Antimicrobial sensitivity in enterobacteria from AIDS patients, Zambia. (Dispatches).

Enterobacteria contribute to two serious clinical syndromes seen in African AIDS patients: diarrhea and septicemia. In West Africa, prophylaxis with sulfamethoxazole-trimethoprim (SXT) reduced illnesses. We report reduced sensitivity of enterobacteria to available antimicrobial agents in Zambia, with only 22% of nontyphoidal salmonellae and 6% of shigellae sensitive to SXT.

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Diarrhea and septicemia, two of the most important clinical problems of African AIDS patients, are both associated with high rates of illness and death. Treatment with antimicrobial agents may play an important role in reducing illness and possibly death. Chemoprophylaxis (for example, with cotrimoxazole or sulfamethoxazole-trimethoprim [SXT]) has been shown to be effective in reducing illness and death (1,2). The evidence base relating to patterns of antimicrobial resistance in Africa is small, and antimicrobial agents are often chosen on the basis of availability and expense. Some evidence indicates that resistance patterns vary across Africa, with resistance to SXT in nontyphoidal salmonellae of 14% in Abidjan and 83% in Malawi (3). We report the prevalence of infection with three major enterobacteria in Zambian adults and children with AIDS, followed by an analysis of antimicrobial sensitivity patterns.

The Study

To determine the prevalence of infection in adults and children, cultures were performed by standard techniques on fecal samples from several groups of adults and children, all residents of Lusaka, the capital of Zambia. Group A was 124 adults and 105 children, all HIV-seropositive patients with persistent diarrhea, studied from 1995 to 1999 during three clinical trials of antiprotozoal or nutritional therapies. The average number of samples tested was 2.1 for each adult and 2.8 for each child. Group B was 216 adults enrolled in a longitudinal study of intestinal infection in a cohort of adults in a representative urban community in Lusaka; this group was studied to provide an estimate of asymptomatic carriage rates.

To define the profile of antimicrobial sensitivity, isolates from Group A were analyzed together with additional isolates of nontyphoidal salmonellae, Shigella dysenteriae, and S. flexneri from a third source (Group C): routine stool or blood cultures from AIDS patients in the University Teaching Hospital from 1995 to 1999. All isolates were cultured and tested for antimicrobial susceptibility by using standard antimicrobial discs (Oxoid Ltd, Basingstoke, UK) on Mueller-Hinton agar. Zones of growth inhibition were compared with standard tables (4), and control organisms of known sensitivity were tested beside clinical isolates for verification.

Of 124 adults with persistent diarrhea in Group A, 6 (5%) were infected with nontyphoidal Salmonella spp. and 9 (7%) with S. flexneri or S. dysenteriae. Of 105 children with persistent diarrhea, also in Group A, 21 (20%) were infected with nontyphoidal Salmonella spp. and 3 (3%) with S. flexneri or S. dysenteriae. In Group B, 7 (4%) of 174 adults had one or more fecal samples positive for nontyphoidal Salmonella spp. in one year (1999), and 10 (6%) had one or more positive for S. flexneri or S. dysenteriae. As each adult submitted samples approximately monthly (for a total of 1,440 samples), the point prevalence in these asymptomatic adults was <1% for either infection.

Studies of patients with HIV-related persistent diarrhea in other countries in Africa have found the prevalence of enterobacterial infection to be higher. In Rwanda and Kenya, prevalences of nontyphoidal salmonellae were 11% and 16%, respectively, and of shigellae were 22% and 4%, respectively (5,6). In recent years, HIV seroprevalence in Lusaka has been estimated to be 22% to 30% (7), and the overall rate of HIV-related diarrhea is high (8).

Conclusions

Antimicrobial sensitivity patterns indicate that resistance is a substantial problem among enterobacteria in Lusaka (Table). The isolates we tested came from a tertiary hospital, which may have resulted in some selection bias, as treatment failures may be overrepresented in such patients. However, only a few bacteria tested were sensitive to SXT, in marked contrast to data from West Africa and more closely resembling the situation in Malawi (3). This level of resistance may compromise the usefulness of SXT in preventing bacterial infection in HIV-infected persons, although any effect in preventing Pneumocystis carinii pneumonia or isosporiasis would be valuable. Emergence of resistance to SXT was noted in San Francisco after its widespread use as prophylaxis against pneumocystosis (9). For treatment of infection with these enterobacteria in Zambia, only the more expensive antimicrobial agents now seem to be reliable. Providing effective, affordable parenteral antimicrobial agents for the efficient treatment of septicemic infection in hospitals and health centers is likely to be difficult. As clinical response sometimes occurs even when susceptibility testing in vitro suggests that the antimicrobial agent used is ineffective, controlled clinical trials are needed for these infections in different geographic regions of Africa.

Antimicrobial sensitivity appeared to decrease from 1995 to 1999, when these isolates were being collected. For example, over this period gentamicin resistance increased from 0% to 32% in S. flexneri and from 0% to 34% in nontyphoidal salmonellae (p<0.001). In S. flexneri, cefuroxime resistance increased from 22% to 88% and cephalexin resistance from 18% to 42% over the same period (p = 0.001). The scale of use of cephalosporins in the community did not suggest that selection pressure for resistance was likely to be high. Mechanisms of resistance to cephalosporins include reduced permeability and modification of penicillin-binding protein, and emergence appears to be rapid.

