%)

 

-

 

n=9201

 

ICU/HDU

rank (%)

1 (40%)

2 (11%)

 

3 (11%)

4 (8%)

 

5 (5%)

6 (5%)

(3%)

8 (2%)

(2%)

10 (2%)

Urine

Non-

7

9

 

2 (21%)E.

3 (13%)S.

Enterococci species

4 (11%)K.

Candida species

6 (3%)S.

5 (7%)A.

P. aeruginosa

8 (2%)P.

S. aureus

-P.

M. marganii

 

n=1669

ICU rank

(%)

3 (8%)

1 (9%)

-

2 (9%)

-

6 (4%)

 

7 (4%)

5 (5%)

4 (5%)

Respiratory specimens

n=6303

 

ICU/HDU

rank (%)

1 (12%)

2 (8%)

 

3 (6%)

(4%)

5 (4%)

6 (4%)

7 (3%)

8 (3%)

(2%)

10 (2%)

Non-

4

9

 

Organism

P. aeruginosa

aureus

H. influenzae

Klebsiella

species

S. pneumoniae

baumannii

M. catarrhalis

E. coli

Enterobacter

species

S. maltophilia

 

n=366

ICU rank

(%)

2 (10%)

1 (38%)

5 (7%)

 

6 (5%)

4 (9%)

9 (1%)

7 (2%)

10 (1%)

-

Blood

n=1801

Non-

ICU/HDU

rank (%)

1 (24%)

2 (15%)

3 (9%)

4 (8%)

5 (7%)

6 (3%)

7 (2%)

8 (2%)

9 (2%)

10 (2%)

 

Organism

coli

Coagulase-negative

staphylococci

pneumoniae

3 (9%)Bacillus

species

aureus

Enterococcus species

-A.

baumannii

aeruginosa

B. fragilis group

mirabilis

Part I: Antibiotic resistance – local scenario

Table 2. Intrinsic and associated resistance to antimicrobial agents among five nosocomial pathogens.

 

INTRINSIC

ASSOCIATED

BACTERIA

RESISTANCE

RESISTANCE

MRSA

All beta-lactams, beta- lactam/beta-lactamase inhibitor combinations

Common: erythromycin, clindamycin, aminoglycosides, cotrimoxazole, fluoroquinolones

VRE

All cephalosporins, cotrimoxazole, clindamycin, aminoglycosides

Common: ampicillin, imipenem, meropenem, vancomycin, high level aminoglycoside resistance

ESBL-producing Enterobacteriaceae (CTX-M, SHV-, TEM- derived)

All cephalosporins including fourth generation cephalosporin (7), all penicillins, aztreonam

Common:

fluoroquinolones,

gentamicin,

cotrimoxazole

Derepressed AmpC-type mutant among E. cloacae, C. freundii, S. marcescens

First, second and third generation cephalosporins, most

Common:

fluoroquinolones,

gentamicin,

beta-lactam/beta-

cotrimoxazole

 

lactamase inhibitor combinations, cefoxitin

A. baumannii

Ampicillin, first and second generation cephalosporins

Third generation cephalosporins, fluoroquinolones, aminoglycosides, ( imipenem, meropenem)

 

(8)

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)

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).

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).

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.

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).

Vancomycin-resistant enterococci

VRE here refers to E. faecium and E. faecalis with resistance to glycopeptides (vancomycin MIC 8 g/mL or teicoplanin MIC 16 g/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

1. 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).

Part I: Antibiotic resistance – local scenario

2. 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).

3. 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).

4. 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.

5. 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).

6. 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.

7. 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).

8. 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

Part I: Antibiotic resistance – local scenario

Enterobacteriaceae were resistant to amoxicillin-clavulanate, ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin- tazobactam and cefoperazone-sulbactam (20).

Enterobacter spp.

1. 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.

2. 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.

3. 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).

4. 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-

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.

Part II: Antimicrobial stewardship programme

Part II: Antimicrobial stewardship programme

Part II: Antimicrobial stewardship programme

Antimicrobial stewardship program: summary

The present summary is based on an article in the Hong Kong Medical Journal (47).

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?

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).

Part II: Antimicrobial stewardship programme

2. What is the rationale for optimizing antimicrobial use?

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.

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

In

developed

countries,

studies

have

found

that

30-40%

of

resistance (52;53;56;57).

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)

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

Part II: Antimicrobial stewardship programme

the likely pathogens, such activities can be viewed as a strategy to enhance patient safety.

