A multi-center randomized trial to assess the efficacy of gatifloxacin versus ciprofloxacin for the treatment of shigellosis in Vietnamese children

Background

The bacterial genus Shigella is the leading cause of dysentery. There have been significant increases in the proportion of Shigella isolated that demonstrate resistance to nalidixic acid. While nalidixic acid is no longer considered as a therapeutic agent for shigellosis, the fluoroquinolone ciprofloxacin is the current recommendation of the World Health Organization. Resistance to nalidixic acid is a marker of reduced susceptibility to older generation fluoroquinolones, such as ciprofloxacin. We aimed to assess the efficacy of gatifloxacin versus ciprofloxacin in the treatment of uncomplicated shigellosis in children.

Methodology/Principal Findings

We conducted a randomized, open-label, controlled trial with two parallel arms at two hospitals in southern Vietnam. The study was designed as a superiority trial and children with dysentery meeting the inclusion criteria were invited to participate. Participants received either gatifloxacin (10 mg/kg/day) in a single daily dose for 3 days or ciprofloxacin (30 mg/kg/day) in two divided doses for 3 days. The primary outcome measure was treatment failure; secondary outcome measures were time to the cessation of individual symptoms. Four hundred and ninety four patients were randomized to receive either gatifloxacin (n  =  249) or ciprofloxacin (n  =  245), of which 107 had a positive Shigella stool culture. We could not demonstrate superiority of gatifloxacin and observed similar clinical failure rate in both groups (gatifloxacin; 12.0% and ciprofloxacin; 11.0%, p  =  0.72). The median (inter-quartile range) time from illness onset to cessation of all symptoms was 95 (66–126) hours for gatifloxacin recipients and 93 (68–120) hours for the ciprofloxacin recipients (Hazard Ratio [95%CI]  =  0.98 [0.82–1.17], p  =  0.83).

Conclusions

We conclude that in Vietnam, where nalidixic acid resistant Shigellae are highly prevalent, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute shigellosis.

Trial Registration

Controlled trials number ISRCTN55945881     

Declining responsiveness of Plasmodium falciparum infections to artemisinin-based combination treatments on the Kenyan coast

Background

The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.

Methods

On the Kenyan coast we studied the treatment responses in 474 children 6–59 months old with uncomplicated P. falciparum malaria in a randomized controlled trial of dihydroartemisinin-piperaquine vs. artemether-lumefantrine from 2005 to 2008. (ISRCTN88705995)

Results

The proportion of patients with residual parasitemia on day 1 rose from 55% in 2005–2006 to 87% in 2007–2008 (odds ratio, 5.4, 95%CI, 2.7–11.1; P<0.001) and from 81% to 95% (OR, 4.1, 95%CI, 1.7–9.9; P = 0.002) in the DHA-PPQ and AM-LM groups, respectively. In parallel, Kaplan-Meier estimated risks of apparent recrudescent infection by day 84 increased from 7% to 14% (P = 0.1) and from 6% to 15% (P = 0.05) with DHA-PPQ and AM-LM, respectively. Coinciding with decreasing transmission in the study area, clinical tolerance to parasitemia (defined as absence of fever) declined between 2005–2006 and 2007–2008 (OR body temperature >37.5°C, 2.8, 1.9–4.1; P<0.001). Neither in vitro sensitivity of parasites to DHA nor levels of antibodies against parasite extract accounted for parasite clearance rates or changes thereof.

Conclusions

The significant, albeit small, decline through time of parasitological response rates to treatment with ACTs may be due to the emergence of parasites with reduced drug sensitivity, to the coincident reduction in population-level clinical immunity, or both. Maintaining the efficacy of artemisinin-based therapy in Africa would benefit from a better understanding of the mechanisms underlying reduced parasite clearance rates.

Trial Registration

Controlled-Trials.com ISRCTN88705995     

Elderly subjects have a delayed antibody response and prolonged viraemia following yellow fever vaccination: a prospective controlled cohort study

Background

Yellow fever vaccination (YF-17D) can cause serious adverse events (SAEs). The mechanism of these SAEs is poorly understood. Older age has been identified as a risk factor. We tested the hypothesis that the humoral immune response to yellow fever vaccine develops more slowly in elderly than in younger subjects.

Method

We vaccinated young volunteers (18–28 yrs, N = 30) and elderly travelers (60–81 yrs, N = 28) with YF-17D and measured their neutralizing antibody titers and plasma YF-17D RNA copy numbers before vaccination and 3, 5, 10, 14 and 28 days after vaccination.

Results

Ten days after vaccination seroprotection was attained by 77% (23/30) of the young participants and by 50% (14/28) of the elderly participants (p = 0.03). Accordingly, the Geometric Mean Titer of younger participants was higher than the GMT of the elderly participants. At day 10 the difference was +2.9 IU/ml (95% CI 1.8–4.7, p = 0.00004) and at day 14 +1.8 IU/ml (95% CI 1.1–2.9, p = 0.02, using a mixed linear model. Viraemia was more common in the elderly (86%, 24/28) than in the younger participants (60%, 14/30) (p = 0.03) with higher YF-17D RNA copy numbers in the elderly participants.

