Kathrine R. Tan

Doxycycline for Malaria Chemoprophylaxis and Treatment: Report from the CDC Expert Meeting on Malaria Chemoprophylaxis

Doxycycline, a synthetically derived tetracycline, is a partially efficacious causal prophylactic (liver stage of Plasmodium) drug and a slow acting blood schizontocidal agent highly effective for the prevention of malaria. When used in conjunction with a fast acting schizontocidal agent, it is also highly effective for malaria treatment. Doxycycline is especially useful as a prophylaxis in areas with chloroquine and multidrug-resistant Plasmodium falciparum malaria. Although not recommended for pregnant women and children < 8 years of age, severe adverse events are rarely reported for doxycycline. This report examines the evidence behind current recommendations for the use of doxycycline for malaria and summarizes the available literature on its safety and tolerability.

Extensive drug resistance acquired during treatment of multidrug-resistant tuberculosis.

BACKGROUND Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance. METHODS To assess the GLCs impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC. RESULTS In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16-.47) for XDR tuberculosis, 0.28 (.17-.45) for FQ, and 0.15 (.06-.39) to 0.60 (.34-1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07-.62) for acquired XDR tuberculosis and 0.23 (.09-.59) for acquired FQ resistance. CONCLUSIONS Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards.

Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance

BACKGROUND Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. METHODS Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. RESULTS Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. CONCLUSIONS Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

Abbreviated atovaquone-proguanil prophylaxis regimens in travellers after leaving malaria-endemic areas: A systematic review

BACKGROUND We evaluated existing data on the prophylactic efficacy of atovaquone-proguanil (AP) in order to determine whether prophylaxis in travellers can be discontinued on the day of return from a malaria-endemic area instead of seven days after return as per currently recommended post-travel schedule. METHODS PubMed and Embase databases were searched to identify relevant studies. This PROSPERO-registered systematic review followed PRISMA guidelines. The search strategy included terms or synonyms relevant to AP combined with terms to identify articles relating to prophylactic use of AP and inhibitory and half-life properties of AP. Studies considered for inclusion were: randomized controlled trials, cohort studies, quasi-experimental studies, open-label trials, patient-control studies, cross-sectional studies; as well as case-series and non-clinical studies. Data on study design, characteristics of participants, interventions, and outcomes were extracted. Primary outcomes considered relevant were prophylactic efficacy and prolonged inhibitory activity and half-life properties of AP. RESULTS The initial search identified 1,482 publications, of which 40 were selected based on screening. Following full text review, 32 studies were included and categorized into two groups, namely studies in support of the current post-travel regimen (with a total of 2,866 subjects) and studies in support of an alternative regimen (with a total of 533 subjects). CONCLUSION There is limited direct and indirect evidence to suggest that an abbreviated post-travel regimen for AP may be effective. Proguanil, however, has a short half-life and is essential for the synergistic effect of the combination. Stopping AP early may result in mono-prophylaxis with atovaquone and possibly select for atovaquone-resistant parasites. Furthermore, the quality of the studies in support of the current post-travel regimen outweighs the quality of the studies in support of an alternative short, post-travel regimen, and the total sample size of the studies to support stopping AP early comprises a small percentage of the total sample size of the studies performed to establish the efficacy of the current AP regimen. Additional research is required - especially from studies evaluating impact on malaria parasitaemia and clinical illness and conducted among travellers in high malaria risk settings - before an abbreviated regimen can be recommended in current practice. PROSPERO REGISTRATION NUMBER CRD42017055244.

Investigation of a case of suspected transfusion-transmitted malaria: TTM INVESTIGATION BEST PRACTICES

Transfusion‐transmitted malaria (TTM) is a rare occurrence with serious consequences for the recipient. A case study is presented as an example of best practices for conducting a TTM investigation.