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).

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?

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.

Part II: Antimicrobial stewardship programme

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.

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?

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).

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

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.

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)

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.

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

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

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.

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

physicians.

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

usage.

6. Ongoing monitoring and analysis of antimicrobial agents

usage.

7. Ongoing surveillance of antimicrobial susceptibility.

8. Monitoring adherence to advice on choice of antimicrobial

agents.

9. Usage feedback to physicians.

Part II: Antimicrobial stewardship programme

Table 4. Potential barriers to reaching the strategic goals

Barrier

Countermeasures and improvement strategies

Ownership and accountability

 

1. Lack of ownership and

 

accountability for recognizing and reporting trends.

2. Failure to integrate work of laboratory, infection control, medical, nursing, and intensive care-unit staffs.

1. Designate responsibility and accountability for the process.

2. Set up a multi-disciplinary team to develop a collaborative system and monitor results.

Staff knowledge and practice

 

1. Lack of time for the laboratory

1. Ensure adequacy of laboratory and infection-control staffing and prioritize

and/or infection control staff to generate and analyze data.

2. Lack of time for healthcare providers to examine and discuss data and inconsistent or erroneous interpretation of data by staff.

activities of staff so that data can be generated and analyzed.

2. Report data in an easy-to read/interpret format and, when appropriate, include data interpretation in the report.

Physician attitudes

 

1.

Lack of trust in the hospital administration

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 results.

Expertise

 

1.

Lack of expertise in biostatistics (e.g. presenting trends and analyzing data).

1. Ensure availability of consultants, especially when designing analytic strategy and interpreting trend data.

Reference (82)

Part II: Antimicrobial stewardship programme

State-of-the art: Limiting antimicrobial resistance

1. US surveys: 22-65% usage of antibiotics in the hospitals is inappropriate.

2. 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.

3. 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 vancomycin

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, and VRE.

1. 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).

2. 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).

3. 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

Part II: Antimicrobial stewardship programme

days)

colonization (100).

were

independently

associated

with

VRE

infection

or

4. 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).

5. 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).

6. 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 use

antibiotic

resistance

after

changes

in

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:

1. 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.

2. 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-

Part II: Antimicrobial stewardship programme

control study, the use of beta-lactam/beta-lactamase inhibitor combination was shown to be a protective factor (105).

3. 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).

Table 5. Summary of published data on antimicrobial strategies as an intervention to reduce ESBL resistance.

33

3GC, third generation cephalosporins; BLBLI, beta-lactam/beta-lactamase inhibitor; CRKP, ceftazidime-resistant K. pneumoniae.

Part II: Antimicrobial stewardship programme

IMPACT Third Edition (Version 3.0)

Other observations

 

Cefotaxime-resistant Acinetobacter by

>100%

   

Imipenem-resistant P. aeruginosa by

69%

% KP resistant to BLBLI also (36 to 19% in A and 22 to 14% in B)

Outcome ESBL rate remain <10% next 4 years

Mean incidence of CRKP by 34%

CRKP from >30% to <10%

ESBL carriage from 33 to 40% to 0%.

 

CRKP ESBL by

44%.

Hospital A: CRKP from 22 to 15%. Hospital B: CRKP from 10 to 5%.

Intervention/result Minimize use of ceftazidime (marked and sustained ); addition of piperacillin-

 

tazobactam to formulary (usage ) Use of BLBLI emphasized and the use of 3GCs, vancomycin and clindamycin restricted; addition of ampicillin-sulbactam and piperacillin-tazobactam to

formulary. Ceftazidime was replaced by imipenem.

Restriction of 3GC (usage by 87% after intervention).

Class restriction of cephalosporins (usage by 80% after intervention). Usage replaced by

imipenem. Physician education on association of ceftazidime use and CRKP. Use of ceftazidime by 71% (hospital A) and 27% (hospital B).

Setting (type of study)

Year period (Ref)

1

6-28% in within

K.1994

in ESBL

Epidemic rise from

pneumoniae

99 (108)

year in a medical centre

(intervention study)

institute1993

in one

Spread of VRE

98 (109)

control

infection

despite

continued

measures (intervention study).

90 (110) Outbreak of CRKP in one medical1989 centre. Use of ceftazidime 600% in the 2 years before outbreak (intervention study).

of ESBL-1993

A clonal outbreak

95 (111)

in an ICU

K. pneumoniae

producing

(intervention study).