Conclusions

We found that elderly subjects had a delayed antibody response and higher viraemia levels after yellow fever primovaccination. We postulate that with older age, a weaker immune response to yellow fever vaccine allows the attenuated virus to cause higher viraemia levels which may increase the risk of developing SAEs. This may be one piece in the puzzle of the pathophysiology of YEL-AVD.

Trial Registration

Trialregitser.nl NTR1040     

The impact of retail-sector delivery of artemether-lumefantrine on malaria treatment of children under five in Kenya: a cluster randomized controlled trial

Background

It has been proposed that artemisinin-based combination therapy (ACT) be subsidised in the private sector in order to improve affordability and access. This study in western Kenya aimed to evaluate the impact of providing subsidized artemether–lumefantrine (AL) through retail providers on the coverage of prompt, effective antimalarial treatment for febrile children aged 3–59 months.

Methods and Findings

We used a cluster-randomized, controlled design with nine control and nine intervention sublocations, equally distributed across three districts in western Kenya. Cross-sectional household surveys were conducted before and after the delivery of the intervention. The intervention comprised provision of subsidized packs of paediatric ACT to retail outlets, training of retail outlet staff, and community awareness activities. The primary outcome was defined as the proportion of children aged 3–59 months reporting fever in the past 2 weeks who started treatment with AL on the same day or following day of fever onset. Data were collected using structured questionnaires and analyzed based on cluster-level summaries, comparing control to intervention arms, while adjusting for other covariates. Data were collected on 2,749 children in the target age group at baseline and 2,662 at follow-up. 29% of children experienced fever within 2 weeks before the interview. At follow-up, the percentage of children receiving AL on the day of fever or the following day had risen by 14.6% points in the control arm (from 5.3% [standard deviation (SD): 3.2%] to 19.9% [SD: 10.0%]) and 40.2% points in the intervention arm (from 4.7% [SD: 3.4%] to 44.9% [SD: 11.7%]). The percentage of children receiving AL was significantly greater in the intervention arm at follow-up, with a difference between the arms of 25.0% points (95% confidence interval [CI]: 14.1%, 35.9%; unadjusted p = 0.0002, adjusted p = 0.0001). No significant differences were observed between arms in the proportion of caregivers who sought treatment for their child''s fever by source, or in the child''s adherence to AL.

Conclusions

Subsidizing ACT in the retail sector can significantly increase ACT coverage for reported fevers in rural areas. Further research is needed on the impact and cost-effectiveness of such subsidy programmes at a national scale.

Trial Registration

Current Controlled Trials ISRCTN59275137 and Kenya Pharmacy and Poisons Board Ethical Committee for Clinical Trials PPB/ECCT/08/07. Please see later in the article for the Editors'' Summary     

Low efficacy of single-dose albendazole and mebendazole against hookworm and effect on concomitant helminth infection in Lao PDR

Background

Albendazole and mebendazole are increasingly deployed for preventive chemotherapy targeting soil-transmitted helminth (STH) infections. We assessed the efficacy of single oral doses of albendazole (400 mg) and mebendazole (500 mg) for the treatment of hookworm infection in school-aged children in Lao PDR. Since Opisthorchis viverrini is co-endemic in our study setting, the effect of the two drugs could also be determined against this liver fluke.

Methodology

We conducted a randomized, open-label, two-arm trial. In total, 200 children infected with hookworm (determined by quadruplicate Kato-Katz thick smears derived from two stool samples) were randomly assigned to albendazole (n = 100) and mebendazole (n = 100). Cure rate (CR; percentage of children who became egg-negative after treatment), and egg reduction rate (ERR; reduction in the geometric mean fecal egg count at treatment follow-up compared to baseline) at 21–23 days posttreatment were used as primary outcome measures. Adverse events were monitored 3 hours post treatment.

Principal Findings

Single-dose albendazole and mebendazole resulted in CRs of 36.0% and 17.6% (odds ratio: 0.4; 95% confidence interval: 0.2–0.8; P = 0.01), and ERRs of 86.7% and 76.3%, respectively. In children co-infected with O. viverrini, albendazole and mebendazole showed low CRs (33.3% and 24.2%, respectively) and moderate ERRs (82.1% and 78.2%, respectively).

Conclusions/Significance

Both albendazole and mebendazole showed disappointing CRs against hookworm, but albendazole cured infection and reduced intensity of infection with a higher efficacy than mebendazole. Single-dose administrations showed an effect against O. viverrini, and hence it will be interesting to monitor potential ancillary benefits of a preventive chemotherapy strategy that targets STHs in areas where opisthorchiasis is co-endemic.

