BackgroundThe Benefits of Universal Gloves and Gowns cluster randomized trial found varying effects on MRSA and VRE and no increase in adverse events. The aim of this study was to assess whether the intervention decreases the acquisition of antibiotic-resistant Gram-negative bacteria. MethodsSecondary analysis of 20 hospital intensive care unit, randomized trial. The intervention consisted of healthcare workers wearing gloves and gowns when entering any patient room compared to standard care. The primary composite outcome was acquisition of any antibiotic-resistant Gram-negative bacteria based on surveillance cultures. FindingsA total of 40,492 admission and discharge perianal swabs from 20,246 individual patient admissions were included in the primary outcome. For the primary outcome of acquisition of any antibiotic-resistant Gram-negative bacteria, the intervention had a RR of 0.90 (95% CI 0.71 to 1.12, p= 0.34). Effects on the secondary outcomes of individual bacteria acquisition were as follows: carbapenem-resistant Enterobacteriaceae [RR 0.86 (95% CI, 0.60 to 1.24), p=0.43], carbapenem-resistant Acinetobacter [RR 0.81 (95% CI, 0.52 to 1.27) p=0.36], carbapenem-resistant Pseudomonas [RR 0.88 (95% CI, 0.55 to 1.42) p=0.62], ESBL producing bacteria [RR 0.94, (95% CI, 0.71 to 1.24) p=0.67]. InterpretationUniversal glove and gown use in the ICU was associated with a non-statistically significant decrease in acquisition of antibiotic-resistant Gram-negative bacteria. Individual hospitals should consider the intervention based on the importance of these organisms at their hospital, effect sizes, confidence intervals, and cost of instituting the intervention. Trial registrationClinicaltrials.gov identifier NCT01318213

Rising levels of antimicrobial resistance pose serious dangers to patients, population health, food security, and economic stability worldwide. In response to this threat, the United Nations and the World Health Organization have called for multisectoral, multidisciplinary action, recognizing that human, animal, and environmental health are interdependent. While the pharmaceutical industry clearly has a leading role in developing novel antimicrobials and vaccines, it is also active in many areas supporting antimicrobial stewardship. This article describes why pharmaceutical companies invest in antimicrobial stewardship, outlines why they are well suited to help address this issue, and provides examples of how the pharmaceutical industry can support the responsible use of antimicrobials. Merck & Co., Inc. (Kenilworth, NJ, USA), a large, globally-operating pharmaceutical company that develops and markets both human and veterinary antimicrobials and vaccines is used as a case-study for illustrating industry involvement in antimicrobial stewardship efforts.

BackgroundAlthough prevention of mother-to-child transmission (PMTCT) interventions have substantially reduced vertical HIV infection in sub-Saharan Africa, mortality and growth among children who are HIV-exposed remain uncertain. MethodsSHINE was a cluster-randomised trial of improved infant and young child feeding (IYCF) and/or water, sanitation and hygiene in two rural Zimbabwean districts with 15% antenatal HIV prevalence and >80% PMTCT coverage. Pregnant women enrolled between November 2012 and March 2015 underwent HIV testing. Children had longitudinal HIV testing and anthropometry. We compared mortality and growth between children who were HIV-exposed and HIV-unexposed through 18 months. Children receiving the IYCF intervention were excluded from growth analyses. FindingsAmong 4727 live births, 51/738 (7%) children who were HIV-exposed and 198/3989 (5%) children who were HIV-unexposed died (hazard ratio 1.41, 95%CI 1.02, 1.93). Among 738 children exposed to HIV, 25 (3%) tested HIV-positive, 596 (81%) were HIV-exposed uninfected (CHEU), and 117 (16%) had unknown HIV status by 18 months; overall transmission estimates were 4.3-7.7%. In CHEU compared to children unexposed to HIV, mean length-for-age Z-scores at 18 months were 0.38 (95%CI 0.24, 0.51) standard deviations lower, and stunting prevalence was 16 percentage points (95%CI 10,22) higher (51% versus 34%). Among 367 children exposed to HIV in non-IYCF arms, 147 (40%) were alive, HIV-free and non-stunted at 18 months, compared to 1169/1956 (60%) children unexposed to HIV (absolute difference 20%; 95%CI 15, 26). InterpretationIn rural Zimbabwe, mortality remains 40% higher among children exposed to HIV, vertical transmission exceeds elimination targets, and half of CHEU are stunted. We propose the composite outcome of ‘Alive, HIV-free and thriving’ should be the long-term goal of PMTCT programmes.

