Kamal Hamed

Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria: a systematic review and meta-analysis of day 7 lumefantrine concentrations and therapeutic response using individual patient data

Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the ‘therapeutic’ day 7 lumefantrine concentration threshold needs to be defined better, particularly for important patient and parasite sub-populations. The WorldWide Antimalarial Resistance Network (WWARN) conducted a large pooled analysis of individual pharmacokinetic-pharmacodynamic data from patients treated with artemether-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies. Risk of bias in individual studies was evaluated based on study design, methodology and missing data. Of 31 studies identified through a systematic review, 26 studies were shared with WWARN and 21 studies with 2,787 patients were included. Recrudescence was associated with low day 7 lumefantrine concentrations (HR 1.59 (95 % CI 1.36 to 1.85) per halving of day 7 concentrations) and high baseline parasitemia (HR 1.87 (95 % CI 1.22 to 2.87) per 10-fold increase). Adjusted for mg/kg dose, day 7 concentrations were lowest in very young children (<3 years), among whom underweight-for-age children had 23 % (95 % CI −1 to 41 %) lower concentrations than adequately nourished children of the same age and 53 % (95 % CI 37 to 65 %) lower concentrations than adults. Day 7 lumefantrine concentrations were 44 % (95 % CI 38 to 49 %) lower following unsupervised treatment. The highest risk of recrudescence was observed in areas of emerging artemisinin resistance and very low transmission intensity. For all other populations studied, day 7 concentrations ≥200 ng/ml were associated with >98 % cure rates (if parasitemia <135,000/μL). Current artemether-lumefantrine dosing recommendations achieve day 7 lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas with emerging parasite resistance. In these groups, adherence and treatment response should be monitored closely. Higher, more frequent, or prolonged dosage regimens should now be evaluated in very young children, particularly if malnourished, and in patients with hyperparasitemia.

Single-Day, Patient-Initiated Famciclovir Therapy for Recurrent Genital Herpes: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND Orally administered antiviral therapy for genital herpes improves the time to lesion healing and resolves symptoms during an outbreak. Although traditional therapy for a recurrent episode for healthy adults has consisted of twice-daily dosing for 5 days, recent studies have indicated that shorter courses of antiviral therapy are effective. This study was conducted to assess the efficacy and safety of a patient-initiated, single-day regimen of famciclovir therapy, compared with placebo, in immunocompetent adult patients with recurrent genital herpes. METHODS This multicenter, multinational, randomized, double-blind, parallel-group, placebo-controlled study compared single-day, patient-initiated oral famciclovir (1000 mg given twice daily) with placebo for the treatment of recurrent genital herpes. Patients were instructed to initiate therapy within 6 h after onset of prodromal symptoms or genital herpes lesions. RESULTS Famciclovir reduced (P < .001) the time to healing of nonaborted lesions (i.e., those that progressed [corrected] beyond the papule stage) (median time, 4.3 vs. 6.1 days) and all nonaborted and aborted lesions (median time, 3.5 vs. 5.0 days), compared with placebo. The proportion of patients with aborted lesions was larger in the famciclovir group than in the placebo group (23.3% vs. 12.7%; P = .003). Adverse events in the famciclovir group were infrequent overall; most were of mild-to-moderate severity and were similar to adverse events in the placebo group. CONCLUSIONS A single-day regimen of patient-initiated famciclovir treatment was well tolerated and safe, and the healing of recurrent genital herpes lesions occurred approximately 2 days faster than with placebo. Moreover, single-day famciclovir treatment stopped the development or progression of lesions beyond the papule stage. This convenient single-day regimen has the potential for improving patient compliance and satisfaction with therapy.