Clinical Trial Registration

Current Controlled Trials ISRCTN29126001     

1,2-Octanediol, a novel surfactant, for treating head louse infestation: identification of activity, formulation, and randomised, controlled trials

Background

Interest in developing physically active pediculicides has identified new active substances. The objective was to evaluate a new treatment for clinical efficacy.

Methods and Findings

We describe the selection of 1,2-octanediol as a potential pediculicide. Clinical studies were community based. The main outcome measure was no live lice, after two treatments, with follow up visits over 14 days.Study 1 was a proof of concept with 18/20 (90%) participants cured.Study 2 was a multicentre, parallel, randomised, observer-blind study (520 participants) that compared 0.5% malathion liquid with 1,2-octanediol lotion (20% alcohol) applied 2–2.5 hours or 8 hours/overnight. 1,2-octanediol lotion was significantly (p<0.0005) more effective with success for 124/175 (70.9%) RR = 1.50 (97.5% CI, 1.22 to 1.85) for 2–2.5 hours, and 153/174 (87.9%) RR = 1.86 (97.5% CI, 1.54 to 2.26) for 8 hours/overnight compared with 81/171 (47.4%) for malathion.Study 3, a two centre, parallel, randomised, observer-blind study (121 participants), compared 1,2-octanediol lotion, 2–2.5 hours with 1,2-octanediol alcohol free mousse applied for 2–2.5 hours or 8 hours/overnight. The mousse applied for 8 hours/overnight cured 31/40 (77.5%), compared with 24/40 (60.0%) for lotion (RR = 1.29, 95% CI, 0.95 to 1.75; NNT = 5.7) but mousse applied for 2–2.5 hours 17/41 (41.5%) was less effective than lotion (RR = 0.69, 95% CI, 0.44 to 1.08).Adverse events were more common using 1,2-octanediol lotion at both 2–2.5 hours (12.0%, p = 0.001) and 8 hours/overnight (14.9%, p<0.0005), compared with 0.5% malathion (2.3%). Similar reactions were more frequent (p<0.045) using lotion compared with mousse.

Conclusions

1,2-octanediol was found to eliminate head louse infestation. It is believed to disrupt the insect''s cuticular lipid, resulting in dehydration. The alcohol free mousse is more acceptable exhibiting significantly fewer adverse reactions.

Trial registrations

Controlled-Trials.com ISRCTN66611560, ISRCTN91870666, ISRCTN28722846     

Efficacy of Praziquantel against Schistosoma mekongi and Opisthorchis viverrini: A Randomized, Single-Blinded Dose-Comparison Trial

Background

Schistosomiasis and opisthorchiasis are of public health importance in Southeast Asia. Praziquantel (PZQ) is the drug of choice for morbidity control but few dose comparisons have been made.

Methodology

Ninety-three schoolchildren were enrolled in an area of Lao PDR where Schistosoma mekongi and Opisthorchis viverrini coexist for a PZQ dose-comparison trial. Prevalence and intensity of infections were determined by a rigorous diagnostic effort (3 stool specimens, each examined with triplicate Kato-Katz) before and 28–30 days after treatment. Ninety children with full baseline data were randomized to receive PZQ: the 40 mg/kg standard single dose (n = 45) or a 75 mg/kg total dose (50 mg/kg+25 mg/kg, 4 hours apart; n = 45). Adverse events were assessed at 3 and 24 hours posttreatment.

Principal Findings

Baseline infection prevalence of S. mekongi and O. viverrini were 87.8% and 98.9%, respectively. S. mekongi cure rates were 75.0% (95% confidence interval (CI): 56.6–88.5%) and 80.8% (95% CI: 60.6–93.4%) for 40 mg/kg and 75 mg/kg PZQ, respectively (P = 0.60). O. viverrini cure rates were significantly different at 71.4% (95% CI: 53.4–84.4%) and 96.6% (95% CI: not defined), respectively (P = 0.009). Egg reduction rates (ERRs) against O. viverrini were very high for both doses (>99%), but slightly lower for S. mekongi at 40 mg/kg (96.4% vs. 98.1%) and not influenced by increasing diagnostic effort. O. viverrini cure rates would have been overestimated and no statistical difference between doses found if efficacy was based on a minimum sampling effort (single Kato-Katz before and after treatment). Adverse events were common (96%), mainly mild with no significant differences between the two treatment groups.

Conclusions/Significance

Cure rate from the 75 mg/kg PZQ dose was more efficacious than 40 mg/kg against O. viverrini but not against S. mekongi infections, while ERRs were similar for both doses.

Trial Registration

Controlled-Trials.com ISRCTN57714676     

Antibiotic selection pressure and macrolide resistance in nasopharyngeal Streptococcus pneumoniae: a cluster-randomized clinical trial

Background

It is widely thought that widespread antibiotic use selects for community antibiotic resistance, though this has been difficult to prove in the setting of a community-randomized clinical trial. In this study, we used a randomized clinical trial design to assess whether macrolide resistance was higher in communities treated with mass azithromycin for trachoma, compared to untreated control communities.