BackgroundThe prevalence of bronchiectasis (BE) is high in patients with chronic obstructive pulmonary disease (COPD). BE impacts their clinical course and prognosis. Yet, the temporal evolution of BE in these patients is unknown. This study seeks to assess the temporal evolution of BE in COPD patients MethodsIn 2013 we reported a cohort of 201 COPD patients (GOLD II-IV) recruited between 2004 and 2007. Patients were followed up clinically, at least every 6 months, for a median of 102 (77-116.5) months. To investigate the temporal evolution of BE, in 2015 a second high-resolution computed tomography scan (HRCT) was obtained in survivors and compared with the one obtained at recruitment. ResultsOut of the 201 patients initially recruited, 99 (49.3%) died during follow-up. The second HRCT could be obtained in 77 patients (78% of survivors) and showed that: (1) in 27.3% of patients BE never developed, in 36.4% they remained stable, in 16.9% they increased in size and/or extension and in 19.5% new BE emerged; and, (2) the presence of chronic muco-purulent or purulent sputum (HR 2.8 [95%CI:1.3-5.8]), frequency of hospitalization episodes due to exacerbations of COPD (HR 1.2 [95%CI:1.1-1.5]) and number of any potentially pathogenic microorganism (PPM) isolations (HR 1.1 [95%CI:1.02-1.3]) were independent risk factors for the progression of existing BE or the emergence of new ones. ConclusionsThe presence of chronic purulent sputum production, number of PPM isolated in sputum and number of hospitalizations due to exacerbations of COPD are independent, preventable and treatable risk factors of BE progression in patients with COPD

Despite the elimination of measles in the US in the year 2000, cases continue to occur with measles outbreaks having occurred in various jurisdictions in the US in 2018 and 2019. Understanding the cost associated to measles outbreaks can inform cost-of-illness and cost-effectiveness studies of measles and measles prevention. We performed a literature review and identified 10 published studies from 2001-2018 that presented cost estimates from 11 measles outbreaks. Median total costs per measles outbreak were $152,308 (range, $9,862-$1,063,936); median cost per case was $32,805 (range, $7,396-$76,154) and median cost per contact was $223 (range, $81-$746). There was limited data on direct and indirect costs associated with measles. These findings highlight how costly measles outbreaks can be, the value of this information for public health department budgeting, and the importance of more broadly documenting the cost of measles outbreaks.

BackgroundGonorrhea diagnosis rates in the U.S. increased by 75% during 2009-2017, predominantly in men. It is unclear whether the increase among men is being driven by more screening, an increase in the prevalence of disease, or both. We sought to evaluate changes in gonorrhea testing patterns and positivity among men in Massachusetts. MethodsThe analysis included men ≥15 years who received care during 2010-2017 in three clinical practice groups. We calculated annual percentages of men who received a gonorrhea test and men with at least one positive result, among men tested. Log-binomial regression models were used to examine trends in these outcomes. We adjusted for clinical and demographic characteristics that may influence predilection to test and probability of gonorrhea disease. ResultsOn average 306,348 men had encounters each year. There was a significant increase in men with at least one gonorrhea test from 2010 (3.1%) to 2017 (6.4%; adjusted annual RR: 1.12, 95% CI 1.12,1.13). There was a significant, albeit lesser, increase in the percentage of tested men with at least one positive result (1.0% in 2010 to 1.5% in 2017; adjusted annual RR: 1.07, 95% CI 1.04,1.09). ConclusionsWe estimated significant increases in the proportion of men tested at least once in a year for gonorrhea and the proportion of tested men with at least one positive gonorrhea result between 2010 and 2017. These results suggest that observed increases in gonorrhea rates could be explained by both increases in screening and the prevalence of gonorrhea.

