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Newsletter Vol. 29 No. 2




From Premonition to Precision: Africa’s Pressing Need for Laboratory Diagnostics and Appropriate Surveillance



Iruka Okeke, Ph.D.
Associate Professor of Molecular Microbiology
Haverford College

 




Japheth A. Opintan is a Microbiology lecturer currently completing his Ph.D. at the University of Ghana Medical School. Iruka N. Okeke is Associate Professor of Molecular Microbiology at Haverford College and author of Divining Without Seeds: The Case for Strengthening Laboratory Medicine in Africa (Cornell University Press, 2011).

Ghanaian graduate student Japheth Opintan thought hard and long before he selected his Masters’ thesis project. While not a condition for his program, it was important to him that his project be applicable to healthcare in his country and that it could be completed within a restricted budget. Invasive bacillary diarrhea caused by Shigella was believed to be highly prevalent and having read so much about the global problem of drug resistance, Japheth wondered whether the antimicrobials recommended for treating invasive diarrhea in Ghana were up to the task. He decided to culture diarrheal specimens and then determine the susceptibility patterns of Shigella isolates. He hypothesized that – as the textbooks say for ‘Africa’ –Shigella would be a principal etiologic agent of diarrhea in Accra, and that he would see resistance to at least some drugs commonly used in Ghana. Given the limited resources in his lab and data from the 1980s available for sample size predictions, he expected to be able to test his hypothesis with under 300 specimens collected within a year, well within the scope of a Master’s thesis research project.

National standard treatment guidelines in Ghana as well as elsewhere in Africa encourage health practitioners to treat bloody diarrheas with orally-active antibiotics that were originally active against Shigella. These typically include trimethoprim-sulphamethoxazole, aminopenicillins and most recently, the fluoroquinolones. Japheth’s study used patient specimens at a teaching hospital in a country where only problematic or refractory cases are likely to be considered for laboratory diagnosis, something that often biases studies towards Shigella isolation. Nonetheless, the young scientist was in for a surprise: 16 months and 594 carefully-processed specimens later, he had just 24 Shigella isolates. His hypothesis on drug resistance was supported: the paltry Shigella collection was multiply-resistant and he’d localized the resistance genes to plasmids. However, to get even this small number of isolates and complete his dissertation, he had screened more than twice as many specimens as he originally intended [1].

The astonishing rarity of Shigella in the Opintan et al study is not likely due to methodological flaws or a temporary drop in Shigella prevalence. Indeed, the only thing odd about it is our collective surprise. The data simply point to other organisms as principal causes of invasive diarrhea in Accra. In a study performed in Western Nigeria in the same decade as Japheth’s, we too isolated Shigella from only 7.1% of stools from patients with diarrhea and 3.6% of controls [2]. We found pathogens that are less frequently sought in Nigeria to be more strongly associated with all and with bloody diarrheas. Shigella has remained common place and relevant at some locations, including some in Africa. However, the fact of the matter is that even though studies from the 1970s and 1980s reported high rates of Shigella in many West African countries, some parts have seen a decline since then and most parts have seen no surveillance for decades. The evidence base for many national guidelines that recommend valuable drugs like the fluoroquinolones for empirical treatment of invasive diarrhea is insufficient and other syndromic protocols are similarly undersupported [3]. In the Nigeria study, Shiga-toxin-producing Escherichia coli, for which fluoroquinolones are contraindicated because they increase bacterial toxin production, were three times more common than Shigella [2,4]. Thus, whilst needlessly selecting for quinolone resistance, these drugs could also be harming more patients than they are helping for this specific syndrome.

There is no infectious disease crystal ball. We cannot predict the Shigella prevalence at any locale, nor will we know when epidemiological changes occur, without routine laboratory investigation and surveillance. Similarly, patients should not have to depend on healthworker intuition to be sure that they receive the best available treatments. Clinicians need information about the epidemiology of life-threatening enteric infections in their locality. When they have knowledge about local etiology and susceptibility patterns, patients are more likely to get cost effective prescriptions at their first visit and selective pressure for drug resistance can be kept as low as possible. And when the first antimicrobial course is unsuccessful, prescribers need microbiology results to guide their next pick. But sadly, necessary laboratory support for managing bloody diarrheas is lacking in most African clinics. Research projects like Japheth’s are similarly uncommon, and far too many prescriptions are based on outdated traditions or unsupported guesses.