Methods and Findings

In a cluster-randomized trial for trachoma control in Ethiopia, 12 communities were randomized to receive mass azithromycin treatment of children aged 1–10 years at months 0, 3, 6, and 9. Twelve control communities were randomized to receive no antibiotic treatments until the conclusion of the study. Nasopharyngeal swabs were collected from randomly selected children in the treated group at baseline and month 12, and in the control group at month 12. Antibiotic susceptibility testing was performed on Streptococcus pneumoniae isolated from the swabs using Etest strips. In the treated group, the mean prevalence of azithromycin resistance among all monitored children increased from 3.6% (95% confidence interval [CI] 0.8%–8.9%) at baseline, to 46.9% (37.5%–57.5%) at month 12 (p = 0.003). In control communities, azithromycin resistance was 9.2% (95% CI 6.7%–13.3%) at month 12, significantly lower than the treated group (p<0.0001). Penicillin resistance was identified in 0.8% (95% CI 0%–4.2%) of isolates in the control group at 1 year, and in no isolates in the children-treated group at baseline or 1 year.

Conclusions

This cluster-randomized clinical trial demonstrated that compared to untreated control communities, nasopharyngeal pneumococcal resistance to macrolides was significantly higher in communities randomized to intensive azithromycin treatment. Mass azithromycin distributions were given more frequently than currently recommended by the World Health Organization''s trachoma program. Azithromycin use in this setting did not select for resistance to penicillins, which remain the drug of choice for pneumococcal infections.

Trial registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00322972","term_id":"NCT00322972"}}NCT00322972 Please see later in the article for the Editors'' Summary     

Persistence of Mycoplasma genitalium following azithromycin therapy

Background

To determine clinical outcomes and cure rates for M.genitalium genital infection in men and women following azithromycin 1 g.

Methodology

Patients attending Melbourne Sexual Health Centre between March 2005 and November 2007 with urethritis/epididymitis, cervicitis/pelvic inflammatory disease and sexual contacts of M.genitalium were tested for M.genitalium by polymerase chain reaction (PCR). M.genitalium-infection was treated with 1 g of azithromycin and a test-of-cure (toc) was performed one month post-azithromycin. Response to azithromycin, and response to moxifloxacin (400 mg daily for 10 days) in individuals with persistent infection post-azithromycin, was determined.

Principal Findings

Of 1538 males and 313 females tested, 161 males (11%) and 30 females (10%) were infected with M.genitalium. A toc was available on 131 (69%) infected individuals (median = 36 days [range 12-373]). Of 120 individuals prescribed azithromycin only pre-toc, M.genitalium was eradicated in 101 (84%, 95% confidence intervals [CI]: 77–90%) and persisted in 19 (16%, 95% CI: 10–23%). Eleven individuals with persistent infection (9%, 95% CI: 5–15%) had no risk of reinfection from untreated-partners, while eight (7%, 95% CI: 3–12%) may have been at risk of reinfection from doxycycline-treated or untreated-partners. Moxifloxacin was effective in eradicating persistent infection in all cases not responding to azithromycin. Patients with persistent-M.genitalium were more likely to experience persistent symptoms (91%), compared to patients in whom M.genitalium was eradicated (17%), p<0.0001.

Conclusion

Use of azithromycin 1 g in M.genitalium-infected patients was associated with unacceptable rates of persistent infection, which was eradicated with moxifloxacin. These findings highlight the importance of follow-up in M.genitalium-infected patients prescribed azithromycin, and the need to monitor for the development of resistance. Research to determine optimal first and second-line therapeutic agents for M.genitalium is needed.     

Effect of a nutrition supplement and physical activity program on pneumonia and walking capacity in Chilean older people: a factorial cluster randomized trial

Background

Ageing is associated with increased risk of poor health and functional decline. Uncertainties about the health-related benefits of nutrition and physical activity for older people have precluded their widespread implementation. We investigated the effectiveness and cost-effectiveness of a national nutritional supplementation program and/or a physical activity intervention among older people in Chile.

Methods and Findings

We conducted a cluster randomized factorial trial among low to middle socioeconomic status adults aged 65–67.9 years living in Santiago, Chile. We randomized 28 clusters (health centers) into the study and recruited 2,799 individuals in 2005 (∼100 per cluster). The interventions were a daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions, or neither, for 24 months. The primary outcomes, assessed blind to allocation, were incidence of pneumonia over 24 months, and physical function assessed by walking capacity 24 months after enrolment. Adherence was good for the nutritional supplement (∼75%), and moderate for the physical activity intervention (∼43%). Over 24 months the incidence rate of pneumonia did not differ between intervention and control clusters (32.5 versus 32.6 per 1,000 person years respectively; risk ratio = 1.00; 95% confidence interval 0.61–1.63; p = 0.99). In intention-to-treat analysis, after 24 months there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters; 95% confidence interval 13.9–53.8; p = 0.001). The overall cost of the physical activity intervention over 24 months was US$164/participant; equivalent to US$4.84/extra meter walked. The number of falls and fractures was balanced across physical activity intervention arms and no serious adverse events were reported for either intervention.