BackgroundWhen trying to control regional spread of antibiotic-resistant pathogens like carbapenem-resistant Enterobacteriaceae (CRE), decision-makers must choose the highest yield facilities to target for interventions. The question is, with limited resources, how best to choose these facilities. MethodsUsing our Regional Healthcare Ecosystem Analyst-generated agent-based model of all Chicago metropolitan area inpatient facilities, we simulated CRE’s spread and different ways of choosing facilities to apply a prevention bundle (screening, chlorhexidine bathing, hand-hygiene, geographic separation, and patient registry) to a resource-limited 1,686 inpatient beds. ResultsRandomly selecting facilities did not impact prevalence, but averted 620 new carriers and 175 infections, saving $6.3 million in total costs compared to no intervention. Selecting facilities by type (e.g., LTACHs) yielded a 16.1% relative prevalence decrease, preventing 1,960 cases and 558 infections, saving $62.4 million more than random selection. Choosing the largest facilities was better than random selection, but not than by type. Selecting by considering connections to other facilities (i.e., out-degree) yielded a 9.5% relative prevalence decrease, preventing 1,580 cases, 470 infections, and saving $51.6 million more than random selection. Selecting facilities using a combination of these metrics yielded the greatest reduction (19.0% relative prevalence decrease, preventing 1,840 cases, 554 infections, saving $59.6 million compared to random selection). ConclusionWhile choosing target facilities based on single metrics (e.g., most inpatient beds, most connections to other facilities) achieved better control than randomly choosing facilities, more effective targeting occurred when considering how these and other factors (e.g., patient length-of-stay, care for higher-risk patients) interacted as a system.

BackgroundIn Melanesia, the prevalence of trachomatous inflammation—follicular (TF) suggests public health-level interventions against active trachoma are needed. However, the prevalence of trachomatous trichiasis (TT) is below the threshold for elimination as a public health problem and evidence of conjunctival infection with trachoma’s causative organism (Chlamydia trachomatis, Ct) is rare. Here, we examine the prevalence of ocular infection with Ct and previous exposure to Ct in three districts of Papua New Guinea. MethodsAll individuals aged 1–9 years who were examined for clinical signs of trachoma in three Global Trachoma Mapping Project evaluation units (EUs) were eligble to take part in this study (n=3181). Conjuntival swabs were collected from 349 children with TF and tested by PCR to assess for ocular Ct infection. Dried blood spots were collected from 2572 children and tested for anti-Pgp3 antibodies using a multiplex assay. ResultsThe proportion of children with TF who had Ctinfection was low across all three EUs (overall 2%). Anti-Pgp3 seroprevalence was 5.2% overall and there was no association between anti-Pgp3 antibody level and presence of TF. In two EUs, age-specific seroprevalence did not increase significantly with increasing age in the 1–9-year-old population. In the third EU, there was a statistically significant change with age but the overall seroprevalence and peak age-secific seroprevalence was very low. ConclusionBased on these results, together with similar findings from the Solomon Islands and Vanuatu, the use of TF to guide antibiotic mass drug administration decisions in Melanesia should be reviewed.

BackgroundPharyngitis due to group A Streptococcus (GAS) represents a major cause of outpatient visits and antibiotic use in the United States. A leading vaccine candidate targets 30 of the >200 emm types of GAS. We aimed to assess natural protection conferred by GAS against respiratory symptoms. MethodsIn a 5-year study among school-aged children in Pittsburgh, Pennsylvania, pharyngeal cultures were obtained from children at 2-week intervals, and active surveillance was conducted for respiratory illnesses. We assessed protection via the relative odds of previous detection of homologous strains (defined by field-inversion gel electrophoresis banding pattern), emm types, and emm clusters at visits where GAS was detected with symptoms, versus visits where GAS was detected without symptoms. We used a cluster bootstrap of children to adjust estimates for repeated sampling. ResultsAt visits where previously-detected GAS emm types were identified, we estimated 81.8% (95%CI: 67.1-91.7%) protection against typical pharyngitis symptoms among children re-acquiring the same strain, and 94.5% (83.5-98.6%) protection among children acquiring a distinct strain. We estimated 77.1% (33.7-96.3%) protection against typical symptoms among children acquiring partially-heterologous emm types belonging to a previously-detected emm cluster. Protection was evident after both symptomatic and asymptomatic detections of GAS. We did not identify strong evidence of protection against atypical respiratory symptoms. ConclusionsWithin a 5-year longitudinal study, previous detection of GAS emm types was associated with protection against typical symptoms when homologous strains were subsequently detected. Naturally-acquired protection against partially-heterologous types suggests emm type-based vaccines may have broader strain coverage than what has been previously assumed.