Malaria Diagnostic Practices in United States Laboratories, 2017

In the United States, the gold standard for malaria diagnosis is microscopic blood smear examination. Because malaria is not endemic in the United States, diagnostic capabilities may be limited, causing delays in diagnosis and increased morbidity and mortality. ABSTRACT In the United States, the gold standard for malaria diagnosis is microscopic blood smear examination. Because malaria is not endemic in the United States, diagnostic capabilities may be limited, causing delays in diagnosis and increased morbidity and mortality. A survey of the malaria diagnostic practices of U.S. laboratories was conducted from June to July 2017; members of the American Society for Microbiologys listserv received a questionnaire inquiring about malaria diagnostic test availability, techniques, and reporting. Results were assessed using the Clinical and Laboratory Standards Institute (CLSI) guidelines for malaria diagnostics. After excluding incomplete and duplicate responses, responses representing 175 laboratories were included. Most labs (99%) received at least one specimen annually for malaria diagnosis, and 31% reported receiving only 1 to 10 specimens. The majority (74%) diagnosed five or fewer cases of malaria per year. Most (90%) performed blood smears on-site. Two-thirds (70%) provided initial blood smear results within 4 h. Although diagnostic testing for malaria was available 24/7 at 74% (141) of responding laboratories, only 12% (17) met criteria for analysis and reporting of malaria testing, significantly more than reported in a similar survey in 2010 (3%; P < 0.05). The majority of laboratories surveyed had the capability for timely diagnosis of malaria; few comply with CLSI guidelines. Inexperience may factor into this noncompliance; many laboratories see few to no cases of malaria per year. Although reported adherence to CLSI guidelines was higher than in 2010, there is a need to further improve laboratory compliance with recommendations.

Case 28-2015: A Man with Febrile Symptoms after Traveling from Liberia.

n engl j med 374;3 nejm.org January 21, 2016 293 priate approach to such situations should they arise. However, we think that expecting airlines to provide a complete set of medical supplies on all commercial flights is not appropriate. A commercial aircraft is, in fact, simply that — a commercial aircraft. Passengers must exercise good judgment with regard to the advisability of air travel if they have or expect to have illness or injury that should preclude it. Of course, we also understand that some events occur without warning. There is also the problem of training flight attendants to use the supplies. In most instances, the only training flight attendants receive involves very basic first aid, which allows for only limited interventions. Volunteer health care providers can provide assistance, but their range of abilities may also limit care. Furthermore, an airline assumes some liability by placing medical equipment on an aircraft that its personnel are not sufficiently trained to use. If certain equipment is mandated by law or a legitimate standard of care exists, then the relevant equipment or material must be provided. However, it is important to bear in mind that in-flight medical emergencies present a wide variety of challenges that require not only the appropriate equipment but also appropriate training in the use of that equipment.

Reply to Shaz et al

TO THE EDITOR—We appreciate the comments from Shaz et al [1] regarding the limitations of our article [2] on the use of exchange transfusion (ET) for severe malaria. We would like to take this opportunity for further discussion considering the differences in recommendations between our article and that of the Ameri-can Society for Apheresis (ASFA) special issue [3]. The ASFA drew its evidence from a limited pool of literature, mostly case studies. Our recommendations were based on the results of our study and the findings of a comprehensive literature review. Our study was underpowered, as was mentioned in our article. Given the 1.9% difference in mortality rates, a sample size of 5071 ET patients and 20 284 nonET patients would have been needed to see a significant difference, but this is not feasibly achieved. In the 25 years of US national surveillance data examined, there were only 176 patients receiving ET for severe malaria. Further analysis shows that inclusion of missing data does not change our observations. Imputing missing data for 5 ET patients who survived, mentioned as a limitation in the Shaz et al letter, resulted in similar results for survival as when these 5 cases were excluded (odds ratio = 0.87 [95% confidence interval, .46–1.63]). To examine the impact of including the 38% of severe malaria cases with missing survival data, we assumed that all ET patients and 84.1% of nonET patients survived (proportions observed among those with a known survival outcome) and reanalyzed the data with these patients included. There was no significant difference in survival outcomes (χ 2 = 1.18; df = 1; P = .28). We attempted to control for missing parasite density by matching those with known parasite-mia. For those with unknown parasite-mia, we matched on clinical criteria to achieve some parity of severity of illness. Furthermore, 1 retrospective cohort study since the Riddle et al meta-analysis found that of patients with parasitemias at >10%, survival among those with ET versus those without ET was not statistically different [4]. Online translation was required for only 8 of the 193 articles, of which 5 had an English-language summary available on PubMed. Of the 3 that did not, 2 were case reports, and the other was a general review of malaria treatment. Therefore, using online translation for those few articles would not have affected the findings of the comprehensive literature review. ASFA suggests that ET should …