Conclusions

Chile''s nutritional supplementation program for older people is not effective in reducing the incidence of pneumonia. This trial suggests that the provision of locally accessible physical activity classes in a transition economy population can be a cost-effective means of enhancing physical function in later life.

Trial registration

Current Controlled Trials ISRCTN 48153354 Please see later in the article for the Editors'' Summary     

Gatifloxacin Versus Ofloxacin for the Treatment of Uncomplicated Enteric Fever in Nepal: An Open-Label,Randomized, Controlled Trial

Background

Fluoroquinolones are the most commonly used group of antimicrobials for the treatment of enteric fever, but no direct comparison between two fluoroquinolones has been performed in a large randomised trial. An open-label randomized trial was conducted to investigate whether gatifloxacin is more effective than ofloxacin in the treatment of uncomplicated enteric fever caused by nalidixic acid-resistant Salmonella enterica serovars Typhi and Paratyphi A.

Methodology and Principal Findings

Adults and children clinically diagnosed with uncomplicated enteric fever were enrolled in the study to receive gatifloxacin (10 mg/kg/day) in a single dose or ofloxacin (20 mg/kg/day) in two divided doses for 7 days. Patients were followed for six months. The primary outcome was treatment failure in patients infected with nalidixic acid resistant isolates. 627 patients with a median age of 17 (IQR 9–23) years were randomised. Of the 218 patients with culture confirmed enteric fever, 170 patients were infected with nalidixic acid-resistant isolates. In the ofloxacin group, 6 out of 83 patients had treatment failure compared to 5 out of 87 in the gatifloxacin group (hazard ratio [HR] of time to failure 0.81, 95% CI 0.25 to 2.65, p = 0.73). The median time to fever clearance was 4.70 days (IQR 2.98–5.90) in the ofloxacin group versus 3.31 days (IQR 2.29–4.75) in the gatifloxacin group (HR = 1.59, 95% CI 1.16 to 2.18, p = 0.004). The results in all blood culture-confirmed patients and all randomized patients were comparable.

Conclusion

Gatifloxacin was not superior to ofloxacin in preventing failure, but use of gatifloxacin did result in more prompt fever clearance time compared to ofloxacin. Trial registration: ISRCTN 63006567 (www.controlled-trials.com).     

Community risk factors for ocular Chlamydia infection in Niger: pre-treatment results from a cluster-randomized trachoma trial

Background

Trachoma control programs utilize mass azithromycin distributions to treat ocular Chlamydia trachomatis as part of an effort to eliminate this disease world-wide. But it remains unclear what the community-level risk factors are for infection.

Methods

This cluster-randomized, controlled trial entered 48 randomly selected communities in a 2×2 factorial design evaluating the effect of different treatment frequencies and treatment coverage levels. A pretreatment census and examination established the prevalence of risk factors for clinical trachoma and ocular chlamydia infection including years of education of household head, distance to primary water source, presence of household latrine, and facial cleanliness (ocular discharge, nasal discharge, and presence of facial flies). Univariate and multivariate associations were tested using linear regression and Bayes model averaging.

Findings

There were a total of 24,536 participants (4,484 children aged 0–5 years) in 6,235 households in the study. Before treatment in May to July 2010, the community-level prevalence of active trachoma (TF or TI utilizing the World Health Organization [WHO] grading system) was 26.0% (95% CI: 21.9% to 30.0%) and the mean community-level prevalence of chlamydia infection by Amplicor PCR was 20.7% (95% CI: 16.5% to 24.9%) in children aged 0–5 years. Univariate analysis showed that nasal discharge (0.29, 95% CI: 0.04 to 0.54; P = 0.03), presence of flies on the face (0.40, 95% CI: 0.17 to 0.64; P = 0.001), and years of formal education completed by the head of household (0.07, 95% CI: 0.07 to 0.13; P = 0.03) were independent risk factors for chlamydia infection. In multivariate analysis, facial flies (0.26, 95% CI: 0.02 to 0.49; P = 0.03) and years of formal education completed by the head of household (0.06, 95% CI: 0.008 to 0.11; P = 0.02) were associated risk factors for ocular chlamydial infection.

Interpretation

We have found that the presence of facial flies and years of education of the head of the household are risk factors for chlamydia infection when the analysis is done at the community level.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00792922","term_id":"NCT00792922"}}NCT00792922     

A Randomised Trial Evaluating the Safety and Immunogenicity of the Novel Single Oral Dose Typhoid Vaccine M01ZH09 in Healthy Vietnamese Children

Background

The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC ⁻ ssaV ⁻) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile.