A systematic review of the safety and efficacy of artemether-lumefantrine against uncomplicated Plasmodium falciparum malaria during pregnancy

Malaria during pregnancy, particularly Plasmodium falciparum malaria, has been linked to increased morbidity and mortality, which must be reduced by both preventive measures and effective case management. The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) to treat uncomplicated falciparum malaria during the second and third trimesters of pregnancy, and quinine plus clindamycin during the first trimester. However, the national policies of many African countries currently recommend quinine throughout pregnancy. Therefore, the aim of this article is to provide a summary of the available data on the safety and efficacy of artemether-lumefantrine (AL) in pregnancy. An English-language search identified 16 publications from 1989 to October 2011 with reports of artemether or AL exposure in pregnancy, including randomized clinical trials, observational studies and systematic reviews. Overall, there were 1,103 reports of AL use in pregnant women: 890 second/third trimester exposures; 212 first trimester exposures; and one case where the trimester of exposure was not reported. In the second and third trimesters, AL was not associated with increased adverse pregnancy outcomes as compared with quinine or sulphadoxine-pyrimethamine, showed improved tolerability relative to quinine, and its efficacy was non-inferior to quinine. There is evidence to suggest that the pharmacokinetics of anti-malarial drugs may change in pregnancy, although the impact on efficacy and safety needs to be studied further, especially since the majority of studies report high cure rates and adequate tolerability. As there are fewer reports of AL safety in the first trimester, additional data are required to assess the potential to use AL in the first trimester. Though the available safety and efficacy data support the use of AL in the second and third trimesters, there is still a need for further information. These findings reinforce the WHO recommendation to treat uncomplicated falciparum malaria with quinine plus clindamycin in early pregnancy and ACT in later pregnancy.

Open label, multicenter study of gatifloxacin treatment of recurrent otitis media and acute otitis media treatment failure.

Background. Recurrent otitis media and treatment failures of acute infections are refractory to therapy. Newer fluoroquinolones have excellent activity against respiratory pathogens, but their use in children has been limited because of concerns about adverse effects. Methods. This was an open label, multicenter trial in which patients with recurrent otitis media or acute otitis media (AOM) treatment failure were treated with 10 mg/kg gatifloxacin oral suspension once daily for 10 days. Before treatment a tympanocentesis or a swab of middle ear fluid was obtained. Nasopharyngeal swabs were obtained at baseline and at the end of therapy. Efficacy was evaluated 3 to 10 days after cessation of treatment and at 3 to 4 weeks. Safety monitoring included special attention to any sign or symptom suggestive of joint or bone abnormality. Results. The study enrolled 254 patients 6 months to 7 years of age, with one-half (52%) of the patients having recurrent otitis media, 17% having AOM treatment failure and 28% having both. Cure was achieved posttreatment in 88% of 198 clinically evaluable patients, with similar outcomes for patients younger or older than 2 years of age. Of the 45 evaluable patients with Streptococcus pneumoniae, 38 (84%) were cured, including 25 of 28 with penicillin-nonsusceptible strains. Also cured were 89% of those with Haemophilus influenzae and those with Moraxella catarrhalis. No selection of resistance to gatifloxacin was detected among nasopharyngeal pathogens. Eighty-three percent of the children had sustained cure at the 4 weeks follow-up visit. Adverse events were primarily mild gastrointestinal, with no occurrences of arthropathy. Conclusion. Gatifloxacin is safe and effective for treatment of recurrent otitis media and AOM treatment failure in children.

Bacteriologic and clinical efficacy of oral gatifloxacin for the treatment of recurrent/nonresponsive acute otitis media: an open label, noncomparative, double tympanocentesis study