BackgroundFrom 2015/16 through 2017/18, injectable, trivalent inactivated influenza vaccines (IIV3) and a nasal spray, tetravalent live-attenuated influenza vaccine (LAIV4) were used in parallel in Finland. To understand how well vaccination with each vaccine type protected children against influenza under real-life conditions, vaccine effectiveness in two-year-olds was estimated for all three seasons. MethodsEach season, a nationwide register-based cohort study was conducted. The study population comprised 60,088 children in 2015/16, 60,860 children in 2016/17 and 60,345 children in 2017/18. Laboratory-confirmed influenza was the study outcome. Seasonal influenza vaccination with either LAIV4 or IIV3 was the time-dependent exposure of interest. Vaccine effectiveness was defined as 1 minus the hazard ratio comparing vaccinated with unvaccinated children. ResultsFrom 2015/16 through 2017/18, the effectiveness of LAIV4 against influenza of any virus type was estimated at 54.2% (95% confidence interval, 32.2%–69.0%), 20.3% (-12.7% to 43.6%) and 30.5% (10.9%–45.9%); the corresponding effectiveness of IIV3 was 77.2% (48.9%–89.8%), 24.5% (-29.8% to 56.1%) and -20.1% (-61.5% to 10.7%). Neither of the influenza vaccines clearly excelled in protecting children. The LAIV4 effectiveness against type B was greater than against type A and greater than the IIV3 effectiveness against type B. ConclusionsTo understand how influenza vaccines could be improved, vaccine effectiveness must be analyzed by vaccine and virus type. Effectiveness estimates expressing also overall protection levels are needed to guide individual and programmatic decision-making processes. Supported by this analysis, the vaccination program in Finland now recommends LAIV4 and injectable, tetravalent inactivated influenza vaccines replacing IIV3.

BackgroundDiabetes was identified as a tuberculosis (TB) risk factor mostly in retrospective studies with limited assessment of metabolic variables. The prospective Effects of Diabetes on Tuberculosis Severity study compared adults with pulmonary TB in Chennai, India, who were classified as having diabetes or normal glucose tolerance at enrollment. MethodsBaseline TB severity, sputum conversion, and treatment outcomes (cure, failure, death, or lost) were compared between groups with respect to glycemic status and body mass index (BMI). ResultsThe cohort of 389 participants included 256 with diabetes and 133 with normal glucose tolerance. Low BMI (<18.5 kg/m2) was present in 99 (74.4%) of non-diabetic participants and 85 (33.2%) of those with diabetes. Among participants with normal or high BMI, rates of cure, treatment failure, or death did not vary by glycemic status. Participants with low BMI had the highest radiographic severity of disease, the longest time to sputum culture conversion, and the highest rates of treatment failure and death. Among participants with low BMI, poorly controlled diabetes (HbA1c ≥8.0%) was unexpectedly associated with better TB treatment outcomes. High visceral adiposity index was associated with adverse outcomes and despite overall correlation with HbA1c, was elevated in some low BMI individuals with normal glucose tolerance. ConclusionsIn this South Indian cohort, low BMI was significantly associated with increased risk for adverse TB treatment outcomes while comorbid poorly controlled diabetes lessened that risk. High visceral adiposity index with or without dysglycemia might reflect a novel TB susceptibility mechanism linked to adipose tissue dysfunction.

