JAC Advance Access originally published online on June 1, 2007
Journal of Antimicrobial Chemotherapy 2007 60(1):194-197; doi:10.1093/jac/dkm133
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Correspondence |
Reversibility of antimicrobial resistance in respiratory isolates in HIV-positive Cambodian children after 36 months of HAART
1 House of Family Max. Colbe Clinic for Sick Children of St Elizabeth College of Health Sciences, Phnom Penh, Cambodia 2 St Elizabeth College of Health and Social Sciences, Bratislava, Slovak Republic 3 National Reference Laboratory of Testing of Antimicrobial Resistance, University Hospital, Nitra, Slovak Republic
* Corresponding author. Tel: +421-2-592-49-586; Fax: +421-2-592-49-607; E-mail: vladimir.krcmery{at}szu.sk
Keywords: antibiotic resistance , MRSA , immune reconstitution
There are few data on the relationship between immune status and highly active antiretroviral therapy (HAART) in children with AIDS and incidence of antimicrobial resistance in opportunistic infections.1,2 Children with HIV, especially with low CD4 cells, have more opportunistic infections and therefore receive more prophylactic/therapeutic antibiotics and may be more colonized/infected with resistant organisms.1,2 However, data related to HAART and colonization or infection with resistant organisms of children living outside the USA and EU are rare.3,4
We carried out a study with Cambodian children to see whether restoration of the immune system after 36 months of treatment with HAART has an impact on antibiotic resistance and its reversibility. Study participants were HIV-positive children treated with HAART (stavudine, lamivudine and nevirapine or efavirenz). Respiratory tract isolates (nose, pharyngeal and ear swabs) from 32 previously antiretroviral therapy-naive children aged 3–11 years were assessed every 3 months within 36 months of HAART. All samples were transported by air in Amyes transport medium (Difco, Vienna) from Phnom Penh within 24 h of sampling to the National Reference Laboratory in Slovakia. Duration of HAART, antitubercular therapy (isoniazid, rifampicin and pyrazinamide) and exposure to antibiotics were correlated with bacterial colonization of respiratory tract isolates and resistance phenotype. We focused on colonization with erythromycin-resistant Streptococcus pyogenes, penicillin-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), ampicillin-resistant Haemophilus influenzae, ampicillin + gentamicin + co-trimoxazole-resistant Escherichia coli, gentamicin + ciprofloxacin + ceftazidime-resistant Klebsiella/Enterobacter spp., gentamicin + ciprofloxacin-resistant Pseudomonas aeruginosa and gentamicin + ceftazidime-resistant Acinetobacter baumannii.
Table 1 shows the relationship between the duration of HAART and colonization with different bacteria. MRSA appeared to emerge after 6–12 months of HAART in comparison with the pre-HAART period (it was 90% to 93% after 9–12 months versus 50% in the HAART-naive, P < 0.01). The proportion of MRSA increased from 50% to 55% in the first 6 months and to 85.7% after 18 months, but then decreased to 51.9% after 36 months of HAART. Reversibility of S. aureus resistance was longer and took approximately 24–36 months. However, the proportion of MRSA among S. aureus increased more rapidly (after 9–18 months of HAART), but after 21 months it decreased. Emergence of MRSA can be explained by the amount of antibiotics administered to children during the first 12 months during their immune restoration, but the marked decrease (reversibility) in resistance after 18–21 months and again after 27–33 months (Figure 1) is difficult to explain. Probably, improvement of cell immunity plays some role in the reversibility of resistance as opportunistic bacterial infections are less frequent and antibiotic therapy is less commonly administered. Emergence of penicillin-resistant pneumococci was slower. Penicillin resistance in pneumococci started to increase very late, after 24 months of HAART (0% at baseline in HAART-naive and about 33 to 7% of all Gram-positive bacteria after 21–36 months of HAART). We expected more rapid development of penicillin resistance in pneumococci, rather than only after 24 months. The presence of multiresistant Klebsiella and Enterobacter spp. was already high at baseline and in the first months of HAART, and the proportion of multiresistant Gram-negative bacteria (MR-GNB) decreased later to 0% and 32% (P < 0.02). It is interesting that despite the high consumption of anti-infective drugs during the first 3–9 months of HAART (all children received within 1–9 months of treatment at least prophylactic doses of co-trimoxazole twice weekly, cefuroxime or cefixime, azithromycin and amoxicillin, and 
50% of the children also received ciprofloxacin for the treatment of respiratory tract infections) only six erythromycin-resistant S. pyogenes and only one ampicillin-resistant H. influenzae were detected. Surprisingly, those exposed to co-trimoxazole had significantly less MR-GNB than other children. An opposite phenomenon was expected, as an increase in co-trimoxazole resistance has been noted in the beginning of AIDS era, 14 years ago, when introducing this antibiotic combination into the anti-PCP prophylaxis in children with AIDS.3,4 However, HAART was not available at that time.
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‘High’ resistance in S. pyogenes, S. aureus, Klebsiella spp. and Enterobacter spp. during the first 3–9 months of HAART was probably due to heavy antibiotic exposure for treatment of frequent opportunistic infections and due to immunodeficiency (CD4 depletion) in children with AIDS and tuberculosis. Also, antiretroviral and antitubercular agents (e.g. rifampicin) may be responsible for the selection of bacterial mutants with overexpression of genes coding for resistance to multiple antibiotics. In addition, baseline resistance in Cambodia is also very high, mainly among Gram-negative bacteria. This is probably due to an inappropriate antibiotic therapeutic policy in the community (all antibiotics are available as over-the-counter drugs).
In conclusion, we have no explanation for high ‘at baseline’ colonization with MR-GNB (e.g. ceftazidime-resistant Enterobacter and Klebsiella spp.) in children who were antibiotic- and HAART-naive. We also have no explanation for the reversibility of resistance (increasing susceptibility) after 9 months of HAART therapy in Gram-negative bacteria and after 21 months in Gram-positive bacteria despite continuous prophylactic/intermittent administration of co-trimoxazole to all children with AIDS. Probably, improvement in the immune system plays a more important role in the reversibility of the antimicrobial resistance than intermittent prophylactic administration of co-trimoxazole.
None to declare.
Acknowledgements
The collection of cultures from HIV-positive patients was approved by the Ethics Committee of the University of Trnava, School of Public Health on 26 October 2003. This material was presented in part at the Seventh European Congress of Chemotherapy and Infection, Firenze, Italy, 2005 (Abstract P337). This work was supported by grant 1/5056/VEGA from the Ministry of Education of Slovak Republic.
References
1 Chintu C, Bhat GJ, Walker AS, et al. Co-trimoxazole as prophylaxis against opportunistic infections in HIV-infected Zambian children (CHAP): a double-blind randomised placebo-controlled trial. Lancet (2004) 364:1865–71.[CrossRef][Web of Science][Medline]
2 Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J (2001) 20:40–8.[CrossRef][Web of Science][Medline]
3
Hughes WT, Leoung G, Kramer F, et al. Comparison of atovaquone (566C80) with trimethoprim–sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS. N Engl J Med (1993) 328:1521–7.
4 Hughes WT, Dankner WM, Yogev R, et al. Comparison of atovaquone and azithromycin with trimethoprim–sulfamethoxazole for the prevention of serious bacterial infections in children with HIV Infection. Clin Infect Dis (2005) 40:136–45.[CrossRef][Web of Science][Medline]
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