Objectives

We conducted a randomised placebo controlled, single-blind trial to evaluate the safety and immunogenicity of M01ZH09 in healthy Vietnamese children aged 5 to 14 years.

Methods

Subjects were randomly assigned to receive either a nominal dose of 5×10⁹ CFU of M01ZH09 or placebo and were followed up for 28 days. The primary safety outcome was the proportion of subjects with any adverse event attributed to M01ZH09. The primary immunogenicity endpoint was the proportion of subjects who showed a positive immune response to M01ZH09 in the Salmonella Typhi lipopolysaccharide (LPS) specific serum IgA and IgG ELISA.

Principal Findings

One hundred and fifty-one children were enrolled, 101 subjects received M01ZH09 and 50 subjects received placebo. An intention to treat analysis was conducted. There were no serious adverse events and no bacteraemias. In the M01ZH09 group, 26 (26%; 95% CI, 18–5%) of 101 subjects experienced adverse events compared to 11 (22%; 95% CI, 12–36%) of 50 subjects in the placebo group (odds ratio (OR) [95%CI]  = 1.23 [0.550–2.747]; p = 0.691). Faecal shedding of S. Typhi (Ty2 aroC ⁻ ssaV ⁻) ZH9 was detected in 51 (51%; 95% CI, 41–61%) of 100 M01ZH09 subjects. No shedding was detected beyond day 3. A positive immune response, defined as 70% increase (1.7 fold change) in LPS specific serum IgG (day 14 or 28) and/or 50% increase (1.5 fold change) in LPS specific serum IgA (day 7 or 14) from baseline was detected in 98 (97%; 95% CI, 92–99%) of 101 M01ZH09 recipients and 8 (16%; 95% CI, 7–29%) of 50 placebo recipients. Twenty-eight (100%; 95% CI, 88–100%) of 28 vaccine recipients who were evaluated in the LPS specific IgA ELISPOT assay showed a positive response compared to none of the 14 placebo recipients tested.

Conclusions

This was the first phase II trial of a novel oral candidate typhoid vaccine in children in an endemic country. M01ZH09 had an appropriate safety profile and was immunogenic in children.

Trial Registration

Controlled-trials.comISRCTN91111837     

Postoperative fever: the potential relationship with prognosis in node negative breast cancer patients

Background

Postoperative fever may serve as an indirect sign to reflect the alterations of the host milieu caused by surgery. It still remains open to investigation whether postoperative fever has a bearing on prognosis in patients with lymph node negative breast cancers.

Methods

We performed a retrospective study of 883 female unilateral patients with lymph node negative breast cancer. Fever was defined as an oral temperature ≥38 in one week postoperation. Survival curves were performed with Kaplan-Meier method, and annual relapse hazard was estimated by hazard function.

Findings

The fever patients were older than those without fever (P<0.0001). Hypertensive patients had a propensity for fever after surgery (P = 0.011). A statistically significant difference was yielded in the incidence of fever among HR+/ERBB2-, ERBB2+, HR-/ERBB2- subgroups (P = 0.012). In the univariate survival analysis, we observed postoperative fever patients were more likely to recur than those without fever (P = 0.0027). The Cox proportional hazards regression analysis showed that postoperative fever (P = 0.044, RR = 1.89, 95%CI 1.02–3.52) as well as the HR/ERBB2 subgroups (P = 0.013, HR = 1.60, 95%CI 1.09–2.31) was an independent prognostic factor for relapse-free survival.

Conclusion

Postoperative fever may contribute to relapse in node negative breast cancer patients, which suggests that changes in host milieu related to fever might accelerate the growth of micro-metastatic foci. It may be more precise to integrate both tumor- and host-related factors for the evaluation of relapse risk.     

A Multi-Country Non-Inferiority Cluster Randomized Trial of Frontloaded Smear Microscopy for the Diagnosis of Pulmonary Tuberculosis

Background

More than 50 million people around the world are investigated for tuberculosis using sputum smear microscopy annually. This process requires repeated visits and patients often drop out.