K.1995

An outbreak in of a ESBL-producing

hospital since

pneumoniae

96 (112)

1990 (intervention study).

Clonal outbreak of CRKP in hospital A. Polyclonal outbreak of CRKP in hospital B (intervention study).

1996 (113)

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.

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 <10x10 9 /L).

4. Signs & symptoms related to infection are improving.

5. Patient is not neutropenic (neutrophil count >2 x10 9 /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.

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? Likely susceptibility pattern Community- or hospital-acquired infection? Monotherapy or combination therapy?

Education Collection and analysis of local data Pocket reference guide

 
and analysis of local data Pocket reference guide   When culture and susceptibility results are available

When culture and susceptibility results are available

 
 

Known-pathogen therapy (KPT)

 

Narrowest spectrum according to laboratory results Follow guidelines on the judicious use of ceftazidime, imipenem/ertapenem/ meropenem, vancomycin/teicoplanin/ linezolid

Cascade reporting of sensitivity Daily review of prescription of “big gun” antibiotics by ASP team. Daily reporting of deviations from guidelines to clinical microbiologist/ID physician ASP team to give daily immediate concurrent feedback (ICF) to prescribers.

daily immediate concurrent feedback (ICF) to prescribers.   Switch therapy (116;117)   A switch from

 

Switch therapy (116;117)

 

A switch from intravenous to oral therapy Criteria for switch therapy Clinical diagnosis compatible with oral therapy Patient has functioning gastrointestinal tract Patient is afebrile (for >24h) Signs and symptoms related to infection are improving or resolved The WBC count is normalizing

Daily review of patients on IV “big gun” antibiotics by ASP team Daily recommendation for “switching” by ASP team

 

Daily recommendation for “switching” by ASP team   Stop therapy   Type of infection Clinical responses

Stop therapy

 

Type of infection Clinical responses Follow-up culture results where appropriate

Education

 

Part III: Selected Antimicrobial agents

Part III: Guidelines for selected antimicrobials use

Part III: Selected Antimicrobial agents

Vancomycin

Situations in which the use of vancomycin/teicoplanin is appropriate (6;83)

1. Treatment of serious infections caused by beta-lactam resistant Gram-positive bacteria (e.g. MRSA, coagulase-negative staphylococci).

2. 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).

3. When Clostridium difficile colitis fails to respond to metronidazole therapy or is severe and life-threatening.

4. 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).

5. 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 advised

1. 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

2. Routine surgical prophylaxis other than in a patient who has serious allergy to beta-lactam antimicrobial agents.

3. 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).

Part III: Selected Antimicrobial agents

4. 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.

5. 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).

6. Systemic or local (e.g. antibiotic lock) prophylaxis against infection (or colonization) of indwelling (central or peripheral) intravascular catheters.

7. As routine prophylaxis, before insertion of Hickman/Brovac catheter or Tenckhoff catheter.

tract

8. As

part

of

the

regimen

for

selective

digestive

decontamination.

9. 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 monitoring

1. 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).

2. 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 g/mL.

Routine TDM is not indicated in most patients because vancomycin pharmacokinetics are sufficiently predictable that safe and effective vancomycin dosage regimens (giving trough

Part III: Selected Antimicrobial agents

levels 5-10 g/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

(119)

(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 g/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 g/mL for treatment of MRSA hospital-acquired pneumonia (123). Current literature does not support peak concentration measurement (124).

3. 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 table/nomogram.

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.

Part III: Selected Antimicrobial agents

Table 7. Dosage table for vancomycin

Creatinine clearance ( mL/min)

Vancomycin dose (mg/24 h)

100

1,545

90

1,390

80

1,235

70

1,080

60

925

50

770

40

620

30

465

20

310

10

155

Adapted from vancomycin package insert July 2004 .

4. Vancomycin in 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 g/mL and trough 5-10 g/mL were 1.9 g (±0.5 g) q8h.

Part III: Selected Antimicrobial agents

Table 8. Calculation of vancomycin dosage for morbidly obese patient

Steps

Calculation

Scenario: Female/30yr, body weight 200 kg, height 1.8 m, serum creatinine 80 mol/L

Determine if the patient is morbidly obese

TBW/IBW ratio:

200/70.7 = 2.8

0.8 1.25 = normal

 

>1.25 1.9 = obese

>1.9 = morbid obesity

Determine dose of vancomycin

30 mg/kg TBW/day

6 g per day if normal renal function. (administer as IV 2 g q8h; infuse each 2 g dose over at least 2 h)

Estimate creatinine clearance (CrCl)

Cockcroft-Gault formula 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 g/mL

Adjust dosing interval according to trough level

Equations:

1. 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)

2. 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 mol/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 mol/L

a TBW, total body weight

Part III: Selected Antimicrobial agents

Quinupristin/dalfopristin and linezolid

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.

