Quality of anti-malarial drugs provided by public and private healthcare providers in south-east Nigeria

BACKGROUND: There is little existing knowledge about actual quality of drugs provided by different providers in Nigeria and in many sub-Saharan African countries. Such information is important for improving malaria treatment that will help in the development and implementation of actions designed to improve the quality of treatment. The objective of the study was to determine the quality of drugs used for the treatment of malaria in a broad spectrum of public and private healthcare providers. METHODS: The study was undertaken in six towns (three urban and three rural) in Anambra state, south-east Nigeria. Anti-malarials (225 samples), which included artesunate, dihydroartemisinin, sulphadoxine-pyrimethamine (SP), quinine, and chloroquine, were either purchased or collected from randomly selected providers. The quality of these drugs was assessed by laboratory analysis of the dissolution profile using published pharmacopoeial monograms and measuring the amount of active ingredient using high performance liquid chromatography (HPLC). FINDINGS: It was found that 60 (37%) of the anti-malarials tested did not meet the United States Pharmacopoeia (USP) specifications for the amount of active ingredients, with the suspect drugs either lacking the active ingredients or containing suboptimal quantities of the active ingredients. Quinine (46%) and SP formulations (39%) were among drugs that did not satisfy the tolerance limits published in USP monograms. A total of 78% of the suspect drugs were from private facilities, mostly low-level providers, such as patent medicine dealers (vendors). CONCLUSION: This study found that there was a high prevalence of poor quality drugs. The findings provide areas for public intervention to improve the quality of malaria treatment services. There should be enforced checks and regulation of drug supply management as well as stiffer penalties for people stocking substandard and counterfeit drugs

Comparison of Bioavailability Between the Most Available Generic Tablet Formulation Containing Artemether and Lumefantrine on the Tanzanian Market and the Innovator's Product.

Existence of anti-malarial generic drugs with low bioavailability marketed on sub-Saharan Africa has raised a concern on patients achieving therapeutic concentrations after intake of these products. This work compared bioavailability of one generic tablet formulation with innovator's product. Both were fixed dose combination tablet formulations containing artemether and lumefantrine.MethodologyThe study was conducted in Dar Es Salaam, Tanzania, in which a survey of the most abundant generic containing artemether-lumefantrine tablet formulation was carried out in retail pharmacies. The most widely available generic (Artefan(R), Ajanta Pharma Ltd, Maharashtra, India) was sampled for bioavailability comparison with Coartem(R) (Novartis Pharma, Basel, Switzerland) - the innovator's product. A randomized, two-treatment cross-over study was conducted in 18 healthy Tanzanian black male volunteers. Each volunteer received Artefan(R) (test) and Coartem(R) (as reference) formulation separated by 42 days of drug-free washout period. Serial blood samples were collected up to 168 hours after oral administration of a single dose of each treatment. Quantitation of lumefantrine plasma levels was done using HPLC with UV detection. Bioequivalence of the two products was assessed in accordance with the US Food and Drug Authority (FDA) guidelines. The most widely available generic in pharmacies was Artefan(R) from India. All eighteen enrolled volunteers completed the study and both test and reference tablet formulations were well tolerated. It was possible to quantify lumefantrine alone, therefore, the pharmacokinetic parameters reported herein are for lumefantrine. The geometric mean ratios for Cmax, AUC0-t and AUC0-[infinity] were 84% in all cases and within FDA recommended bioequivalence limits of 80% -- 125%, but the 90% confidence intervals were outside FDA recommended limits (CI 49--143%, 53 - 137%, 52 - 135% respectively). There were no statistical significant differences between the two formulations with regard to PK parameters (P > 0.05). Although the ratios of AUCs and Cmax were within the acceptable FDA range, bioequivalence between Artefan(R) and Coartem(R) tablet formulations was not demonstrated due to failure to comply with the FDA 90 % confidence interval criteria. Based on the observed total drug exposure (AUCs), Artefan(R) is likely to produce a similar therapeutic response as Coartem(R)

Poor quality vital anti-malarials in Africa - an urgent neglected public health priority

BACKGROUND: Plasmodium falciparum malaria remains a major public health problem. A vital component of malaria control rests on the availability of good quality artemisinin-derivative based combination therapy (ACT) at the correct dose. However, there are increasing reports of poor quality anti-malarials in Africa. METHODS: Seven collections of artemisinin derivative monotherapies, ACT and halofantrine anti-malarials of suspicious quality were collected in 2002/10 in eleven African countries and in Asia en route to Africa. Packaging, chemical composition (high performance liquid chromatography, direct ionization mass spectrometry, X-ray diffractometry, stable isotope analysis) and botanical investigations were performed. RESULTS: Counterfeit artesunate containing chloroquine, counterfeit dihydroartemisinin (DHA) containing paracetamol (acetaminophen), counterfeit DHA-piperaquine containing sildenafil, counterfeit artemether-lumefantrine containing pyrimethamine, counterfeit halofantrine containing artemisinin, and substandard/counterfeit or degraded artesunate and artesunate+amodiaquine in eight countries are described. Pollen analysis was consistent with manufacture of counterfeits in eastern Asia. These data do not allow estimation of the frequency of poor quality anti-malarials in Africa. CONCLUSIONS: Criminals are producing diverse harmful anti-malarial counterfeits with important public health consequences. The presence of artesunate monotherapy, substandard and/or degraded and counterfeit medicines containing sub-therapeutic amounts of unexpected anti-malarials will engender drug resistance. With the threatening spread of artemisinin resistance to Africa, much greater investment is required to ensure the quality of ACTs and removal of artemisinin monotherapies. The International Health Regulations may need to be invoked to counter these serious public health problems