Methods and Findings

This clinical trial of adults with cough ≥2 wk duration (in Ethiopia, Nepal, Nigeria, and Yemen) compared the sensitivity/specificity of two sputum samples collected “on the spot” during the first visit plus one sputum sample collected the following morning (spot-spot-morning [SSM]) versus the standard spot-morning-spot (SMS) scheme. Analyses were per protocol analysis (PPA) and intention to treat (ITT). A sub-analysis compared just the first two smears of each scheme, spot-spot and spot-morning.In total, 6,627 patients (3,052 SSM/3,575 SMS) were enrolled; 6,466 had culture and 1,526 were culture-positive. The sensitivity of SSM (ITT, 70.2%, 95% CI 66.5%–73.9%) was non-inferior to the sensitivity of SMS (PPA, 65.9%, 95% CI 62.3%–69.5%). Similarly, the specificity of SSM (ITT, 96.9%, 95% CI 93.2%–99.9%) was non-inferior to the specificity of SMS (ITT, 97.6%, 95% CI 94.0%–99.9%). The sensitivity of spot-spot (ITT, 63.6%, 95% CI 59.7%–67.5%) was also non-inferior to spot-morning (ITT, 64.8%, 95% CI 61.3%–68.3%), as the difference was within the selected −5% non-inferiority limit (difference ITT = 1.4%, 95% CI −3.7% to 6.6%). Patients screened using the SSM scheme were more likely to provide the first two specimens than patients screened with the SMS scheme (98% versus 94.2%, p<0.01). The PPA and ITT analysis resulted in similar results.

Conclusions

The sensitivity and specificity of SSM are non-inferior to those of SMS, with a higher proportion of patients submitting specimens. The scheme identifies most smear-positive patients on the first day of consultation.

Trial Registration

Current Controlled Trials ISRCTN53339491 Please see later in the article for the Editors'' Summary     

Intermittent preventive treatment of malaria provides substantial protection against malaria in children already protected by an insecticide-treated bednet in Burkina Faso: a randomised, double-blind, placebo-controlled trial

Background

Intermittent preventive treatment of malaria in children (IPTc) is a promising new approach to the control of malaria in areas of seasonal malaria transmission but it is not known if IPTc adds to the protection provided by an insecticide-treated net (ITN).

Methods and Findings

An individually randomised, double-blind, placebo-controlled trial of seasonal IPTc was conducted in Burkina Faso in children aged 3 to 59 months who were provided with a long-lasting insecticide-treated bednet (LLIN). Three rounds of treatment with sulphadoxine pyrimethamine plus amodiaquine or placebos were given at monthly intervals during the malaria transmission season. Passive surveillance for malaria episodes was established, a cross-sectional survey was conducted at the end of the malaria transmission season, and use of ITNs was monitored during the intervention period. Incidence rates of malaria were compared using a Cox regression model and generalized linear models were fitted to examine the effect of IPTc on the prevalence of malaria infection, anaemia, and on anthropometric indicators. 3,052 children were screened and 3,014 were enrolled in the trial; 1,505 in the control arm and 1,509 in the intervention arm. Similar proportions of children in the two treatment arms were reported to sleep under an LLIN during the intervention period (93%). The incidence of malaria, defined as fever or history of fever with parasitaemia ≥5,000/µl, was 2.88 (95% confidence interval [CI] 2.70–3.06) per child during the intervention period in the control arm versus 0.87 (95% CI 0.78–0.97) in the intervention arm, a protective efficacy (PE) of 70% (95% CI 66%–74%) (p<0.001). There was a 69% (95% CI 6%–90%) reduction in incidence of severe malaria (p = 0.04) and a 46% (95% CI 7%–69%) (p = 0.03) reduction in the incidence of all-cause hospital admissions. IPTc reduced the prevalence of malaria infection at the end of the malaria transmission season by 73% (95% CI 68%–77%) (p<0.001) and that of moderately severe anaemia by 56% (95% CI 36%–70%) (p<0.001). IPTc reduced the risks of wasting (risk ratio [RR] = 0.79; 95% CI 0.65–1.00) (p = 0.05) and of being underweight (RR = 0.84; 95% CI 0.72–0.99) (p = 0.03). Children who received IPTc were 2.8 (95% CI 2.3–3.5) (p<0.001) times more likely to vomit than children who received placebo but no drug-related serious adverse event was recorded.

Conclusions

IPT of malaria provides substantial protection against malaria in children who sleep under an ITN. There is now strong evidence to support the integration of IPTc into malaria control strategies in areas of seasonal malaria transmission.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00738946","term_id":"NCT00738946"}}NCT00738946 Please see later in the article for the Editors'' Summary     

Effect of newborn resuscitation training on health worker practices in Pumwani Hospital, Kenya

Background

Birth asphyxia kills 0.7 to 1.6 million newborns a year globally with 99% of deaths in developing countries. Effective newborn resuscitation could reduce this burden of disease but the training of health-care providers in low income settings is often outdated. Our aim was to determine if a simple one day newborn resuscitation training (NRT) alters health worker resuscitation practices in a public hospital setting in Kenya.

Methods/Principal Findings

We conducted a randomised, controlled trial with health workers receiving early training with NRT (n = 28) or late training (the control group, n = 55). The training was adapted locally from the approach of the UK Resuscitation Council. The primary outcome was the proportion of appropriate initial resuscitation steps with the frequency of inappropriate practices as a secondary outcome. Data were collected on 97 and 115 resuscitation episodes over 7 weeks after early training in the intervention and control groups respectively. Trained providers demonstrated a higher proportion of adequate initial resuscitation steps compared to the control group (trained 66% vs control 27%; risk ratio 2.45, [95% CI 1.75–3.42], p<0.001, adjusted for clustering). In addition, there was a statistically significant reduction in the frequency of inappropriate and potentially harmful practices per resuscitation in the trained group (trained 0.53 vs control 0.92; mean difference 0.40, [95% CI 0.13–0.66], p = 0.004).

