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Background Treatment of melioidosis comprises intravenous drugs for at least 10 days, followed by oral trimethoprim-sulfamethoxazole (TMP-SMX) for 12 to 20 weeks. Oral TMP-SMX is recommended for 12 weeks in Australia and 20 weeks in Thailand. Methods For this open-label, pragmatic, multicenter, noninferiority, randomized controlled trial, we enrolled patients with culture-confirmed melioidosis who had received oral eradication treatment for 12 weeks and had no clinical evidence of active melioidosis. We randomly assigned patients to stop treatment (12-week regimen) or continue treatment for another 8 weeks (20-week regimen). The primary end point was culture-confirmed recurrent melioidosis within 1 year after enrollment. The noninferiority margin was a hazard ratio (HR) of 2.0. The secondary composite end point, combining overall recurrent melioidosis and mortality, was assessed post hoc. Results We enrolled 658 patients: 322 to the 12-week regimen and 336 to the 20-week regimen. There were 5 patients (2%) in the 12-week regimen and 2 patients (1%) in the 20-week regimen who developed culture-confirmed recurrent melioidosis (HR, 2.66; 95% confidence interval [CI],.52–13.69). The criterion for noninferiority of the primary event was not met (1-sided P =.37). However, all-cause mortality was significantly lower in the 12-week regimen group than in the 20-week regimen group (1 [.3%] vs 11 [3%], respectively; HR, 0.10; 95% CI,.01–.74). The criterion for noninferiority of the secondary composite end point, combining overall recurrent melioidosis and mortality, was met (1-sided P =.022). Conclusions Based on the lower total mortality and noninferiority of the secondary composite end point observed, we recommend the 12-week regimen of TMP-SMX for oral eradication treatment of melioidosis. Clinical Trials Registration NCT01420341. [ABSTRACT FROM AUTHOR]

Scrub typhus, a neglected infectious disease caused by the obligate intracellular bacterium Orientia tsutsugamushi , is a major cause of fever across the Asia Pacific region with more than a billion people at risk. Treatment with antibiotics such as doxycycline or chloramphenicol is effective for the majority of patients. In the 1990s, reports from northern Thailand raised a troubling observation; some scrub typhus patients responded poorly to doxycycline, which investigators attributed to doxycycline resistance. Despite the controversial nature of these reports, independent verification was neglected, with subsequent studies speculating on the role of doxycycline resistance in contributing to failure of treatment or prophylaxis. In this review, we have outlined the evidence for drug-resistant Orientia tsutsugamushi , assessed the evidence for doxycycline resistance, and highlight more recent findings unsupportive of doxycycline resistance. We conclude that doxycycline resistance is a misconception, with treatment outcome likely to be determined by other bacterial, host, and pharmacological factors. [ABSTRACT FROM AUTHOR]

Background Cambodia introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in January 2015 using a 3 + 0 dosing schedule and no catch-up campaign. We investigated the effects of this introduction on pneumococcal colonization and invasive disease in children aged <5 years. Methods There were 6 colonization surveys done between January 2014 and January 2018 in children attending the outpatient department of a nongovernmental pediatric hospital in Siem Reap. Nasopharyngeal swabs were analyzed by phenotypic and genotypic methods to detect pneumococcal serotypes and antimicrobial resistance. Invasive pneumococcal disease (IPD) data for January 2012–December 2018 were retrieved from hospital databases. Pre-PCV IPD data and pre-/post-PCV colonization data were modelled to estimate vaccine effectiveness (VE). Results Comparing 2014 with 2016–2018, and using adjusted prevalence ratios, VE estimates for colonization were 16.6% (95% confidence interval [CI] 10.6–21.8) for all pneumococci and 39.2% (95% CI 26.7–46.1) for vaccine serotype (VT) pneumococci. There was a 26.0% (95% CI 17.7–33.0) decrease in multidrug-resistant pneumococcal colonization. The IPD incidence was estimated to have declined by 26.4% (95% CI 14.4–35.8) by 2018, with a decrease of 36.3% (95% CI 23.8–46.9) for VT IPD and an increase of 101.4% (95% CI 62.0–145.4) for non-VT IPD. Conclusions Following PCV13 introduction into the Cambodian immunization schedule, there have been declines in VT pneumococcal colonization and disease in children aged <5 years. Modelling of dominant serotype colonization data produced plausible VE estimates. [ABSTRACT FROM AUTHOR]