BackgroundEndocarditis, once predominately found in older adults, is increasingly common among younger persons who inject drugs. Untreated opioid use disorder (OUD) complicates endocarditis management. We aimed to determine if rates of overdose and rehospitalization differ between persons with OUD with endocarditis who are initiated on medications for OUD (MOUDs) within 30 days of hospital discharge and those who are not. MethodsWe performed a retrospective cohort study using a large commercial health insurance claims database of persons 18 years and older between July 1, 2010 and June 30, 2016. Primary outcomes included opioid-related overdoses and 1-year all-cause rehospitalization. We calculated incidence rates for the primary outcomes and developed Cox hazards models to predict time from discharge to each primary outcome as a function of receipt of MOUDs. ResultsThe cohort included 768 individuals (mean age 39 years, 51% male). Only 5.7% of people received MOUDs in the 30 days following hospitalization. The opioid-related overdose rate among those who did receive MOUDs in the 30 days following hospitalization was lower than among those who did not (5.8 per 100 person-years (95% CI, 5.1-6.4) vs. 7.3 per 100-person years (95% CI, 7.1-7.5), respectively). The rate of one-year rehospitalization among those who received MOUDs was also lower than those who did not (162.0 per 100 person-years (95% CI, 157.4-166.6) vs 255.4 per 100 person-years (95% CI, 254.0-256.8), respectively). In the Cox hazards models, the receipt of MOUDs was not associated with either of the outcomes. ConclusionsMOUD receipt following endocarditis may improve important health-related outcomes in commercially-insured persons with OUD.

medications for opioid use disorder (MOUD)HIVrapid startpersons who inject drugsendocarditis

BackgroundLate-onset sepsis (LOS) with Staphylococcus epidermidis is common in preterm infants, but the immunological mechanisms underlying heightened susceptibility are poorly understood. AimTo characterise the ontogeny of cytokine responses to live S. epidermidis in preterm infants with and without subsequent Gram-positive LOS. MethodsA prospective observational cohort study of preterm infants (<30 weeks gestational age, GA) with blood sampling on days 1, 7, 14, 21 and 28 of life. Cytokine responses in peripheral whole blood stimulated with live S. epidermidis were analysed by 11-plex immunoassay. ResultsOf 129 infants (mean GA 26.2 weeks, mean BW 887g), 23 (17.8%) had confirmed LOS with Gram-positive organisms and 15 (11.6%) infants had clinical sepsis, with median onset at 13 and 15 days, respectively. ConclusionsCytokine responses to live S. epidermidis challenge are impaired in infants with LOS and precede the onset of clinical illness. Quantifying pathogen-specific cytokine responses at day 7 may identify high risk preterm infants at greatest risk of LOS and prospective replication is warranted.

BackgroundStudies estimate that 30-50% of antibiotics prescribed for hospitalized patients are inappropriate, but pediatric data are limited. Characterization of inappropriate prescribing practices for children are needed to guide pediatric antimicrobial stewardship. MethodsCross-sectional analysis of antibiotic prescribing at 32 US children’s hospitals. Subjects included hospitalized children with ≥1 antibiotic order at 0800 on one day per calendar quarter, over six quarters (Quarter 3 2016 – Quarter 4 2017). Antimicrobial stewardship program (ASP) physicians and/or pharmacists used a standardized survey to collect data on antibiotic orders and evaluate appropriateness. The primary outcome was the percentage of antibiotics prescribed for infectious use that were classified as suboptimal, defined as inappropriate or needing modification. ResultsOf 34 927 children hospitalized on survey days, 12 213 (35.0%) had ≥1 active antibiotic order. Among 11 784 patients receiving antibiotics for infectious use, 25.9% were prescribed ≥1 suboptimal antibiotic. Of the 17 110 antibiotic orders prescribed for infectious use, 21.0% were considered suboptimal. Most common reasons for inappropriate use were bug-drug mismatch (27.7%), surgical prophylaxis >24 hours (17.7%), overly broad empiric therapy (11.2%), and unnecessary treatment (11.0%). The majority of recommended modifications were to stop (44.7%) or narrow (19.7%) the drug. ASPs would not have routinely reviewed 46.1% of suboptimal orders. ConclusionsAcross 32 children’s hospitals, approximately 1 in 3 hospitalized children are receiving one or more antibiotics at any given time. One quarter of these children are receiving suboptimal therapy, and nearly half of suboptimal use is not captured by current ASP practices.

