May 19, 2010 — Resistance to antibiotics prescribed in primary care may last up to 12 months, according to the results of a study reported Online First May 19 in the BMJ. An accompanying analysis and editorial point out the need to develop new antibiotics while conserving those that are currently available.

"In general practice, there are concerns that some common infections are becoming increasingly difficult to treat and that illnesses due to antibiotic resistant bacteria may take longer to resolve," write Céire Costelloe from the University of Bristol, Bristol, United Kingdom, and colleagues. "Some antimicrobial resistance may result from indiscriminate or poor use of antibiotics. In response, initiatives at the local, national, and international levels are trying to promote 'antibiotic stewardship,' with the goal of improving the appropriateness of antimicrobial use."

The goal of this systematic literature review and meta-analysis was to study the development of subsequent antibiotic resistance in patients prescribed antibiotics in primary care. Using MeSH terms and text words to electronically search MEDLINE, EMBASE, and Cochrane, the investigators identified 4373 pertinent observational and experimental studies. Two independent reviewers evaluated the quality of eligible studies and extracted data. For studies presenting similar outcomes, meta-analyses were performed.

Of 24 studies selected for review, 22 were of patients with symptomatic infection and 2 were of healthy volunteers. There were 5 randomized trials, as well as 19 observational studies, of which 2 were prospective.

In 5 studies of urinary tract bacteria enrolling a total of 14,348 participants, the pooled odds ratio (OR) for resistance was 2.5 (95% confidence interval [CI], 2.1 - 2.9) within 2 months of antibiotic treatment and 1.33 (95% CI, 1.2 - 1.5) within 12 months. In 7 studies of respiratory tract bacteria enrolling a total of 2605 participants, pooled ORs for the same periods, respectively, were 2.4 (95% CI, 1.4 - 3.9) and 2.4 (95% CI, 1.3 - 4.50).

Longer duration of antibiotic use and multiple courses prescribed were associated with higher rates of resistance, based on studies reporting these variables. Studies comparing different antibiotics for their potential to cause resistance showed no consistent effects. For amoxicillin and trimethoprim, there was evidence of a dose-response relationship.

There was only 1 prospective study in which changes in resistance were reported during a long period. In this study, pooled ORs decreased from 12.2 (95% CI, 6.8 - 22.1) at 1 week to 6.1 (95% CI, 2.8 - 13.4) at 1 month, 3.6 (95% CI, 2.2 - 6.0) at 2 months, and 2.2 (95% CI, 1.3 - 3.6) at 6 months.

"Individuals prescribed an antibiotic in primary care for a respiratory or urinary infection develop bacterial resistance to that antibiotic," the study authors write. "The effect is greatest in the month immediately after treatment but may persist for up to 12 months. This effect not only increases the population carriage of organisms resistant to first line antibiotics, but also creates the conditions for increased use of second line antibiotics in the community."

Limitations of this meta-analysis include those of the included studies, possible reverse causality and confounding, heterogeneity between studies, and possible publication bias.

"Our findings also provide evidence to support the Standing Medical Advisory Committee report recommendations that the fewest number of antibiotic courses should be prescribed for the shortest period possible," the study authors conclude. "And they draw attention to the increased risk of resistance to commonly used first line antibiotics: if a patient has received one or more courses of such antibiotics in the previous 12 months and further antibiotic treatment is necessary, for a subsequent respiratory or urinary infection, consideration should be given to choosing a different antibiotic. This final implication serves to highlight that the only way to avoid the vicious cycle of resistance leading to the ever greater use of more powerful broad spectrum antibiotics is to avoid their initial use whenever possible."

Analysis and Editorial: New Antibiotics Needed

An accompanying analysis by Chantal M. Morel, from London School of Economics and Political Science in London, United Kingdom, and Elias Mossialos, from European Observatory on Health Systems and Policies in London, encourage development of new antibiotics effective against multidrug-resistant bacteria. They suggest that financial incentives could facilitate such antibiotic development, and highlight several strategies for these incentives, including partnerships between industry and academic institutions.

"In view of the rapid growth of antibiotic resistance among Gram negative pathogens, the intricacies of the antibiotics market, and the cost savings from improved treatment, there is a public health as well as economic justification for intervention," Drs. Morel and Mossialos write. "Incentives to develop new antibiotics should be designed with some early funding to ignite interest and appropriate rewards for the high risks of research and development. Such action needs to be accompanied by parallel efforts to redress and dismantle incentive structures that lead to overuse of antibiotics, which is currently fuelling the spread of resistant bacteria."

An accompanying editorial by Anthony So, from Terry Sanford School of Public Policy at Duke University in Durham, North Carolina, and colleagues also urges economic strategies to promote development of new antibiotics, as well as policies to conserve existing antibacterial drugs.