The majority of diarrheas should not be treated with antibacterial drugs but bloody diarrhea is sometimes life-threatening and therefore antimicrobials as well as rehydration are recommended in such cases. The more likely that the first prescription is the right one, the less likely that the patient will be harmed, the disease will spread or needless selective pressure for resistance will be high. Culture and susceptibility testing for Shigella and other bacteria is potentially too slow to inform each patient’s therapy but it is critical for identifying outbreaks and providing the surveillance information that makes it possible to respond rationally to future patients’. The fact that many African hospitals cannot provide this very basic service for bloody diarrheas, life-threatening bloodstream- or even central-nervous system infections is not just problematic, it is unconscionable [5,6,7]. And if and when such services are available, clinicians need to be encouraged to use them [8].

Can the etiologic agents of invasive diarrheas be detected rapidly when the point-of-care is not a district hospital? For some pathogens, microscopic methods and admittedly expensive immunological tests already exist. They are not ideal but are surprisingly cost-effective - now that we urgently need to protect our dwindling antibacterial arsenal – and need to be deployed wherever useful and possible. Before we rule out testing in the many rural African clinics without laboratories and with budgets that are too constrained to use these tests, we should remind ourselves that there are now commercially available diagnostics that can detect the etiology of calf diarrhea on farms within a few minutes. If tests that can inform treatment can be performed in a muddy field, they can also be used in a village clinic. Although challenging, it is possible to invent and deploy simple but useful tests for curable diseases that afflict so many people in poor countries but which might not have the economic incentive that large-scale agriculture can offer.

Invasive diarrhea is only one example of a potentially deadly syndrome that has multiple possible etiologies, each occasioning a different specific treatment that is threatened by antimicrobial resistance. We need to identify and overcome the roadblocks that stifle diagnostic development, that make drugs that select for expensive resistance problems cheaper to overuse than diagnostics, and the perception that infection-management tools are a luxury rather than a necessity [7,9]. Patients and clinicians should have access to diagnostics that are Affordable, Sensitive, Specific, User-friendly, Rapid and Robust, Equipment-free and Deliverable to areas of need (“ASSURED”)[10,11]. Only then will we have the infrastructure to ensure that patients get the best treatment while simultaneously conserving antimicrobials by targeting them to those specific cases where they will be effective.
 




References
1. Opintan J, Newman MJ (2007) Distribution of serogroups and serotypes of multiple drug resistant Shigella isolates. Ghana Med J 41:4-8.
2. Okeke IN, Ojo O, Lamikanra A, Kaper JB (2003) Etiology of acute diarrhea in adults in southwestern Nigeria. J Clin Microbiol 41: 4525-4530.
3. Muula AS, Maseko FC (2006) Medical laboratory services in Africa deserve more. Clin Infect Dis 42:1503.
4. Zhang X, McDaniel AD, Wolf LE, Keusch GT, Waldor MK, et al. (2000) Quinolone antibiotics induce Shiga toxin-encoding bacteriophages, toxin production, and death in mice. J Infect Dis 181:664-670.
5. Tegbaru B, Meless H, Kassu A, Tesema D, Gezahegn N, et al. (2004) Laboratory services in hospitals and regional laboratories in Ethiopia. Ethiop J Health Dev 18:43-47.
6. Ishengoma DR, Rwegoshora RT, Mdira KY, Kamugisha ML, Anga EO, et al. (2009) Health laboratories in the Tanga region of Tanzania: the quality of diagnostic services for malaria and other communicable diseases. Ann Trop Med Parasitol 103:441-453.
7. Okeke IN (2011) Divining without seeds : the case for strengthening laboratory medicine in Africa. Ithaca: ILR Press.
8. Polage CR, Bedu-Addo G, Owusu-Ofori A, Frimpong E, Lloyd W, et al. (2006) Laboratory use in Ghana: physician perception and practice. Am J Trop Med Hyg 75:526-531.
9. Okeke IN, Peeling RW, Goossens H, Auckenthaler R, Olmsted SS, et al. (2011) Diagnostics as essential tools for containing antibacterial resistance. Drug Resist Updat 14:95-106.
10. Mabey D, Peeling RW, Ustianowski A, Perkins MD (2004) Diagnostics for the developing world. Nat Rev Microbiol 2:231-240.
11. Peeling RW, Mabey D, Herring A, Hook EW, 3rd (2006) Why do we need quality-assured diagnostic tests for sexually transmitted infections? Nat Rev Microbiol 4:S7-19.
 




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