The current post-exposure prophylaxis regimen for Tick Borne Relapsing Fever (TBRF) consists of 5 days Doxycycline. In this observational study of 77 spelunkers at high-risk for TBRF, a single dose of 100 mg Doxycycline taken up to 72 hours after exposure to ticks was 100% effective in preventing the disease.

BackgroundThe UK is experiencing a rapid increase in invasive pneumococcal disease (IPD) caused by serotypes 8, 12F and 9N; their clinical characteristics and outcomes have not been described. MethodsPublic Health England conducts enhanced national surveillance of IPD. Since 2014, general practitioners were requested to complete a surveillance questionnaire for all confirmed cases. IPD cases due to emerging serotypes were compared with those included in the 13-valent pneumococcal conjugate vaccine (PCV13) and the remaining non-PCV13 serotypes. ResultsThere were 21,592 IPD cases over four epidemiological years (2014/15-2017/18), including 20,108 (93.1%) with serotyped isolates and 17,450 (86.8%) with completed questionnaires. PCV13 serotypes were responsible for 20.1% (n=4,033) cases, while serotype 8 (3,881/20,108, 19.3%), 12F (2,365/20,108, 11.8%), and 9N (1,296/20,108, 6.5%) were together responsible for 37.5% of IPD cases. Invasive pneumonia was the most common presentation (11,424/16,346; 69.9%) and, overall, 64.1% (n=11,033) had an underlying comorbidity. The median age at IPD due to serotypes 8 (59 years; IQR, 45-72) and 12F (56 years; 41-70) was lower than serotype 9N (67 years; 53-80), PCV13 serotypes (68 years; 52-81) and the remaining non-PCV13 serotypes (70 years; 53-82). Serotype 9N IPD cases also had higher comorbidity prevalence (748/1,087, 68.8%) compared to serotype 8 (1,901/3,228, 58.9%) or 12F (1,042/1,994, 52.3%), and higher case fatality rate (212/1,128, 18.8%) compared to 8.7% (291/3,365) or 10.0% (209/2,086), respectively. ConclusionsSerotypes 8 and 12F were more likely to cause IPD in younger, healthier individuals and less likely to be fatal, while serotype 9N affected older adults with comorbidities and had a higher case fatality rate.

BackgroundPneumococcal conjugate vaccine (PCV) implementation has led to a sharp decrease in invasive pneumococcal disease (IPD) due to the reduction in PCV serotypes. We aimed to describe the changes in the spectrum of IPD and its clinical presentations after 13-valent PCV (PCV13) implementation. MethodsThis prospective, hospital-based, active surveillance involved 130 pediatric wards and microbiology departments throughout France. We analyzed IPD cases from 2011 to 2016 for which a pneumococcal isolate was sent to the National Reference Center for Pneumococci for serotyping. Clinical data recorded were medical history, vaccination status, type of IPD, clinical features, and short-term evolution. ResultsAmong 1082 IPD cases, we observed a 35.3% decrease (95% confidence interval, 29.2%–41.8%]) and the median age shifted from 38.3 months to 23.7 months (P = .007). The change in IPD type was mostly due to a reduction in bacteremic pneumonia frequency (from 42.1% to 19.1%; P < .001). Among the emerging non-PCV13 types (NVTs), those known to have the highest disease potential (8, 12F, 24F, and 33F) were isolated more frequently in patients without underlying conditions and were able to induce all IPD clinical presentations including bacteremic pneumonia. Conversely, serotypes with lower disease potential (15A, 15BC, 16F, and 23B) were rarely isolated from bacteremic pneumonia cases and were particularly involved in IPD in patients with underlying conditions (35.8%). ConclusionsBesides the decrease in IPD after 7-valent, then 13-valent PCV implementation, the spectrum of the remaining IPD cases showed significant changes, with substantial discrepancies across NVTs implicated in terms of clinical features and underlying conditions.