Background. Deployment of mefloquine-artesunate (MAS3) on the Thailand-Myanmar border has led to a sustained reduction in falciparum malaria, although antimalarial efficacy has declined substantially in recent years. The role of Plasmodium falciparum K13 mutations (a marker of artemisinin resistance) in reducing treatment efficacy remains controversial. Methods. Between 2003 and 2013, we studied the efficacy of MAS3 in 1005 patients with uncomplicated P. falciparum malaria in relation to molecular markers of resistance. Results. Polymerase chain reaction (PCR)-adjusted cure rates declined from 100% in 2003 to 81.1% in 2013 as the proportions of isolates with multiple Pfmdr1 copies doubled from 32.4% to 64.7% and those with K13 mutations increased from 6.7% to 83.4%. K13 mutations conferring moderate artemisinin resistance (notably E252Q) predominated initially but were later overtaken by propeller mutations associated with slower parasite clearance (notably C580Y). Those infected with both multiple Pfmdr1 copy number and a K13 propeller mutation were 14 times more likely to fail treatment. The PCR-adjusted cure rate was 57.8% (95% confidence interval [CI], 45.4, 68.3) compared with 97.8% (95% CI, 93.3, 99.3) in patients with K13 wild type and Pfmdr1 single copy. K13 propeller mutation alone was a strong risk factor for recrudescence (P = .009). The combined population attributable fraction of recrudescence associated with K13 mutation and Pfmdr1 amplification was 82%. Conclusions. The increasing prevalence of K13 mutations was the decisive factor for the recent and rapid decline in efficacy of artemisinin-based combination (MAS3) on the Thailand-Myanmar border. [ABSTRACT FROM AUTHOR]

A review was performed to determine the evidence base for scrub typhus indirect immunofluorescence assay (IFA) methodologies and the criteria for positive results. This review included a total of 109 publications, which comprised 123 eligible studies for analysis (14 publications included 2 substudies). There was considerable underreporting of the IFA methodology and seropositivity criteria used, with most studies using a defined cutoff titer rather than an increase in the titer in paired samples. The choice of positivity cutoff titer varied by country and purpose of the IFA test. This variation limits the comparability of seroprevalence rates between studies and, more seriously, raises questions about the appropriateness of the cutoffs for positive IFA results chosen for diagnosis of acute scrub typhus infection. We suggest that the diagnosis of scrub typhus using IFA should be based on a ⩾4-fold increase in the titer in paired serum samples and should only be based on a single sample titer when there is an adequate local evidence base. [ABSTRACT FROM AUTHOR]

Background. The serological diagnosis of acute dengue virus infection relies on the detection of dengue-specific immunoglobulin M (IgM) antibodies. Immunochromatographic tests are rapid diagnostic tests (RDTs) that can be performed at the bedside, but they have not been fully validated for diagnosis of dengue infection. Methods. More than 20 RDTs for diagnosis of acute dengue infection are commercially available. Of these, 8 were selected for evaluation of performance by use of characterized dengue and nondengue serum specimens, and results were compared with those of a previously published dengue IgM/IgG enzyme-linked immunosorbent assay in conjunction with dengue virus serotyping by reverse-transcriptase polymerase chain reaction. Results. Assay sensitivities were low, ranging from 6.4% (95% confidence interval [CI], 4.0%–9.7%) to 65.3% (95% CI, 59.9%–70.5%), and specificities ranged from 69.1% (95% CI, 61.4%–76.0%) to 100% (95% CI, 97.8%–100%). Of the 8 tests, only 2 had sensitivities of 150%, the level considered to be clinically useful, and, of these, 1 had relatively low specificity (69.1%). Samples collected early in the infection were less likely to test positive than those collected later. A thermal stability study demonstrated a loss in performance of some RDTs when they were stored at a high ambient temperature for 3 months. Conclusions. Users of RDTs for dengue should be aware that many of these tests have a diagnostic accuracy that falls well below the manufacturers' claims. If an acute specimen yields a negative result, a convalescent serum sample should be tested to confirm the result. No RDT adequately differentiated primary and secondary dengue infections, and the tests should not be used for this purpose. [ABSTRACT FROM AUTHOR]