Background. Gatifloxacin is an 8-methoxyfluoroquinolone with good activity against respiratory pathogens. Objectives. To document the bacteriologic and clinical efficacy of gatifloxacin in recurrent/nonresponsive acute otitis media (AOM). Methods. One hundred sixty patients 6 to 48 months of age with recurrent/nonresponsive AOM received gatifloxacin suspension (10 mg/kg once daily for 10 days). Recurrent AOM was defined as ≥3 AOM episodes during the previous 6 months or ≥4 AOM episodes during the previous 12 months. Nonresponsive AOM was defined as AOM occurring ≤14 days after completing antibiotic treatment or not improving after ≥48 h of therapy. Middle ear fluid (MEF) obtained by tympanocentesis pretreatment (Day 1) and 3 to 5 days after initiation of treatment (Days 4 to 6) was cultured. Additional MEF cultures were obtained if clinical failure or recurrence of AOM occurred. Bacteriologic failure was defined by culture-positive MEF during treatment. Patients were followed until Days 22 to 28. Susceptibility was determined by broth microdilution. Results. One hundred twenty-eight (80%) patients completed treatment, and 32 discontinued the study prematurely (adverse events, 17; lost to follow-up, 10; consent withdrawal, 3; and laboratory abnormalities, 2). From 89 patients (median age, 1 year; median number of prior AOM episodes, 4; range, 0 to 12), 121 pathogens were recovered:Haemophilus influenzae, 74 (61%); Streptococcus pneumoniae, 36 (30%); Moraxella catarrhalis, 9 (7%); and Streptococcus pyogenes, 2 (2%). The 36 S. pneumoniae isolates were susceptible to gatifloxacin (MIC50 0.25 &mgr;g/ml); 26 of 36 (72%) were penicillin-nonsusceptible (15 fully resistant). All 74 H. influenzae isolates were susceptible to gatifloxacin (MIC ≤ 0.03 mg/ml). Fourteen of 74 (19%) and 9 of 9 (100%) H. influenzae and M. catarrhalis isolates, respectively, produced beta-lactamase. Bacteriologic eradication was achieved for 118 of 121 (98%) pathogens: 74 of 74 H. influenzae; 34 of 36 (94%) S. pneumoniae; 9 of 9 M. catarrhalis; and 1 of 2 S. pyogenes. Clinical improvement/cure at end of treatment was seen in 103 of 114 (90%) clinically evaluable patients. Clinical recurrence of AOM after completion of therapy occurred in 31 patients. Of the 27 recurrent AOM cases in which tympanocentesis was performed, there were 16 (59%) new infections, 4 (15%) culture-negative results and only 7 (26%) true bacteriologic relapses. Adverse events were recorded in 21 of 160 (13%) patients: vomiting, 16; diarrhea, 3; maculopapular rash, 2. No articular adverse events were recorded. Conclusion. Gatifloxacin is efficacious and safe for the treatment of recurrent/nonresponsive AOM.

Single-Day, Patient-Initiated Famciclovir Therapy versus 3-Day Valacyclovir Regimen for Recurrent Genital Herpes: A Randomized, Double-Blind, Comparative Trial

BACKGROUND Recurrent genital herpes is a major problem for patients worldwide. Early episodic treatment with short-course therapy is effective, often stopping progression of outbreaks. This study is the first head-to-head comparison of single-day famciclovir (1000 mg administered twice daily) versus 3-day valacyclovir (500 mg administered twice daily) for episodic therapy in immunocompetent patients. METHODS In this multicenter, multinational, double-blind, parallel-group study, 1179 adults with a history of recurrent genital herpes were randomized 1:1 to receive either famciclovir or valacyclovir. Patients initiated treatment within 6 h after a recurrence. The primary objective was to establish noninferiority of single-day famciclovir, compared with a 3-day course of valacyclovir, in time to healing of all nonaborted lesions in a modified intent-to-treat population. RESULTS This study established that single-day famciclovir therapy was noninferior to 3-day valacyclovir therapy in reducing time to healing of all nonaborted genital herpes lesions (median time to healing, 4.25 days vs. 4.08 days). Approximately one-third of patients in each treatment group had aborted genital herpes episodes, suggesting that both treatments have similar efficacy in preventing outbreaks or progression of lesions beyond the papule stage. There was no significant difference in time to resolution of symptoms associated with recurrence. The overall incidence of adverse events was similar (23.2% for the famciclovir group vs. 22.3% for the valacyclovir group), with headache, nausea, diarrhea, vomiting, and abdominal pain reported most often. CONCLUSIONS Single-day famciclovir (1000 mg administered twice daily) was similar to 3-day valacyclovir (500 mg administered twice daily) in both efficacy and safety, representing a more convenient treatment for immunocompetent adults with recurrent genital herpes.

Malaria in infants aged less than six months - is it an area of unmet medical need?

