1 Wellcome Trust/Kenya Medical Research Institute (KEMRI), Centre for Geographic Medicine Research Coast, PO Box 230, Kilifi, Kenya; 2 Nuffield Department of Clinical Medicine, Oxford University, John Radcliffe Hospital, Oxford, UK; 3 Department of Academic Paediatrics, Imperial College, London, UK; 4 Department of Paediatrics, University of Oxford, John Radcliffe Hospital, Oxford, UK
Received 14 February 2005; returned 23 March 2005; revised 25 March 2005; accepted 5 April 2005
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Abstract |
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Methods: We used Etest to study antibiotic susceptibility patterns of 90 Gram-negative bacilli cultured in blood or CSF from paediatric inpatients over 8 years.
Results: Susceptibility to amoxicillin 28%, cefotaxime 95% and ciprofloxacin 99% did not vary significantly with age. Susceptibilities for isolates from children aged less than 14 days were: chloramphenicol, 81%; trimethoprim/sulfamethoxazole, 71%; and gentamicin, 91%. From older children, susceptibilities were: chloramphenicol, 62%; trimethoprim/sulfamethoxazole, 39%; and gentamicin, 73%. Chloramphenicol susceptibility was significantly more common among non-typhi salmonellae than other species (79% versus 53%, P<0.0005). The combination of gentamicin and chloramphenicol covered 91% of all isolates. The prevalence of resistance did not increase over time and was not more common in patients with HIV or malnutrition. Age was the only clinical feature that predicted resistance.
Conclusions: Gentamicin or chloramphenicol alone was suboptimal therapy for Gram-negative sepsis, although in this retrospective study, there was no association between resistance and mortality.
Keywords: antibiotic resistance , Gram-negative infections , developing countries , mortality , children
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Introduction |
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In sub-Saharan Africa, the data are patchy. Across five sites in sub-Saharan Africa, resistance to ampicillin and trimethoprim/sulfamethoxazole was almost universal, but susceptibility to chloramphenicol and sometimes gentamicin appeared preserved.39
The objective of this study was to determine the pattern of resistance among Gram-negative bacilli causing invasive bacterial disease for the antibiotics in common use in Kilifi, Kenya and for two potential alternatives; ciprofloxacin and cefotaxime.
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Patients and methods |
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The study population comprised stored frozen isolates of Gram-negative bacilli cultured from blood or cerebrospinal fluid taken from paediatric inpatients at Kilifi District Hospital (KDH), Kenya, isolated between 1 January 1994 and 31 December 2001. KDH is a rural, government-funded hospital with 42 paediatric beds and an average of 4400 admissions per year. Before August 1998, cultures of CSF and blood were initiated on clinical suspicion of meningitis or sepsis; thereafter all acute admissions, except trauma and burns, were investigated with blood cultures.
Treatment of inpatients at KDH is based on WHO guidelines. Young infants 60 days are treated with benzylpenicillin and gentamicin. Older children with suspected meningitis or shock are given benzylpenicillin and chloramphenicol. Amoxicillin or benzylpenicillin is prescribed alone to treat mild or severe pneumonia, respectively; in those with prostration or pulse oximetry readings below 90%, chloramphenicol is substituted. Gentamicin and amoxicillin are used in malnutrition. Trimethoprim/sulfamethoxazole is the commonest outpatient antibiotic in Kilifi District, but is not used for inpatients.
Laboratory methods
Before June 1998, brain heart infusion broth was used to culture blood for 7 days at 37°C in 5% CO2 with sub-cultures at 1, 2 and 7 days. Subsequently, BacTec Peds Plus media (Becton Dickinson, NJ, USA) were incubated for 5 days and sub-cultured as indicated by the BacTec instrument.
Isolates were stored at 70°C in tryptone soya broth with 15% glycerol for up to 8 years. Antimicrobial susceptibilities were determined by Etest in the laboratories of the manufacturer (AB Biodisk, Solna, Sweden).
Data analysis
STATA 8.2 (StataCorp, College Station, TX, USA) was used. Susceptibility breakpoints were taken from the NCCLS guidelines 2003.2 2 was used to test hypotheses of association. Logistic regression models were developed with backward stepwise regression, excluding variables when the likelihood ratio test P value was
0.05. Isolate species and source of isolate were included throughout. Intermediate resistance (I) was classified within resistance (R).