Background. The role of both host and pathogen characteristics in hematogenous seeding following Staphylococcus aureus bacteremia is incompletely understood. Methods. Consecutive patients with intravascular catheter-associated Staphylococcus aureus bacteremia were prospectively recruited over a 91-month period. The corresponding bloodstream isolates were examined for the presence of 35 putative virulence determinants. Patient and bacterial characteristics associated with the development of hematogenous complications (HCs) (i.e., septic arthritis, vertebral osteomyelitis, or endocarditis) were defined. Results. HC occurred in 42 (13%) of 324 patients. Patient characteristics at diagnosis that were associated with HC included community onset (relative risk [RR], 2.25; 95% confidence interval [CI], 1.24-4.07; P = .007), increased symptom duration (odds ratio for each day, 1.14; 95% CI, 1.06-1.2; P<.001), presence of a long-term intravascular catheter or noncatheter prosthesis (RR, 4.02; 95% CI, 1.74-9.27; P<.001), hemodialysis dependence (RR, 3.84; 95% CI, 2.08-7.10; P<.001), and higher APACHE II score (P = .02). Bacterial characteristics included sea (RR, 2.03; 95% CI, 1.16-3.55; P = .011) and methicillin-resistant S. aureus (MRSA) (RR, 2.09; 95% CI, 1.19-3.67; P = .015). Subsequent failure to remove a catheter was also associated with HC (RR, 2.28; 95% CI, 1.22-4.27; P = .011). On multivariable analysis, symptom duration, hemodialysis dependence, presence of a long-term intravascular catheter or a noncatheter device, and infection with MRSA remained significantly associated with HC. Conclusions. This investigation identifies 4 host- and pathogen-related risk factors for hematogenous bacterial seeding and reaffirms the importance of prompt catheter removal. [ABSTRACT FROM AUTHOR]

Presents information on a study which compared capillary permeability in cases of dengue shock syndrome and dengue hemorrhagic fever. Methodology; Results of the study; Discussion.

Nalidixic acid-resistant Salmonella typhi (NARST) was first isolated in Viet Nam in 1993. Analysis of the quinolone resistance-determining region of gyrA in 20 NARST isolates by polymerase chain reaction and single-stranded conformational polymorphism yielded two novel patterns: pattern II corresponding to a point mutation at nucleotide 87 Asp → Gly (n = 17), and pattern III corresponding to a point mutation at nucleotide 83 Ser → Phe (n = 3). In trials of short-course ofloxacin therapy for uncomplicated typhoid, 117 (78%) of 150 patients were infected with multidrug-resistant S. typhi, 18 (15%) of which were NARST. The median time to fever clearance was 156 hours (range, 30-366 hours) for patients infected with NARST and 84 hours (range, 12-378 hours) for those infected with nalidixic acid-susceptible strains (P < .001). Six (33.3%) of 18 NARST infections required retreatment, whereas 1 (0.8%) of 132 infections due to susceptible strains required retreatment (relative risk = 44; 95% confidence interval = 5.6-345; P < .0001). We recommend that short courses of quinolones not be used in patients infected with NARST. [ABSTRACT FROM PUBLISHER]

We prospectively studied 50 Vietnamese patients with blackwater fever (BWF). All patients had fever and hemoglobinuria, 40 (80%) were jaundiced, 25 (50%) had hepatomegaly, 17 (34%) had splenomegaly, and 9 (18%) had hepatosplenomegaly. Twenty-one patients (42%) had impaired renal function, with creatinine clearances of <50 mL/min/m2; however, only four (8%) developed oliguric renal failure, three (6%) of whom required dialysis. Forty-four patients (88%) developed anemia, which was severe (hematocrit, <20%) in 32 (64%). One patient died, representing a death rate for this once-feared disease that is considerably lower than that reported by earlier investigators. BWF was associated with quinine ingestion in 28 patients (56%), glucose-6-phosphate dehydrogenase (G6PD) deficiency in 27 (54%), and concurrent malaria infection in 16 (32%). There was no statistically significant difference in the severity of BWF associated with each of these three factors, as assessed by creatinine clearance and the hematocrit value on admission and by the number of units of blood transfused. There was considerable overlap in the occurrence of G6PD deficiency, quinine ingestion, and malaria, suggesting that these factors may interact and that it may not be justifiable to regard hemoglobinuria caused by G6PD deficiency as a separate syndrome. [ABSTRACT FROM PUBLISHER]

