Trimester-Specific Population Pharmacokinetics and Other Correlates of Variability in Sulphadoxine-Pyrimethamine Disposition Among Ugandan Pregnant Women.

BACKGROUND: Sulphadoxine-pyrimethamine (SP) is widely used as an intermittent preventive treatment for malaria in pregnancy (IPTp). However, pharmacokinetic studies in pregnancy show variable and often contradictory findings. We describe population and trimester-specific differences in SP pharmacokinetics among Ugandan women. METHODS: SP (three tablets) were administered to 34 nonpregnant and 87 pregnant women in the second trimester. Seventy-eight pregnant women were redosed in the third trimester. Blood was collected over time points ranging from 0.5 h to 42 days postdose. Data on the variables age, body weight, height, parity, gestational age, and serum creatinine, alanine transaminase and albumin levels were collected at baseline. Plasma drug assays were performed using high-performance liquid chromatography with ultraviolet detection. Population pharmacokinetic analysis was done using NONMEM software. RESULTS: A two-compartment model with first-order absorption and a lag time best described both the sulphadoxine and pyrimethamine data. Between trimesters, statistically significant differences in central volumes of distribution (V(2)) were observed for both drugs, while differences in the distribution half-life and the terminal elimination half-life were observed for pyrimethamine and sulphadoxine, respectively. Significant covariate relationships were identified on clearance (pregnancy status and serum albumin level) and V(2) (gestational age) for sulphadoxine. For pyrimethamine, clearance (pregnancy status and age) and V(2) (gestational age and body weight) were significant. Considering a 25 % threshold for clinical relevance, only differences in clearance of both drugs between pregnant and nonpregnant women were significant. CONCLUSION: While clinically relevant differences in SP disposition between trimesters were not seen, increased clearance with pregnancy and the increasing volume of distribution in the central compartment with gestational age lend support to the revised World Health Organization guidelines advocating more frequent dosing of SP for IPTp.

Is there a distinction between malaria treatment and intermittent preventive treatment? Insights from a cross-sectional study of anti-malarial drug use among Ugandan pregnant women.

BACKGROUND: In Uganda, treatment of clinical malaria and intermittent preventive treatment with sulphadoxine-pyrimethamine (SP) are common during pregnancy. As a result, both formal and informal reports from antenatal sources suggest possible misuse of SP for malaria treatment among pregnant women. The objective of this study was to investigate anti-malarial drug use patterns among women who had recently suffered malaria illness before and during pregnancy. METHODS: A cross-sectional study in which a structured questionnaire (interviewer-administered) was used to collect data from pregnant women attending an urban antenatal clinic. Details of medicines used to treat malaria episodes suffered before and during pregnancy were captured. A first order Markov probability model was used to estimate probabilities of transitioning between treatment choices made before and during pregnancy. Logistic regression was used to explore whether demographic and obstetric characteristics were associated with transition patterns. RESULTS: Seven hundred women were interviewed among whom 428 had suffered malaria in both instances. Three hundred thirty of these could recall the medicines used in both instances. Women who used ACT/QNN (correct choice) before pregnancy had higher probabilities of transitioning to SP than staying on ACT/QNN during pregnancy (0.463 versus 0.451). Access of medicines from private outlets (clinics and pharmacies) were more than nine times predictive of receiving correct medicines (p=0.035 and p=0.039 respectively). Access of medicines from clinics was 5.9 times protective against receiving SP for malaria treatment (p=0.033). Among those who used SP before pregnancy, there was a 0.75 probability of staying on it during pregnancy. None of the factors explored could explain this observation. CONCLUSION: Use of SP for malaria treatment is common during pregnancy. This may be contributing to adverse pregnancy outcomes. Antenatal care providers should endeavour to emphasize the distinction between treatment and prevention of malaria during pregnancy.

Intermittent use of sulphadoxine-pyrimethamine for malaria prevention: a cross-sectional study of knowledge and practices among Ugandan women attending an urban antenatal clinic.