Despite the protection provided by several factors, including maternal antibodies, the burden of malaria in young infants may be higher than previously thought. Infants with congenital or neonatal malaria may have a different clinical presentation than older children, and diagnosis may be confused with other neonatal diseases due to an overlap of clinical manifestations. In addition, there is little information on the use of artemisinin-based combination therapy in young infants. There is the need for a more accurate estimate of the parasite prevalence and the incidence of clinical malaria in infants under 6 months old, as well as a better characterization of risk factors, pharmacokinetic profiles, safety and efficacy of currently available anti-malarial treatments, in order to develop evidence-based treatment guidelines for this population.

Administration of triclabendazole is safe and effective in controlling fascioliasis in an endemic community of the Bolivian Altiplano.

Background The Bolivian northern Altiplano is characterized by a high prevalence of Fasciola hepatica infection. In order to assess the feasibility, safety and efficacy of large-scale administration of triclabendazole as an appropriate public health measure to control morbidity associated with fascioliasis, a pilot intervention was implemented in 2008. Materials and Methods Schoolchildren from an endemic community were screened for fascioliasis and treated with a single administration of triclabendazole (10 mg/kg). Interviews to assess the occurrence of adverse events were conducted on treatment day, one week later, and one month after treatment. Further parasitological screenings were performed three months after treatment and again two months later (following a further treatment) in order to evaluate the efficacy of the intervention. Results Ninety infected children were administered triclabendazole. Adverse events were infrequent and mild. No serious adverse events were reported. Observed cure rates were 77.8% after one treatment and 97.8% after two treatments, while egg reduction rates ranged between 74% and 90.3% after one treatment, and between 84.2% and 99.9% after two treatments. The proportion of high-intensity infections (≥400 epg) decreased from 7.8% to 1.1% after one treatment and to 0% after two treatments. Conclusion Administration of triclabendazole is a feasible, safe and efficacious public health intervention in an endemic community in the Bolivian Altiplano, suggesting that preventive chemotherapy can be applied to control of fascioliasis. Further investigations are needed to define the most appropriate frequency of treatment.

Famciclovir reduces viral mucosal shedding in HSV-seropositive persons

Objective: Many cases of herpes simplex virus (HSV) infection occur through asymptomatic shedding from persons without evidence of clinical disease. This study explores whether famciclovir reduces HSV shedding in HSV-2 seropositive persons with or without a history of symptomatic genital herpes. Study Design: One hundred twenty-seven HSV-2 seropositive participants were randomly assigned to 42 days of famciclovir, followed by 14 days of washout and 42 days of placebo, or vice versa. All subjects swabbed the genital/perianal area; those with HSV-1 infection also swabbed the oral area daily for HSV DNA PCR. Results: Famciclovir reduced genital and oral HSV shedding from 11.4% of days during the placebo period to 4.7% of days during famciclovir therapy. The reduction was greater in participants with a history of genital herpes (74%) than in those without such a history (30%). In multivariate analyses, famciclovir protected against total (clinical and subclinical) genital shedding among persons with a clinical history of genital herpes (RR, 0.23; 95% CI, 0.15–0.35; P < 0.001). Among HSV-2 seropositive participants without a history of genital herpes, 60% had HSV detected in the genital area at least once during the study. Famciclovir therapy did not result in a statistically significant reduction in total HSV shedding in participants without a history of genital herpes. Conclusion: Famciclovir therapy decreases genital HSV shedding in HSV-seropositive persons, especially those with a history of genital herpes. Overall, antiviral drugs may have varying effects on symptomatic and asymptomatic viral shedding, depending on the clinical history of the disease.

Successful response of metronidazole-resistant trichomonal vaginitis to tinidazole. A case report.

Treatment of metronidazole-resistant Trichomonas vaginalis infection is complicated by the lack of an effective alternative therapeutic regimen. Data on the susceptibility of the organism to metronidazole and other nitroimidazoles are important in managing intractable cases. A case of trichomonal vaginitis with true resistance to metronidazole that responded to treatment with tinidazole is reported.