In recent years, multiresistant strains of Salmonella typhi have emerged in many tropical countries. These strains remain highly sensitive to the fluoroquinolone antibiotics, although use of these drugs by children is considered contraindicated because of their reported toxicity in the cartilage of experimental animals. In a paired, open, randomized study during an epidemic of multidrug-resistant typhoid in southern Vietnam, two short-course ofloxacin regimens (15 mg/kg daily for 3 days and 10 mg/kg daily for 5 days) were compared for the treatment of uncomplicated typhoid fever. Of 438 patients enrolled (of whom 286 were ⩽14 years old), 228 had blood cultures positive for Salmonella species (S. typhi, 207; S. paratyphi A, 19; and S. choleraesuis, 2). There was one treatment failure in a patient who took only one dose of ofloxacin. Otherwise, both regimens were completely effective; there were no proven carriers, and there was no evidence of toxicity, particularly in children. A 3-day course of ofloxacin proved to be safe and highly effective in the treatment of uncomplicated, multidrug-resistant typhoid fever. [ABSTRACT FROM PUBLISHER]

The clinical, the 12-lead, and the 24-hour electrocardiographic findings in 15 consecutively studied Vietnamese children (aged 7 months to 16 years) with severe diphtheria were documented. Five patients died, three from respiratory arrest and two from cardiogenic shock; one of these two patients had complete heart block that necessitated insertion of a pacemaker. Electrocardiographic abnormalities were detected by 24-hour monitoring in all 15 cases, even though most patients had no clinical signs of myocarditis. Rates of supraventricular and ventricular ectopy were elevated and remained high long after other clinical manifestations were no longer noted. The degree of ventricular ectopy at the time of presentation was significantly associated with fatal outcome. In this series, more than two ventricular ectopic beats on a recording upon admission to the hospital predicted fatal outcome with 100% sensitivity and 100% specificity. A variety of nonsustained bradyarrhythmias and tachyarrhythmias were also observed up until discharge from the hospital. The time course of recovery from diphtheritic myocarditis is longer than has been appreciated previously. [ABSTRACT FROM PUBLISHER]

A letter to the editor is presented about the misattribution of central nervous system dysfunction to artesunate therapy.

New treatment strategies are needed for artemisinin-resistant falciparum malaria. This randomized trial shows that neither increasing nor splitting the standard once-daily artesunate dose reverses the markedly reduced parasite clearance rate in patients with artemisinin-resistant falciparum malaria.Background. The emergence of Plasmodium falciparum resistance to artemisinins on the Cambodian and Myanmar-Thai borders poses severe threats to malaria control. We investigated whether increasing or splitting the dose of the short-half-life drug artesunate improves parasite clearance in falciparum malaria in the 2 regions.Methods. In Pailin, western Cambodia (from 2008 to 2010), and Wang Pha, northwestern Thailand (2009–2010), patients with uncomplicated falciparum malaria were randomized to oral artesunate 6 mg/kg/d as a once-daily or twice-daily dose for 7 days, or artesunate 8 mg/kg/d as a once-daily or twice-daily dose for 3 days, followed by mefloquine. Parasite clearance and recrudescence for up to 63 days of follow-up were assessed.Results. A total of 159 patients were enrolled. Overall median (interquartile range [IQR]) parasitemia half-life (half-life) was 6.03 (4.89–7.28) hours in Pailin versus 3.42 (2.20–4.85) hours in Wang Pha (P = .0001). Splitting or increasing the artesunate dose did not shorten half-life in either site. Pharmacokinetic profiles of artesunate and dihydroartemisinin were similar between sites and did not correlate with half-life. Recrudescent infections occurred in 4 of 79 patients in Pailin and 5 of 80 in Wang Pha and was not different between treatment arms (P = .68).Conclusions. Increasing the artesunate treatment dose up to 8 mg/kg/d or splitting the dose does not improve parasite clearance in either artemisinin resistant or more sensitive infections with P. falciparum.Clinical Trials Registration. ISRCTN15351875. [ABSTRACT FROM PUBLISHER]