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Results |
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Table 1 shows the susceptibility patterns of Gram-negative bacilli to four antibiotics that are in frequent use at KDH. Resistance was common, except for two antibiotics that are rarely used in Kilifi: ciprofloxacin and cefotaxime. Non-typhi salmonellae were significantly more susceptible to chloramphenicol than other species (79% versus 53%, P < 0.0005). We calculated the expected cover from combinations of two antibiotics, assuming no synergy or antagonism. Of the commonly available antibiotics, the broadest cover is offered by combining chloramphenicol and gentamicin (91%; 95% CI, 8893%). Amoxicillin and gentamicin would cover 76% (95% CI, 7280%), and amoxicillin and chloramphenicol would cover 65% (95% CI, 6070%).
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Fatal outcome was modelled by logistic regression using 308 patient episodes, including 106 deaths, which had complete data for the explanatory variables HIV status, sex, age and malnutrition. Odds ratios for resistance to individual antibiotics were derived within sub-populations that were likely to have been exposed to the drug according to hospital- and community-based protocols. After excluding neonates (age <28 days), adding terms for trimethoprim/sulfamethoxazole resistance or amoxicillin resistance gave odds ratios of 2.01 (P=0.11) or 0.87 (P=0.75), respectively. For older children without malnutrition (n=132), the odds ratio for chloramphenicol resistance was 2.79 (P=0.15). In malnourished children and neonates, gentamicin resistance was not associated with mortality (OR=1.4, P=0.53, n=214).
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Discussion |
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Resistance to amoxicillin, chloramphenicol, trimethoprim/sulfamethoxazole and gentamicin is common, but the situation is not getting worse. The small improvement in susceptibility in the second half of the study period might be explained by sampling all children, including those with milder disease who are less likely to have received antibiotics before presentation. Secondly, the BacTec Peds Plus media used in the latter half might better support growth of antibiotic exposed organisms, increasing the frequency of susceptible isolates. Within the period 19982001, there was no trend of increasing resistance. The association between a positive malaria slide and isolate susceptibility might reflect prior use of antibiotics and antimalarials before presentation, simultaneously clearing parasites and selecting resistant bacteria.
A significant association was not found between antibiotic resistance and mortality. However, the study was retrospective with reduced numbers after dividing children into groups receiving indicated antibiotics and lacked individual chart review.
Targeting therapy at Gram-negative infections is largely theoretical in the developing world without culture diagnosis, where clinical features determine treatment based on syndromic classification. Analysis of the same inpatient data by syndrome suggests that coverage of WHO recommended antibiotics is in the range 7697%, owing to the preponderance of Gram-positive organisms. A notable exception is malnutrition; where 65% of bacteraemic isolates are Gram-negative.
Alternatives for antibiotic treatment of Gram-negative sepsis in older children include combination therapy with chloramphenicol and gentamicin, or monotherapy with ciprofloxacin or cefotaxime. In vitro studies and animal models show potential antagonism between gentamicin and chloramphenicol,10 but clinical data suggesting worse outcomes from this or similar antibiotic interactions are not available. More broadly effective antibiotics would increase per-patient costs for a 15 kg child treated parenterally for 7 days from 38 cents and $2.30 for gentamicin and chloramphenicol to $108 or $73 for cefotaxime or ciprofloxacin (2 days parenteral, then oral therapy).
Ultimately, therapeutic decisions in any region should not be determined by data from a single site, yet in Africa there is no functioning mechanism to aggregate data from several sites and determine a regional response. Continent-wide networks, such as the WHO network for antimicrobial surveillance (WHONET) and the WHO paediatric bacterial meningitis surveillance project (WHO-AFRO PBM) provide a forum and limited funding for sentinel surveillance but considerable investment in the culture and infrastructure of antimicrobial surveillance, data aggregation and policy response is required. Finally, given the uncertain predictive value of in vitro testing, therapeutic recommendations requiring increased costs would be best guided by prospective clinical trials.
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Acknowledgements |
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References |
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