"Today's dearth in the antibacterial research and development pipeline will take decades to reverse," the editorialists write. "Proof that antibiotic prescribing contributes to resistance in the individual patient and not just at the societal level is the kind of evidence that needs to be communicated to clinicians. ... Nothing less than the future of medicine, from organ transplants to chemotherapy, is at stake, and there will be no second chances."

The University of Bristol and the University of Oxford both received a proportion of their funding from the Department of Health's NIHR School for Primary Care Research. The views expressed in the meta-analysis and review publication are those of the authors and not necessarily those of the Department of Health.

Some of the study authors have disclosed various financial relationships with the University of Bristol and/or the University of Oxford. The authors of the analysis and the editorialists have disclosed no relevant financial relationships.

BMJ. Published online May 19, 2010.

Additional Resource

The Centers for Disease Control and Prevention has published online a progress report on ways to combat antimicrobial resistance.

Clinical Context

Study Highlights

• The investigators searched MEDLINE (1955 to May 2009), EMBASE (1980 to May 2009), Cochrane, and reference lists.
• Inclusion criteria were observational and experimental studies that assessed the link between primary care prescribed antibiotics and antimicrobial resistance in bacteria sampled from any anatomic site at the individual level.
• Exclusion criteria were nonoriginal research, ecologic studies, and studies of antibiotics not prescribed in primary care.
• 24 studies were identified.
• The subjects were 15,505 adults and 12,103 children.
• 22 studies assessed symptomatic infection: 7 studies on urinary tract infection, 7 studies on respiratory tract infection, 2 on otitis media, 1 on chronic obstructive pulmonary disease, 4 on methicillin-resistant Staphylococcus aureus, and 1 on trachoma.
• 2 studies assessed healthy adult volunteers.
• Antibiotics included macrolides in 8 studies, penicillins in 5 studies, sulphonamides and trimethoprim in 6 studies, cephalosporins in 6 studies, tetracyclines in 2 studies, quinolones in 2 studies, nalidixic acid in 1 study, metronidazole in 1 study, nitrofurantoin in 1 study, and any antibiotic in 7 studies.
• The timing between antibiotic use and measurement of resistance ranged from 2 to 104 weeks.
• 5 studies were randomized trials, 17 were retrospective observational studies, and 2 were prospective observational studies.
• Meta-analysis included studies that met at least 3 of 5 quality criteria: reliable measure of antibiotic exposure, reliable measure of resistance, unbiased control selection, incident case identification, and adjustment for major confounders.
• Primary outcome measure was the OR of antibiotic resistance in patients exposed to antibiotics vs those who were not exposed to antibiotics.
• Meta-analysis of 5 studies of urinary tract bacteria in 14,348 subjects showed greater antibiotic resistance after antibiotic exposure vs no antibiotic exposure at all time points, with decreased resistance with time:
  • 0 to 1 month (OR, 4.40)
  • 0 to 2 months (OR, 2.5)
  • 0 to 3 months (OR, 2.48)
  • 0 to 6 months (OR, 2.18)
  • 0 to 12 months (OR, 1.33)
• Meta-analysis of 7 studies of respiratory tract bacteria in 2605 subjects showed greater antibiotic resistance after antibiotic exposure vs no antibiotic exposure, which was stronger at certain intervals:
  • 0 to 1 month (OR, 2.10)
  • 0 to 2 months (OR, 2.37)
  • 0 to 3 months (OR, 1.48)
  • 0 to 6 months (OR, 1.90)
  • 0 to 12 months (OR, 2.37)
• 1 prospective study of respiratory tract bacteria found that children treated with amoxicillin vs those not treated with amoxicillin had an increased mean inhibitory concentration for ampicillin (9.2 vs 2.7 μg/mL) and an increased risk of Haemophilus isolates possessing ICEHin1056 homologues (67% vs 36%).
• 1 randomized controlled trial of respiratory tract bacteria showed that resistance decreased as time increased from 1 week (OR, 12.2), to 1 month (OR, 6.1), to 2 months (OR, 3.6), and to 6 months (OR, 2.2).
• Higher resistance rates were linked with longer duration of antibiotic treatment and 3 or more antibiotic courses.
• Meta-analysis of 3 studies of methicillin-resistant S aureus in skin lesions found an OR of 1.04 for antibiotic exposure in the prior 12 months.
• Limited data showed that different classes of antibiotics did not appear to be linked to resistance rates.
• Study limitations were publication bias in the urinary bacterial studies and study heterogeneity (including differences in populations and definition of resistance).

Clinical Implications

• Individuals who receive antibiotic treatment of respiratory tract or urinary tract infection develop antibiotic resistance, which is greatest in the first month but can persist for 12 months.
• Antibiotic resistance is linked with longer duration and multiple courses of antibiotics. Limited data show that antibiotic resistance is not linked with a particular antibiotic class.