Which antimicrobial agents could be recommended for treatment of bacteremic nontyphoidal salmonellosis? The most reliable results are likely to be obtained with fluoroquinolones or azithromycin, but these are expensive and their availability is limited. Gentamicin or chloramphenicol are less expensive and would be acceptable alternatives, although the probability of adverse effects is greater. Unfortunately, few antimicrobial compounds that are likely to be effective and affordable could also be given easily and safely to AIDS patients in primary and secondary care settings in Zambia. As the epidemic in Zambia enters its third decade, the situation is likely to worsen if no action is taken. We have been able to reduce antimicrobial resistance in Vibrio cholerae by instituting a policy of rotating the recommended antimicrobial agents during epidemics, thereby prolonging the useful life of affordable antimicrobial agents (J. Mwansa, unpub. obs.). This strategy could be extended to enterobacterial infection in AIDS. We are also considering clinical trials with combinations of antimicrobial drugs to treat these clinical syndromes in AIDS patients. As antimicrobial sensitivity patterns seem to vary across Africa, it may be difficult to generalize the results of clinical trials from one part of the continent to another.

Table. Summary of antimicrobial sensitivity patterns for three
enterobacteria isolated from patients with HIV-related persistent
diarrhea in Zambia

                                 No. sensitive (%)

Antimicrobial        Nontyphoidal   Shigella   S. dysenteriae
agent (a)            salmonellae    flexneri

Tetracycline            37 (6)       2 (6)         3 (16)

Chloramphenicol         36 (77)      7 (22)        8 (48)

Gentamicin             119 (75)     24 (77)       18 (95)

Sulphamethoxazole-      25 (22)      3 (10)        0 (0)
trimethoprim

Amoxycillin             74 (48)      9 (30)        7 (37)

Amoxycillin-            95 (60)     27 (87)       12 (63)
clavulanic acid

Cephalexin             105 (66)     23 (74)       17 (89)

Cefuroxime              93 (59)     11 (35)       16 (74)

Cefotaxime             149 (88)     28 (90)       19 (95)

Nalidixic acid         107 (67)     31 (100)      19 (100)

Ciprofloxacin          157 (99)     30 (97)       18 (95)

Erythromycin            22 (14)      0 (0)         4 (21)

Azithromycin            64 (92)      9 (100)      19 (100)

(a) 158 isolates of nontyphoidal salmonellae, 31 isolates of S.
flexneri, and 19 isolates of S. dysenteriae were tested against
all these antimicrobial agents except for azithromycin, against
which 69, 9, and 19 isolates were tested respectively.

Acknowledgments

We thank Pfizer Ltd. for donating azithromycin disks.

This study was supported by Pfizer Ltd. and The Wellcome Trust.

Dr. Mwansa is a consultant microbiologist in the University Teaching Hospital, Lusaka, Zambia. He advises on control of infectious disease for the Ministry of Health and has particular interests in salmonellosis and meningitis.

References

(1.) Anglaret X, Chene G, Attia A, Ture S, Lafont S, Combe S, et al. Early chemoprophylaxis with trimethoprim-sulphamethoxazole for HIV-1 infected adults in Abidjan, Cote d'Ivoire: a randomised trial. Lancet 1999;353:1463-8.

(2.) Wiktor SZ, Sassan-Morokro M, Grant AD, Abouya L, Karon JM, Maurice C, et al. Efficacy of trimethoprim-sulphamethoxazole prophylaxis to decrease morbidity and mortality in HIV-1 infected patients with tuberculosis in Abidjan, Cote d'Ivoire: a randomised controlled trial. Lancet 1999;353:1469-75.

(3.) Boeree MJ, Harries AD, Zijlstra EE, Taylor TE, Molyneux ME. Co-trimoxazole in HIV1 infection [letter]. Lancet 1999;354:334.

(4.) National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; ninth information supplement. Wayne (PA): The Committee; 1999. Document M100-S9, vol. 19.

(5.) Clerinx J, Bogaerts J, Taelman H, Habyarimana JB, Nyirabareja A, Ngendhayo P, et al. Chronic diarrhoea among adults in Kigali, Rwanda: association with bacterial enteropathogens, rectocolonic inflammation, and HIV infection. Clin Infect Dis 1995;21:1282-4.

(6.) Mwachari C, Batchelor BIF, Paul J, Waiyaki PG, Gilks CF. Chronic diarrhoea among HIV-infected adult patients in Nairobi, Kenya. J Infect 1998;37:48-53.

(7.) Fylkesnes K, Ndhlovu Z, Kasumba K, Musonda RM, Sichone M. Studying dynamics of the HIV epidemic: population-based data compared with sentinel surveillance in Zambia. AIDS 1998; 12:1227-34.

(8.) Kelly P, Baboo KS, Woolf M, Ngwenya B, Luo N, Farthing MJG. Prevalence and aetiology of persistent diarrhoea in adults in urban Zambia. Acta Trop 1996;61:183-90.

(9.) Martin JN, Rose DA, Hadley WK, Perdreau-Remington F, Lam PK, Gerberding JL. Emergence of trimethoprim-sulphamethoxazole resistance in the AIDS era. J Infect Dis 1999;180:1809-18.

Address for correspondence: Paul Kelly, Department of Adult and Paediatric Gastroenterology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Turner Street, London E1 2AD, United Kingdom; fax: [phone]; e-mail: [e-mail]

James Mwansa, * Kabanga Mutela, * Isaac Zulu, * ([dagger]) Beatrice Amadi, * and Paul Kelly * ([dagger])

* University of Zambia School of Medicine, University Teaching Hospital, Lusaka, Zambia; and ([dagger]) St. Bartholomew's & Royal London School of Medicine, London, United Kingdom