What intervention on the use or dosing of antibiotics work to decrease resistance? Jan. 18, 2007 Sung-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 AntibioticDepartmental consumption b Prior specific antibiotic c Prior treatment with any other antibiotic c Gentamicin1.03 (0.70–1.50)2.12 (1.29–3.48)1.81 (1.40–2.33) Amikacin1.80 (1.00–3.24)2.40 (1.31–4.40)1.31 (1.49–2.20) Cefuroxime1.12 (1.01–1.23)3.24 (1.97–5.34)2.77 (1.99–3.87) Ceftazidime1.45 (1.19–1.76)3.88 (1.89–7.97)1.55 (1.18–2.04) Ciprofloxacin d 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 campaign HELENA SEPPALA, et al. NEJM 1997 Intervention In 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 remained 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 usage White AC, CID, 1997 Prior authorization –Ben Taub General Hospital is a 575-bed urban teaching hospital in Houston. –Enforcement of the prior-authorization requirement began on 1 January –Intravenous amikacin, ceftazidime, ciprofloxacin, fluconazole, ofloxacin, and ticarcillin/clavulanate. –Faculty of the Infectious Diseases Service, Department of Medicine, were available 24 hours a day to provide antibiotic approval

Restriction of usage White 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 Need staffs support Restriction of usage White AC, CID, 1997

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

Single switch Kollef 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 pneumonia (VAP) –nosocomial bacteremia Study design: –before(6 months) Vs. after (6 months)

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

Before-after design Ceftazidime related drug resistance change 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 cycling Raymond DP, et al. Crit Care Med 2001

Routine cycling

Agent A Agent B Time Resistance Limitation: 1.Short follow up time 2.Different patients population in the before-after setting CiproxinTazocincarbapenemcefepime

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 exposure 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 the 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 design Ramsay 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