Antibiotic susceptibility of Neisseria gonorrhoeae in Vientiane, Lao PDR

Objectives To determine the antibiotic susceptibility of N. gonorrhoeae in the Lao People’s Democratic Republic (Laos). Methods We obtained 158 gonococcal isolates from 12,281 genital samples routinely submitted to a diagnostic laboratory in Vientiane, Laos between 2011 and 2015 and determined their susceptibility to five antibiotics by a standard disk diffusion method. Results The rates of resistance to penicillin (by beta-lactamase production), tetracycline and ciprofloxacin were 89.9%, 99.3% and 84.8% respectively. All isolates were sensitive to ceftriaxone and spectinomycin. Conclusions This situation is similar to that in neighboring countries, but fortunately means that the latest Lao national guidelines for treating gonorrhoea should still be effective.</p

Antibiotic susceptibility of Neisseria gonorrhoeae in Vientiane, Lao PDR

Objectives To determine the antibiotic susceptibility of N. gonorrhoeae in the Lao People’s Democratic Republic (Laos). Methods We obtained 158 gonococcal isolates from 12,281 genital samples routinely submitted to a diagnostic laboratory in Vientiane, Laos between 2011 and 2015 and determined their susceptibility to five antibiotics by a standard disk diffusion method. Results The rates of resistance to penicillin (by beta-lactamase production), tetracycline and ciprofloxacin were 89.9%, 99.3% and 84.8% respectively. All isolates were sensitive to ceftriaxone and spectinomycin. Conclusions This situation is similar to that in neighboring countries, but fortunately means that the latest Lao national guidelines for treating gonorrhoea should still be effective.</p

Impaired clinical response in a patient with uncomplicated falciparum malaria who received poor-quality and underdosed intramuscular artemether.

We describe an adult with uncomplicated Plasmodium falciparum malaria who did not improve clinically despite 5 days of intramuscular artemether therapy. He was prescribed a lower dose (kg body weight) than that recommended, and a vial from the packet contained only 74% of the artemether dose as stated by the manufacturer. The combination of underdosing, poor-quality drug, and the intrinsic low bioavailability of artemether may have contributed to his poor clinical response. Analysis of the packaging and chemical "fingerprinting" of the artemether suggested that the drug was genuine but was either substandard or had deteriorated after manufacture

Invasive Streptococcus agalactiae ST283 infection after fish consumption in two sisters, Lao PDR

Background: Streptococcus agalactiae is a normal commensal of the human gastro-intestinal and female genital tracts. It causes serious disease in neonates and pregnant women, as well as non-pregnant adults. Food-borne outbreaks have also been described. A link between invasive Group B streptococcus (GBS) infection in humans caused by S. agalactiae serotype III-4, sequence type 283 (ST283) and the consumption of raw fresh-water fish was first described in Singapore in 2015. Case presentation: We report the simultaneous occurrence of acute fever and myalgia in two sisters who were visiting Laos. Both were found to have invasive GBS ST283 infection, confirmed by blood culture. Infection was temporally linked to fish consumption. They responded well to intravenous antibiotics within 48 hours. Conclusions: Food-borne transmission of Streptococcus agalactiae is an important and under-recognised source of serious human disease throughout Southeast Asia and possibly beyond

Bacteremia caused by extended-spectrum beta-lactamase–producing Enterobacteriaceae in Vientiane, Lao PDR: a 5-year study

Although there has been an increasing incidence of bacteremia caused by extended-spectrum beta-lactamase (ESBL)&ndash;producing Enterobacteriaceae (ESBL-E) across South East Asia, there are sparse data from the Lao PDR, where laboratory capacity for antimicrobial resistance surveillance is limited. We, therefore, retrospectively reviewed bacteremia caused by ESBL-producing&nbsp;Escherichia coli&nbsp;and&nbsp;Klebsiella pneumoniae&nbsp;between 2010 and 2014 at Mahosot Hospital, Vientiane, Lao PDR. Clinical and laboratory data relating to all episodes of ESBL-E bacteremia were reviewed over the 5-year period and compared with non&ndash;ESBL-E bacteremia. Blood cultures positive for&nbsp;E. coli&nbsp;or&nbsp;K. pneumoniae&nbsp;were identified retrospectively from laboratory records. Clinical and laboratory data were extracted from research databases and case notes and analyzed using STATA. Between 2010 and 2014, we identified 360 patients with&nbsp;E. coli&nbsp;(n&nbsp;= 249) or&nbsp;K. pneumoniae&nbsp;(n&nbsp;= 111) bacteremia, representing 34.8% of all patients with clinically significant bacteremia.&nbsp;Seventy-two (20%) isolates produced ESBL;&nbsp;E. coli&nbsp;accounted for 15.3% (55/360) and&nbsp;K. pneumoniae&nbsp;for 4.7% (17/360), respectively. The incidence of ESBL-producing&nbsp;E. coli&nbsp;bacteremia rose during the study period. By multiple logistic analysis, reported antibiotic use in the previous week was significantly associated with ESBL positivity (P&nbsp;&lt; 0.001, odds ratio 3.89). Although multiresistant, most ESBL-producing&nbsp;E. coli&nbsp;and&nbsp;K. pneumoniae&nbsp;remained susceptible to meropenem (65/65; 100%) and amikacin (64/65; 98.5%). We demonstrated an alarming increase in the incidence of ESBL-E as a cause of bacteremia in Vientiane during the study period. This has implications for empiric therapy of sepsis in Laos, and ongoing surveillance is essential.</p