Antibiograms from community-acquired uropathogens in Gulu, northern Uganda - a cross-sectional study

Urinary tract infections (UTI) are a common medical problem encountered in medical practice. Females are more prone to infection than males, a phenomenon explained by their short urethra and its anatomical proximity to the anal orifice [1, 2]. Because uropathogens largely originate from colonic flora [3], they are easy to predict. This is the rationale for empirical treatment in community-acquired urinary tract infections (CA-UTI) [1, 4]. However, empirical treatment limits opportunities for surveillance of antibiotic resistance among pathogens that cause community-acquired UTI. If regularly updated to match changing susceptibility patterns, empirical treatment is also a convenient strategy for effective resource utilization. This is especially true in developing countries where resource constraints mean that it is often impractical to routinely perform antibiotic sensitivity tests [5]. Reports of uropathogens resistant to previously effective antibiotics have emerged globally in recent years [6–18]. The situation is especially dire in Africa where irrational antibiotic practices are common [18]. Variations in antibiotic resistance patterns are known to occur across different geographical regions, even within the same country [16, 19]. Such variations must be well documented so as to inform local empirical treatment as well as foster rational antibiotic use.

The current edition of the national treatment guidelines in Uganda recommends the use of amoxicillin or cotrimoxazole for empirical treatment of CA-UTI [20]. However, based on our clinical experience at Gulu regional hospital, we suspected that resistance to these antibiotics was possibly high. Therefore, continued empirical use was likely to increase chances of treatment failure, leading to unnecessary patient suffering and increased healthcare costs in the long run. The broad aim of this study was to examine the validity of the current recommendations for empirical treatment of CA-UTI as per the national guidelines. Specifically, we set out to identity uropathogens from community-acquired infections at Gulu regional hospital and thereafter, determine their resistance profiles against the currently recommended antibiotics. In addition, we sought to determine resistance profile against a range of potentially useful alternatives for treatment of CA-UTI in our setting.

This study revealed relatively high frequencies of resistance to most antibiotics tested. Resistance to cotrimoxazole, amoxicillin, nitrofurantoin and nalidixic acid were particularly alarming. This is consistent with our clinical observations as well as findings from other recent studies done in Uganda [14, 26, 27]. Such high levels of resistance are probably due to antibiotic misuse by poorly trained health workers as has been documented in many developing countries [18, 28, 29]. In addition, weak government regulation allows for the importation and sale of substandard drugs, often from unlicensed outlets. This encourages domiciliary self-medication practices that have become commonplace in Uganda [30, 31]. Moreover, it is not uncommon for unqualified health workers to offer clients the option of purchasing small quantities of antibiotics. This leads to inadequate dosing resulting into sub-inhibitory tissue concentrations that facilitate selection of antibiotic-resistant strains. It has been observed that the motives for antibiotic misuse by health workers are similar to those for misuse by lay persons: to cut costs and act expeditiously to treat suspected bacterial infections [28].

The particularly high resistance to cotrimoxazole may be explained by additional factors common in our setting. These include the use of cotrimoxazole as prophylaxis among HIV positive patients [20] and the use of sulfadoxine-pyrimethamine (shares enzyme targets with cotrimoxazole) for routine malaria prophylaxis during pregnancy [20]. In light of these considerations, we strongly suspect that a similar resistance profile occurs in other parts of Uganda. Therefore, UTI treatment with cotrimoxazole is likely to fail, exposing patients to unnecessary distress and an increased risk of complications. Some authors have however questioned the predictive value of in-vitro resistance testing among uropathogens, especially for antibiotics that achieve urinary concentrations much higher than those tested in laboratory assays [6, 32]. For instance, it has been reported that urine levels of trimethoprim and sulfamethoxazole are 35 and 3 times, respectively, the levels in serum [33]. In such cases, it is possible that even with apparent in-vitro resistance, successful cure may be realized. In the present context, this issue may require further investigation.

Nearly 50% of uropathogens (40/82) were resistant to ciprofloxacin (Table 3). This is far above the 20% rate recommended for empirical use of antibiotics for community-acquired UTI [34, 35]. Ironically, a 32% resistance was found with levofloxacin yet this antibiotic has barely been used in our setting owing to prohibitive costs. A fluoroquinolone cross-resistance phenomenon may explain this finding since the two drugs also share an enzyme target. These findings are of great concern considering that fluoroquinolones are reserved for severe or complicated UTI in Uganda [20]. Our study found a 46% resistance to nitrofurantoin (38/82, Table 3) compared to that of Mwaka et al., where only 2% of isolates were reported resistant among non-pregnant women in Kampala [26]. This apparent disparity might have come from the use of nitrofurantoin disks of different potency (300 μg in Mwaka et al., and 50 μg in ours). In addition, socio-demographic differences between the population in Kampala and Gulu (approximately 400 kilometers apart) might have contributed. Being urban and rural populations respectively, differences in lifestyles, occupation, culture, attitudes and literacy exist. These factors (along with genetics) are known to influence disease and health seeking patterns, and may explain geographical variations in antibiotic resistance even within the same country [16, 19].

