BMJ  2008;336:948-949 (26 April), doi:10.1136/bmj.39520.680718.94 (published 8 April 2008)

Making a Difference

Drug Resistant Infections in Poor Countries

A major burden on children

¹ Department of Paediatrics and Child Health, The Aga Khan University, Karachi, Pakistan

Resistance to drugs in many common childhood infections is a growing problem in the developing world, says Zulfiqar Bhutta. Effective programmes to combat resistance are within reach in developing countries, argue Ralph Gonzales and colleagues (doi: 10.1136/bmj.39534.553044.94), but we must move swiftly

Around the world an estimated 10 million children under the age of 5 years die each year, the vast majority (90%) in a mere 42 countries.¹ Of the major causes of death among children, infections such as newborn sepsis, diarrhoeal disorders, pneumonia, meningitis, and malaria are major killers. While much is known about the role that poor availability of interventions has in childhood morbidity and mortality in developing countries, much less is known about the contribution of antimicrobial resistance—but it is likely that the contribution of resistant infections is significant. In a prospective study of 1828 children with signs of systemic infections in Tanzania,² the mortality from Gram negative bloodstream infection (44% of the deaths) was more than double that from malaria (20%) and Gram positive bloodstream infections (17%), and antimicrobial resistance was found to be a significant risk factor for mortality. A literature review has underscored the importance of hospital acquired resistant bacterial infections among newborn infants in developing countries.³

The emergence of antimicrobial resistance is recognised as a major contributor to excess morbidity and healthcare costs in developed countries. In poorer countries, limited laboratory facilities and the lack of robust, population based surveillance systems has meant that information on the effect of antimicrobial resistance on health outcomes is restricted to a small number of infections. Emerging drug resistance in malaria, recognised for many years, has now resulted in many traditional drugs such as chloroquine becoming completely ineffective. An evaluation of trends in malaria treatment in sub-Saharan Africa has shown that continuing use of ineffective chloroquine treatment has contributed to excess malaria mortality.⁴ The case fatality rate for malaria fell as an increasing proportion of children received an effective treatment regimen: adjusted malaria case fatality rates were 5.1% in 1992 and 3.3% in 1994, and the corresponding percentages of children who received effective therapy were 85% in 1992 and 97% in 1993-4.

The increasing resistance of Streptococcus pneumoniae and Haemophilus influenzae to drugs has an effect on pneumonia mortality that is less well recognised, largely because of the difficulty in isolating the organisms from the bloodstream. In a prospective study of children in 5000 Bangladeshi urban households who had invasive pneumococcal disease, the incidence of the disease was 447 episodes per 100 000 child years, and the rates of resistance to penicillin, co-trimoxazole, chloramphenicol, and ciprofloxacin were, respectively, 3%, 82%, 15%, and 24%.⁵ Such evidence of the failure of co-trimoxazole has led to the recommendation to use amoxicillin to treat pneumonia in primary care settings,⁶ but as yet few health systems in the poorest countries have the extra funds needed to implement these recommendations widely. This is akin to the need for combination therapy for effective malaria treatment and to second line treatment for drug resistant tuberculosis in children,⁷ both looming realities in public health systems in sub-Saharan Africa. In South and South East Asia a major burden of childhood bacteraemic infections is related to typhoid fever, as well as the infections listed above. Over the last two decades the prevalence of multidrug resistant typhoid has steadily increased in Asia, and with the widespread use of generic ciprofloxacin and cephalosporins resistance to these second line antibiotics has steadily grown.⁸ Increasing antimicrobial resistance results in a much higher economic burden on the health systems of poor countries, because of the higher likelihood of treatment failure and of complications associated with such infections.⁹

Several factors are associated with the rise of resistance to common infections in developing countries, including the global spread of drug resistant clones as travel becomes easier and local antimicrobial pressure on common organisms. This second factor may be related to inappropriate prescribing of antibiotics, the unregulated availability over the counter of these drugs, and (for reasons of affordability) inappropriate dosages and duration of treatment. Increasing public awareness, improving standards of care, and the appropriate regulation of the use of such antimicrobials are all important steps. A recent evaluation of the effect of the Swedish national programme for the surveillance of antibiotic use and resistance and the implementation of rational antibiotic use showed that antibiotic use among outpatients fell from 15.7 defined daily doses per 1000 people in 1995 to 12.6 per 1000 in 2004.¹⁰ The largest reduction (by 52%) was noted in children, with no measurable negative consequences on admission rates for common upper respiratory infections. However, examples of successful application of such interventions in developing countries are few.

What are the main challenges with regard to antimicrobial resistance in common childhood infections in developing countries? We need better information systems defining the magnitude of the problem and training programmes to optimise treatment with antibiotics. Given that we need to balance antibiotic "access" as well as "excess," measures to regulate antibiotic availability must be accompanied by strengthening workforce capacity and drug supplies in dysfunctional health systems. The crisis of increasing antimicrobial resistance to serious and common childhood bacterial infections is a reality in developing countries, and solutions are urgently needed.

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Competing interests: None declared.

Provenance and peer review: Commissioned; not externally reviewed.

References

1. Jones G, Steketee RW, Black RE, Bhutta ZA, Morris SS; Bellagio Child Survival Study Group. How many child deaths can we prevent this year? Lancet 2003;362:65-71.[CrossRef][ISI][Medline]
2. Blomberg B, Manji KP, Urassa WK, Tamim BS, Mwakagile DS, Jureen R, et al. Antimicrobial resistance predicts death in Tanzanian children with bloodstream infections: a prospective cohort study. BMC Infect Dis 2007;7:43.[CrossRef][Medline]
3. Zaidi AK, Huskins WC, Thaver D, Bhutta ZA, Abbas Z, Goldmann DA. Hospital-acquired neonatal infections in developing countries. Lancet 2005;365:1175-88.[CrossRef][ISI][Medline]
4. Zucker JR, Ruebush TK 2nd, Obonyo C, Otieno J, Campbell CC. The mortality consequences of the continued use of chloroquine in Africa: experience in Siaya, western Kenya. Am J Trop Med Hyg 2003;68:386-90.[Abstract/Free Full Text]
5. Brooks WA, Breiman RF, Goswami D, Hossain A, Alam K, Saha SK, et al. Invasive pneumococcal disease burden and implications for vaccine policy in urban Bangladesh. Am J Trop Med Hyg 2007;77:795-801.[Abstract/Free Full Text]
6. Bhutta ZA. Dealing with childhood pneumonia in developing countries: how can we make a difference? Arch Dis Child 2007;92:286-8.[Free Full Text]
7. Sneag DB, Schaaf HS, Cotton MF, Zar HJ. Failure of chemoprophylaxis with standard antituberculosis agents in child contacts of multidrug-resistant tuberculosis cases. Pediatr Infect Dis J 2007;26:1142-6.[ISI][Medline]
8. Capoor MR, Rawat D, Nair D, Hasan AS, Deb M, Aggarwal P, et al. In vitro activity of azithromycin, newer quinolones and cephalosporins in ciprofloxacin-resistant Salmonella causing enteric fever. J Med Microbiol 2007;56:1490-4.[Abstract/Free Full Text]
9. Bhutta ZA, Ali SR. Reducing antibiotics not enough to stem resistance. Science and Development Network. www.scidev.net/en/opinions/reducing-antibiotics-not-enough-to-stem-resistance.html.
10. Mölstad S, Erntell M, Hanberger H, Melander E, Norman C, Skoog G, et al. Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme. Lancet Infect Dis 2008;8:125-32.[CrossRef][ISI][Medline]

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