What intervention on the use or dosing of antibiotics work to

decrease resistance?

Jan. 18, 2007Sung-Ching Pan

Antibiotics control strategies

Conan MacDougall and Ron E. Polk, CLINICAL MICROBIOLOGY REVIEWS, 2005

Mutation prevention

dose

Agriculture use

Combination therapy

Antibiotics control

• Relationship between antibiotics usage and resistance– Ecological study

• Penicillin use and penicillin resistant S. pneumononas (PRSP)

• Antibiotics use (3rd cephalosporin, macrolide and fluroquilolone) and MRSA

Antibiotics control

• Relationship between antibiotics usage and resistance– Individual study

Antibiotic Departmental consumptionb Prior specific antibioticc Prior treatment with any other antibioticc

Gentamicin 1.03 (0.70–1.50) 2.12 (1.29–3.48) 1.81 (1.40–2.33)

Amikacin 1.80 (1.00–3.24) 2.40 (1.31–4.40) 1.31 (1.49–2.20)

Cefuroxime 1.12 (1.01–1.23) 3.24 (1.97–5.34) 2.77 (1.99–3.87)

Ceftazidime 1.45 (1.19–1.76) 3.88 (1.89–7.97) 1.55 (1.18–2.04)

Ciprofloxacind 1.06 (0.57–1.97) 4.05 (2.00–8.21) 1.27 (0.62–2.70)

Leibovici et al. J Antimicrob Chem, 2001

Antibiotics control

• Relationship between antibiotics usage and resistance- Temporal sequence?– Intervention-change– Discontinue intervention-reverse

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Mutation prevention dose• Control use in agriculture

Education campaignHELENA SEPPALA, et al. NEJM 1997

InterventionIn the

end1991

*Physicians were reached mainly through the Finnish Medical Journal and lectures at national and local meetings for general practitioners.

Limitations

• Ecological study, hard to control confounding

• After the intervention stop, what will happen?

• The problem of this strategy: Decrease use of macrolide, but increase use of other antibiotics, other resistance?– “the total rate of use of antimicrobial agents re

mained unchanged”

Education campaign (hospital/individual level)

• Some researches study the behavior change of antibiotics prescription after education campaign

• Education campaign- antibiotics resistance?

• Publication bias?• Combination with other infection control

strategies

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Mutation prevention dose• Control use in agriculture

Restriction of usageWhite AC, CID, 1997

• Prior authorization– Ben Taub General Hospital is a 575-bed urban teachi

ng hospital in Houston.– Enforcement of the prior-authorization requirement be

gan on 1 January 1994.– Intravenous amikacin, ceftazidime, ciprofloxacin, fluco

nazole, ofloxacin, and ticarcillin/clavulanate.– Faculty of the Infectious Diseases Service, Departme

nt of Medicine, were available 24 hours a day to provide antibiotic approval

Restriction of usageWhite AC, CID, 1997

• Limitation:– Before –after study– Other intervention? in-service programs for surgical ICU staff on

hand washing in November 1993 and July and August 1994.

• Need staffs support

Restriction of usageWhite AC, CID, 1997

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Mutation prevention dose• Control use in agriculture

Single switchKollef MH, et al. AMm J Respir Crit Care Med, 1997

• Switch of empirical for nosocomial pneumonia in ICU from ceftazidime to ciproxin

• Primary outcome: – incidence of ventilator-associated pneumo

nia (VAP)– nosocomial bacteremia

• Study design: – before(6 months) Vs. after (6 months)

Single switchKollef MH, et al. AMm J Respir Crit Care Med, 1997

Single switchKollef MH, et al. AMm J Respir Crit Care Med, 1997

• Before-after design• Ceftazidime related drug resistance chang

e did not clarified– Ceftazidime resistant P. aeruginosa– ESBL K. pneumonia or E.coli

• Problem with this strategy:– How about drug resistance to ciproxin?

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Mutation prevention dose• Control use in agriculture

Routine cyclingRaymond DP, et al. Crit Care Med 2001

Routine cycling

Routine cycling

Agent A Agent A Agent AAgent B Agent B Agent B

Time

Resistance

Limitation:

1. Short follow up time

2. Different patients population in the before-after setting

Ciproxin Tazocin carbapenem cefepime

Routine cycling

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Mutation prevention dose• Control use in agriculture

Combination therapy

• β-lactams+ aminoglycoside:– Pseudomonas

• Carbapemen+aminoglycoside– MDR Acinectobacter baumanii

• Work for therapeutic goal, but for resistance?

Combination therapy El Amari EB, et al. CID 2001

• Case-control study • Influence of previous exp

osure to antibiotic therapy on the susceptibility pattern of Pseudomonas aeruginosa bacteremic isolates

• piperacillin, ceftazidime, imipenem, ciprofloxacin, or aminoglycosides

Combination therapy (meta-analysis of RCT)Bliziotis IA, CID 2005

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Mutation prevention dose• Control use in agriculture

Concentration dependent Vs. Time dependent

The emergence of resistance

Mutation prevention concentration

• Describes the antibacterial concentration that inhibits the growth of the least-susceptible, single step mutant;

• The MIC of the least susceptible organism• There is a low likelihood for spontaneous

mutant formation at or above the MPC.

Mutation prevention concentration

• Limitation on clinical use– MPCs differ among th

e various fluoroquinolones against different pathogens

– the MPC for each antibacterial agent is dependent on the genotypic profile of the organism.

KD2138: parC

KD2139: gyrA

Antibiotics control

• Education campaign• Restriction of usage• Single switch/ antibiotics cycling• Combination therapy• Pk/Pd, Mutation prevention dose• Control use in agriculture

Agriculture use regulation

Antibiotics

resistance

Animal pathogen

Human pathogen

Study designRamsay CE, J. Antimicrob. Chemother, 2003

• Review of 306 studies of interventions to improve antimicrobial prescribing in hospitals, 70% did not meet the minimum criteria of the Cochrane Collaboration’s Effective Practice and Organization of Care Group.

• The most commonly excluded studies were those using uncontrolled before- and-after designs (46%) or inadequate interrupted time series analysis (24%).

Study design

• Interrupted time series with segmented regression: a method of analysis applied to before-and-after quasi-experimental study designs

Study design

• Mathematic modeling:– While a long-term follow up is needed for

before-and-after quasi-experimental study designs

– Control confounding