BACKGROUND: The WHO recommends supervised administration of sulphadoxine-pyrimethamine (SP) as intermittent preventive treatment for malaria (IPTp) during pregnancy. Logistical constraints have however favoured unsupervised intake of SP-IPTp, casting doubts whether recent guidelines requiring more frequent intake can be effectively implemented. To propose strategies for enhancing compliance under limited supervision, this study sought to identify pregnant women's knowledge and practices gaps as well as determine predictors of compliance with SP-IPTp, given under limited supervision. METHODS: A cross-sectional study of 700 women used exit interviews at an urban clinic in Uganda to obtain a descriptive summary of demographic and obstetric characteristics, including knowledge, practice and experiences with SP. Predictors of compliance with SP intake instructions were explored using logistic regression. RESULTS: Median age of respondents was 25 (IQR 22-28) and median parity was two (IQR one to three) while median number of antenatal clinic (ANC) visits was 3.0 (IQR three to four). Most women had completed primary (36%) or ordinary secondary education (25.6%) while 16.1% had not completed primary education. Awareness about SP was high (99.4%) although correct knowledge regarding its use in pregnancy was low (57%), with 15.4% thinking it was used to treat malaria and 26.7% lacking any idea about its use. Correct knowledge on SP use during pregnancy significantly predicted compliance with SP-IPTp instructions (OR 1.98, C.I. 1.12-3.55), while age, education level, parity, number of ANC visits, or history of unwanted effects with SP did not. SP was mostly accessed from hospitals (64.4%) followed by private clinics (16.9%) both for preventive and treatment purposes. SP was considered safe by most women, who were willing to take it again in future, without supervision. CONCLUSION: Despite high awareness, knowledge of SP as an intervention for malaria prevention in pregnancy was low. Correct knowledge on use of SP predicted compliance with SP-IPTp intake instructions. Focused malaria-related education during ANC visits may improve compliance with SP intake amidst limited supervision.

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

BACKGROUND: Urinary tract infections (UTI) are common in clinical practice and empirical treatment is largely employed due to predictability of pathogens. However, variations in antibiotic sensitivity patterns do occur, and documentation is needed to inform local empirical therapy. The current edition of the Uganda Clinical Guidelines recommends amoxicillin or cotrimoxazole as choice drugs for empirical treatment of community-acquired UTI. From our clinical observations, we suspected that this recommendation was not effective in our setting. In order to examine validity, we sought to identify bacteria from community-acquired infections and determine their susceptibility against these antibiotics plus a range of potentially useful alternatives for treatment of UTI. METHODS: A cross-sectional study of mid-stream urine collected from 339 symptomatic patients over a three-month period at Gulu regional referral hospital. Qualitative culture and identification of bacteria and antibiotic sensitivity testing using the modified Kirby-Bauer disk diffusion method was done. Participants' demographic and clinical characteristics were collected using a standard form. Results were analyzed by simple proportions among related variables and confidence intervals computed using binomial exact distribution. RESULTS: Eighty two cultures were positive for UTI. Staphylococcus spp (46.3%) and Escherichia coli (39%) were the most common pathogens. There was high resistance to cotrimoxazole (73.2%), nalidixic acid (52.4%) and amoxicillin (51.2%). The most favorable antibiograms were obtained with gentamicin, amoxicillin-clavulanate and levofloxacin where 85.4%, 72.0%, 67.1% of isolates respectively, were either sensitive or intermediate. Only 51% of isolates were sensitive to ciprofloxacin. CONCLUSION: There was high resistance to most antibiotics tested in this study. The recommendations contained in the current edition of the Uganda Clinical Guidelines are not in tandem with antibiotic sensitivity pattern of uropathogens seen in our setting. Amoxicillin-clavulanate or gentamicin should be considered for replacement of amoxicillin and cotrimoxazole for empirical treatment of UTI in our setting.