Conclusions/Significance

Implementation of a simple, one day newborn resuscitation training can be followed immediately by significant improvement in health workers'' practices. However, evidence of the effects on long term performance or clinical outcomes can only be established by larger cluster randomised trials.

Trial Registration

Controlled-Trials.com ISRCTN92218092     

Miltefosine in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis in Brazil: a randomized and controlled trial

Background

Cutaneous leishmaniasis (CL) is treated with parenteral drugs for decades with decreasing rate cures. Miltefosine is an oral medication with anti-leishmania activity and may increase the cure rates and improve compliance.

Methodology/Principal Findings

This study is a randomized, open-label, controlled clinical trial aimed to evaluate the efficacy and safety of miltefosine versus pentavalent antimony (Sb^v) in the treatment of patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients were enrolled in the trial; 60 were assigned to receive miltefosine and 30 to receive Sb^v. Six months after treatment, in the intention-to-treat analyses, the definitive cure rate was 53.3% in the Sb^v group and 75% in the miltefosine group (difference of 21.7%, 95% CI 0.08% to 42.7%, p = 0.04). Miltefosine was more effective than Sb^v in the age group of 13–65 years-old compared to 2–12 years-old group (78.9% versus 45% p = 0.02; 68.2% versus 70% p = 1.0, respectively). The incidence of adverse events was similar in the Sb^v and miltefosine groups (76.7% vs. 78.3%). Vomiting (41.7%), nausea (40%), and abdominal pain (23.3%) were significantly more frequent in the miltefosine group while arthralgias (20.7%), mialgias (20.7%) and fever (23.3%) were significantly more frequent in the Sb^v group.

Conclusions

This study demonstrates that miltefosine therapy is more effective than standard Sb^v and safe for the treatment of CL caused by Leishmania braziliensis in Bahia, Brazil.

Trial Registration

Clinicaltrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT00600548","term_id":"NCT00600548"}}NCT00600548     

Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: randomised placebo-controlled double-blind trial

Background

To determine if oral metronidazole (MTZ-400mg bid) with 2% vaginal clindamycin-cream (Clind) or a Lactobacillus acidophilus vaginal-probiotic containing oestriol (Prob) reduces 6-month bacterial vaginosis (BV) recurrence.

Methods

Double-blind placebo-controlled parallel-group single-site study with balanced randomization (1∶1∶1) conducted at Melbourne Sexual Health Centre, Australia. Participants with symptomatic BV [Nugent Score (NS) = 7–10 or ≥3 Amsel''s criteria and NS = 4–10], were randomly allocated to MTZ-Clind, MTZ-Prob or MTZ-Placebo and assessed at 1,2,3 and 6 months. MTZ and Clind were administered for 7 days and Prob and Placebo for 12 days. Primary outcome was BV recurrence (NS of 7–10) on self-collected vaginal-swabs over 6-months. Cumulative BV recurrence rates were compared between groups by Chi-squared statistics. Kaplan-Meier, log rank and Cox regression analyses were used to compare time until and risk of BV recurrence between groups.

Results

450 18–50 year old females were randomized and 408 (91%), equally distributed between groups, provided ≥1 NS post-randomization and were included in analyses; 42 (9%) participants with no post-randomization data were excluded. Six-month retention rates were 78% (n = 351). One-month BV recurrence (NS 7–10) rates were 3.6% (5/140), 6.8% (9/133) and 9.6% (13/135) in the MTZ-Clind, MTZ-Prob and MTZ-Placebo groups respectively, p = 0.13. Hazard ratios (HR) for BV recurrence at one-month, adjusted for adherence to vaginal therapy, were 0.43 (95%CI 0.15–1.22) and 0.75 (95% CI 0.32–1.76) in the MTZ-Clind and MTZ-Prob groups compared to MTZ-Plac respectively. Cumulative 6-month BV recurrence was 28.2%; (95%CI 24.0–32.7%) with no difference between groups, p = 0.82; HRs for 6-month BV recurrence for MTZ-Clind and MTZ-Prob compared to MTZ-Plac, adjusted for adherence to vaginal therapy were 1.09(95% CI = 0.70–1.70) and 1.03(95% CI = 0.65–1.63), respectively. No serious adverse events occurred.

Conclusion

Combining the recommended first line therapies of oral metronidazole and vaginal clindamycin, or oral metronidazole with an extended-course of a commercially available vaginal-L.acidophilus probiotic, does not reduce BV recurrence.

Trial Registration

ANZCTR.org.au ACTRN12607000350426