Statistical Methods in Medical Research.

Greater use of antibiotics during the past 50 years has exerted selective pressure on susceptible bacteria and may have favoured the survival of resistant strains. Existing information on antibiotic resistance patterns from pathogens circulating among community-based patients is substantially less than from hospitalized patients on whom guidelines are often based. We therefore chose to assess the relationship between the antibiotic resistance pattern of bacteria circulating in the community and the consumption of antibiotics in the community. Both gray literature and published scientific literature in English and other European languages was examined. Multiple regression analysis was used to analyse whether studies found a positive relationship between antibiotic consumption and resistance. A subsequent meta-analysis and meta-regression was conducted for studies for which a common effect size measure (odds ratio) could be calculated. Electronic searches identified 974 studies but only 243 studies were considered eligible for inclusion by the two independent reviewers who extracted the data. A binomial test revealed a positive relationship between antibiotic consumption and resistance (p < .001) but multiple regression modelling did not produce any significant predictors of study outcome. The meta-analysis generated a significant pooled odds ratio of 2.3 (95% confidence interval 2.2 to 2.5) with a meta-regression producing several significant predictors (F(10,77) = 5.82, p < .01). Countries in southern Europe produced a stronger link between consumption and resistance than other regions. Using a large set of studies we found that antibiotic consumption is associated with the development of antibiotic resistance. A subsequent meta-analysis, with a subsample of the studies, generated several significant predictors. Countries in southern Europe produced a stronger link between consumption and resistance than other regions so efforts at reducing antibiotic consumption may need to be strengthened in this area. Increased consumption of antibiotics may not only produce greater resistance at the individual patient level but may also produce greater resistance at the community, country, and regional levels, which can harm individual patients.

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A systematic review and meta-analysis of the effects of antibiotic consumption on antibiotic resistance

In 1990 it was estimated that 4123 million of the world's 5267 million population—78%—lived in developing countries. Of the 39.5 million deaths in the developing world, 9.2 million were estimated to have been caused by infectious and parasitic disease; infections of the lower respiratory tract were the third most common cause of death worldwide, and diarrhoeal diseases were the fourth.1 Ninety eight per cent of deaths in children occur in the developing world, mostly as a result of infections.

Projections of disability adjusted life years (that is, the years of life without disability) for the year 2020 show great improvement in developing regions: people are living longer without disabilities.2 However, even the most pessimistic model analysed did not take into account the possibility that the development of new antimicrobial drugs might slow or cease, and that rates of drug resistance in bacteria such as pneumococci, Mycobacterium tuberculosis , or Staphylococcus aureus might increase. We chart the progress and impact of bacterial resistance to antimicrobial drugs in the developing world. The information in this review has been assembled from searches of the computerised databases Medline and Bath Information and Data Services, discussions with colleagues, and personal knowledge.

#### Summary points

Although even the most potent and recently developed antimicrobial drugs are available throughout the world, …

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Antimicrobial resistance in developing countries.

The global problem of antimicrobial resistance is particularly pressing in developing countries, where the infectious disease burden is high and cost constraints prevent the widespread application of newer, more expensive agents. Gastrointestinal, respiratory, sexually transmitted, and nosocomial infections are leading causes of disease and death in the developing world, and management of all these conditions has been critically compromised by the appearance and rapid spread of resistance. In this first part of the review, we have summarised the present state of resistance in these infections from the available data. Even though surveillance of resistance in many developing countries is suboptimal, the general picture is one of accelerating rates of resistance spurred by antimicrobial misuse and shortfalls in infection control and public health. Reservoirs for resistance may be present in healthy human and animal populations. Considerable economic and health burdens emanate from bacterial resistance, and research is needed to accurately quantify the problem and propose and evaluate practicable solutions. In part II, to be published next month, we will review potential containment strategies that could address this burgeoning problem.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(05)70189-4.pdf

Antimicrobial resistance in developing countries. Part I: recent trends and current status

Objective. To test whether an educational outreach intervention for families and physicians, based on the Centers for Disease Control and Prevention (CDC) principles of judicious antibiotic use, decreases antimicrobial drug prescribing for children younger than 6 years old. Setting. Twelve practices affiliated with 2 managed care organizations (MCOs) in eastern Massachusetts and northwest Washington State. Patients. All enrolled children younger than 6 years old. Methods. Practices stratified by MCO and size were randomized to intervention or control groups. The intervention included 2 meetings of the practice with a physician peer leader, using CDC-endorsed summaries of judicious prescribing recommendations; feedback on previous prescribing rates were also provided. Parents were mailed a CDC brochure on antibiotic use, and supporting materials were displayed in waiting rooms. Automated enrollment, ambulatory visit, and pharmacy claims were used to determine rates of antibiotic courses dispensed (antibiotics/person-year) during baseline (1996–1997) and intervention (1997–1998) years. The primary analysis (for children 3 to Results. The practices cared for 14 468 and 13 460 children in the 2 study years, respectively; 8815 children contributed data in both years. Sixty-two percent of antibiotic courses were dispensed for otitis media, 6.5% for pharyngitis, 6.3% for sinusitis, and 9.2% for colds and bronchitis. Antibiotic dispensing for children 3 to Conclusions. A limited simultaneous educational outreach intervention for parents and providers reduced antibiotic use among children in primary care practices, even in the setting of substantial secular trends toward decreased prescribing. Future efforts to promote judicious prescribing should continue to build on growing public awareness of antibiotic overuse.

Reducing antibiotic use in children: a randomized trial in 12 practices.

Context.—The spread of drug-resistant Streptococcus pneumoniae in the community is a public health problem in developed and developing
nations, but whether antibiotic use is responsible for the increase in drug
resistance is not known.Objective.—To analyze the relationship between penicillin-resistant S pneumoniae (PR Sp) pharyngeal carriage and
characteristics of β-lactam use.Design.—Observational study of children attending 20 randomly sampled schools.Setting.—The Loiret, in the center of France.Participants.—A total of 941 children, 3 to 6 years old.Main Outcome Measure(s).—Pharyngeal carriage of S pneumoniae, antibiotic
use, and medical events during the preceding 30 days. Pneumococcal penicillin
G sodium minimal inhibitory concentrations and serotyping were performed.Results.—Medical illnesses and the use of antibiotics were not associated with
PR Sp carriage. However, oral β-lactam use was
associated with an increased risk of PR Sp carriage
(odds ratio [OR], 3.0; 95% confidence interval [CI], 1.1-8.3; P=.03). Children treated by low daily doses of an oral β-lactam
(defined as lower than clinical recommendations) had an increased risk of
PR Sp carriage, as compared with children who did
not (OR, 5.9; 95% CI, 2.1-16.7; P =.002). A treatment
of long duration (>5 days) with a β-lactam was associated with an increased
risk of PR Sp carriage (OR, 3.5; 95% CI, 1.3-9.8; P=.02).Conclusions.—Our results suggest that a low daily dose and a long duration of treatment
with an oral β-lactam contribute to the selective pressure in promoting
pharyngeal carriage of PR Sp.

https://jamanetwork.com/journals/jama/articlepdf/187207/joc6b29.pdf

Pierre Geslin

Papers

Low Dosage and Long Treatment Duration of β-Lactam: Risk Factors for Carriage of Penicillin-Resistant Streptococcus pneumoniae