2. Most VRE (n=11) identified in Hong Kong so far are susceptible to linezolid (both E. faecalis and E. faecium) at 4 g/mL and quinupristin/dalfopristin (E. faecium only, at 1 g/mL) (19).

1. Indications

for

linezolid

(Zyvox)

or

Part III: Selected Antimicrobial agents

Table 9. Comparison of linezolid and quinupristin/dalfopristin

 

Linezolid

Quinupristin/dalfopristin

FDA

Yes/2000

Yes/1999 (for serious infections associated with vancomycin- resistant E. faecium)

approval/year

Registration in Hong Kong

Yes

No

Formulary

IV/PO. Bioavailbility of PO linezolid is ~100%.

Only IV

Usual dose

IV/PO 600 mg q12h

IV 7.5 mg/kg q8h (infuse over 1 h in D5)

Central venous catheter for administration

No

Yes

Activity vs. VRE

both vancomycin-resistant E. faecalis and E. faecium

Only vancomycin resistant E. faecium a

Effect on cytochrome P450

Nil (No effect on 1A2, 2C9, 2C19, 2D6, 2E1, 3A4)

Inhibit 3A4 isoenzyme strongly, hence interactions with midazolam, nifedipine, astemizole, terfenadine, cyclosporin (must monitor level), tacrolimus

Monoamine oxidase (MAO) inhibition

Yes (a weak, reversible, nonselective MAO inhibitor), hence potential for interactions with adrenergic and serotonergic drugs.

Nil (No effect on MAO).

Side effects

Thrombocytopenia (related to duration of treatment; incidence 0.3-10%; need monitoring if treated for >7d)

Phlebitis (high incidence if administered via peripheral vein); arthralgia/myalgia (dose related; incidence 1.3-33%)

General

Compatible with both D5 and saline.

Form precipitate with saline. DO NOT flush with saline or heparin after quinupristin/ dalfopristin administration.

compatibility

Renal

No adjustment in dose required in pt. with renal impairment. Give dose after HD.

No adjustment in dose required in pt. with renal impairment or undergoing dialysis.

impairment

Data from package insert of Zyvox and Synercid.

a All E. faecalis isolate (including vancomycin-resistant E. faecalis) are intrinsically resistant to quinupristin/dalfopristin.

Part III: Selected Antimicrobial agents

Ceftazidime

Indications for using ceftazidime (Fortum) (127)

1. Empirical therapy of neutropenic fever, either as monotherapy or in combination with an aminoglycoside (128).

infection by Burkholderia pseudomallei infection

2. Therapy

of

(melioidosis).

Probable case (compatible chest X-ray plus a melioidosis titre of 1/640) or definite case (isolation of B. pseudomallei).

3. Known pathogen therapy of documented infection by susceptible Pseudomonas aeruginosa a , such as:

(a)

Bacteraemia with isolation of Pseudomonas aeruginosa from blood culture.

(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 specimen b .

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. 10 2 -10 3 CFU/mL or moderate/heavy growth for protected specimen brush.

2. 10 3 -10 4 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.

Part III: Selected Antimicrobial agents

Situations/conditions in which ceftazidime is not advised

1. 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

2. 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 g/mL), the drugs of choice are penicillin G (standard or high dose) or amoxicillin or cefotaxime or ceftriaxone (refer to known- pathogen therapy chart).

3. 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.

4. 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.

5. 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.

6. 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.

Part III: Selected Antimicrobial agents

7. Empirical or continued treatment of infection by S. aureus (both MSSA and MRSA).

8. Empirical or continued treatment of infection by all enterococci such as E. faecalis and E. faecium.

9. Empirical treatment for community-acquired meningitis.

Part III: Selected Antimicrobial agents

Imipienem/meropenem/ertapenem

Indications for using imipenem/meropenem/ertapenem

1. 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 blood culture.

Deep-seated

infection

with

isolation

of

ESBL-producing

bacteria from normally

peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc).

sterile

body

site

or

fluid

(CSF,

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 specimens a

2. 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.)