The most favorable antibiograms were obtained with gentamicin and amoxicillin-clavulanic acid where a total of 85.4% and 72.0% of isolates respectively, were either sensitive or intermediate against all organisms (Table 3). Either of these antibiotics could replace the current choices for empirical treatment of community-acquired UTI in our setting. Gentamicin is quite affordable and is already available within our public hospitals. To mitigate toxicity concerns, our physicians have adopted the newer once daily dosing of gentamicin known to be safer yet as effective as multiple dosing schedules [36]. An important drawback however is the fact that gentamicin has to be administered exclusively by injection, and a move towards its adoption is likely to be material and labor intensive. We fear that a resource-constrained healthcare system like ours will be particularly sensitive to additional strain. On the other hand, the high cost of oral amoxicillin-clavulanate means that it may not be available to all those who need it within the public sector.

At 46.3%, Staphylococcal species formed the majority of uropathogens isolated in our study. This was followed by Escherichia coli at 39%. This pattern is slightly different from that seen in most literature, where Escherichia coli commonly predominates [6–13]. Our findings are however similar to those reported by Kyabaggu et al. [14], where Staphylococcal species (32%) followed by Klebsiella (21%) were the commonest uropathogens isolated among patients at a metropolitan hospital in Kampala. Two other studies done at Mulago national referral hospital in Kampala ranked Staphylococcal species second to Escherichia coli among leading causes of asymptomatic bacteriuria among pregnant and non-pregnant women [26, 27]. In our study, most Staphylococcal infections were due to S. saprophyticus (28/38). This organism has generally been found to colonize the urinary tract of sexually active women [37, 38]. Our findings may point in this direction and are implicitly supported by the young study population and the fact that Uganda has one of the highest fertility rates in the world [39]. With a mean age 23 years, female participants in our study were much younger than female participants in a similar European study (mean age 51.6) published recently [40]. Looking at these two populations, differences in sexual patterns that may influence UTI etiology are likely to exist.

This study presents outpatient-based antibiograms of uropathogens isolated from consecutively selected participants presenting to Gulu regional hospital. This represents a fairer picture of antibiotic susceptibility profiles within this community than would be expected from inpatient-based (or laboratory-based) antibiograms. The latter are more likely to reflect a selection bias towards complicated UTI and therefore, to over-estimate resistance prevalence in a particular community [32]. In this study, the proportion of samples that turned out as true UTI was rather small (82/339) compared to the participant number that were recruited with symptoms. The poor correlation between symptoms and positive diagnosis may be explained by the rampant tendency among patients to self-medicate and only visit hospitals when symptoms persist. In such cases, quantitative urine culture is likely to be less sensitive, leaving investigators with a diagnostic dilemma. Consequently, our decision to adhere to the 10⁵ CFU/mL cut-off value might have excluded a significant proportion of UTI cases. In addition, the decision to consider as contaminants, all suspected cases where two or more organisms were isolated might also have contributed to the low numbers observed. Nevertheless, we were able to isolate most species commonly associated with community-acquired UTI in reasonable proportions. As shown in Table 1, some urine samples with leucocyturia did not yield significant bacterial growth on quantitative culture. Further investigations revealed presence of yeast cells in these samples, suggesting a fungal infection. Some urine samples did not yield any significant findings using our criteria despite symptoms. We think these symptoms were due to obstetric or other gynecological diseases that the study did not set out to investigate.

Staphylococcal species and E. coli are major causes of community-acquired UTI in our setting. There is unacceptably high resistance to cotrimoxazole and amoxicillin among uropathogens isolated in our setting. Continued use of these drugs is likely to be associated with a high risk of treatment failure. The recommendations of the Uganda Clinical Guidelines, 2010 are not in tandem with the situation obtaining on the ground in Gulu district. There is need to formulate an appropriate hospital antibiotic policy for the treatment of UTI in our setting. In the meantime, clinicians should take these findings into account whenever prescribing empirically for UTI. We recommend that either gentamicin or amoxicillin-clavulanate be used for empirical treatment of UTI in our setting.