Footnotes

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. 10 2 -10 3 CFU/mL or moderate/heavy growth for protected specimen brush.

2. 10 3 -10 4 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.

Part III: Selected Antimicrobial agents

Situations/conditions in which imipenem/meropenem/ertapenem is not advised

1. 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

2. 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.

3. As known-pathogen therapy for infections caused by organisms susceptible to other beta-lactams.

Part III: Selected Antimicrobial agents

Once daily aminoglycosides

1. 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.

2. Dosing to be based on actual body weight unless the patient is morbidly obese (i.e. 20% over ideal body weight, IBW).

Aminoglycoside

patient

= 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)

obsess

dosing

weight

for

morbidly

3. 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 table.

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 ( mol/L)

(Female: 0.85 above value)

(Unit conversion for serum creatinine: mg/dL x 88.4 = mol/L)

Part III: Selected Antimicrobial agents

CrCl

Initial dosing interval a

(mL/min)

60

q24h

40-60

q36h

20-40

q48h

<20

Follow serial levels to determine time of

next dose (level <1 g/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.

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 designated q24h

Dose at an interval of every

24h

Level falls in the area designated q36h

Dose at an interval of every

36h

Level falls in the area designated q48h

Dose at an interval of every

48h

Level on the line

Choose the longer interval

Level off the normogram at the given time

Stop the scheduled therapy, obtain serial levels to determine the appropriate time of the next dose

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).

pregnancy, burns (>20%), ascites, dialysis, Enterococcal endocarditis (51). IMPACT Third Edition (Version 3.0) 5 3

54

Part III: Selected Antimicrobial agents

IMPACT Third Edition (Version 3.0)

Table 11. General patterns of antifungal susceptibility

S, susceptible; S-DD, susceptibility is dose-dependent; R, resistant

Summary of selected antifungal agents

 

Caspofungin S

(MIC 0.5 g/mL)

S

S

 

S S

(MIC 0.5 g/mL)

 

less active less active MIC 2 g/mL)

R (MIC 32

g/mL) R

R in vitro (mean MIC 60-

70 g/mL) S (mean MIC 1.3

g/mL) ++ (mean MIC 0.1-0.15 g/mL)

R

Voriconazole

S

S

S

S

S

S

S

S

S

+

?

++ (mean MIC

0.4 g/mL) R

Amphotericin B S

S

S-I

S-I

S-R

S

S

S

I

I to R

-

+

+

5-Flucytosine

S

S

S

I-R

S

S

S

S

?

?

?

+

NA

Itraconazole

S

S

S-DD to R

S-DD to R S

S

S

S

S

Some spp. R in vitro

+

+

R

Fluconazole

S

S

S-DD to R

R S

S

S

S

S

R

?

R

albicans

tropicalis

glabrata

krusei

lusitaniae

C. parapsilosis

guillermondii

Cryptococcus

neoformans

Trichosporon

Fusarium

Pseudallescheria

Asperigillus

Mucor

C.

C.

C.

C.

C.

C.

Part III: Selected Antimicrobial agents

Table 12. Comparison of susceptibility of selected fungi to the azoles

Organism (no. of isolates tested) (133-

 

Range

MIC that can

inhibit 50% of all tested isolates

MIC that can inhibit 90% of all tested isolates

(

g/mL)

135)

 
 

(

g/mL)

(

g/mL)

C.

glabrata (n=217)

Fluconazole

0.25

 

128

16

64

Itraconazole

 

0.06

8

1

4

Voriconazole

0.03

8

0.5

2

C.

krusei (n=33)

Fluconazole

 

8 128

 

64

64

Itraconazole

0.12

2

1

2

Voriconazole

0.06

4

0.5

1

Fluconazole-

 

resistant C. albicans

(n=12)

Fluconazole

 

64 128 1 8 0.25 8

 

>128

>128

Itraconazole

>8

>8

Voriconazole

>8

>8

A.

fumigatus (n=284)

Amphotericin B Itraconazole Voriconazole

 

0.125 1 0.125 4 0.125 2

 

0.25

0.5

0.5

1

0.25

0.5

Amphotericin-

 

resistant A. fumagitus (n=15)

Itraconazole

0.25 0.5 0.25 1

 

0.25

0.5

Voriconazole

0.25

1

Itraconazole-

 

resistant A. fumigatus (n=15)

Amphotericin B Voriconazole

 

0.25

1

0.5

0.5

0.25

1

0.5

1

Part III: Selected Antimicrobial agents