BackgroundMaintaining perioperative normothermia is recommended by recent guidelines for the prevention of surgical site infections (SSIs). However, the majority of supporting data originates outside the field of orthopaedic surgery. MethodsThe effect of normothermia was explored using the prospectively collected data of consecutive patients who underwent single-site surgery in 7 tertiary referral hospitals between November 2013 and July 2016. SSIs, urinary tract infections (UTIs), respiratory tract infections (RTIs), cardiac and cerebral events (CCE), and all-cause mortality rates within 30 days after surgery were compared between patients with normothermia (body temperature ≥36°C) and those with hypothermia (<36°C) at the end of surgery, after closure. Multivariable adjusted and inverse-probability weighted regression analyses were performed. ResultsThe final cohort included 8841 patients. Of these, 11.4% (n = 1008) were hypothermic. More than 96% were evaluated in person by the physicians. After adjusting for multiple covariates, normothermia was not significantly associated with SSIs (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI] 0.59–2.33), UTIs (aOR 1.14, 95% CI 0.66–1.95), RTIs (aOR 0.60, 95% CI 0.31–1.19), or CCE (aOR 0.53, 95% CI 0.26–1.09). In contrast, normothermia was associated with a lower risk of 30-day mortality (aOR 0.26, 95% CI 0.11–0.64; P< .01; weighted hazard ratio 0.21, 95% CI 0.07–0.68; P = .002). In a subgroup analysis, normothermia was associated with reduced mortality in all types of surgical procedures. ConclusionsWhereas our findings suggest no clear association with SSI risks following orthopedic surgery, our study supports maintaining perioperative normothermia, as it is associated with reduced 30-day mortality.

BackgroundLimited information exists regarding the burden of emergency department (ED) visits due to scabies in the United States. The goal of this study was to provide population-level estimates regarding scabies visits to American EDs. MethodsThis study was a retrospective analysis of the nationally representative National Emergency Department Sample from 2013 to 2015. Outcomes included adjusted odds for scabies ED visits, adjusted odds for inpatient admission due to scabies in the ED scabies population, predictors for cost of care, and seasonal/regional variation in cost and prevalence of scabies ED visits. ResultsOur patient population included 416 017 218 ED visits from 2013 to 2015, of which 356 267 were due to scabies (prevalence = 85.7 per 100 000 ED visits). The average annual expenditure for scabies ED visits was $67 125 780.36. The average cost of care for a scabies ED visit was $750.91 (±17.41). Patients visiting the ED for scabies were most likely to be male children from lower income quartiles and were most likely to present to the ED on weekdays in the fall, controlling for all other factors. Scabies ED patients that were male, older, insured by Medicare, from the highest income quartile, and from the Midwest/West were most likely to be admitted as inpatients. Older, higher income, Medicare patients in large Northeastern metropolitan cities had the greatest cost of care. ConclusionThis study provides comprehensive nationally representative estimates of the burden of scabies ED visits on the American healthcare system. These findings are important for developing targeted interventions to decrease the incidence and burden of scabies in American EDs.

BackgroundSeparately addressing specific groups of people who share patterns of behavioral change might increase the impact of behavioral interventions to prevent transmission of sexually transmitted infections. We propose a method based on machine learning to assist the identification of such groups among men who have sex with men (MSM). MethodsBy means of unsupervised learning, we inferred “behavioral clusters” based on the recognition of similarities and differences in longitudinal patterns of condomless anal intercourse with nonsteady partners (nsCAI) in the HIV Cohort Study over the last 18 years. We then used supervised learning to investigate whether sociodemographic variables could predict cluster membership. ResultsWe identified 4 behavioral clusters. The largest behavioral cluster (cluster 1) contained 53% of the study population and displayed the most stable behavior. Cluster 3 (17% of the study population) displayed consistently increasing nsCAI. Sociodemographic variables were predictive for both of these clusters. The other 2 clusters displayed more drastic changes: nsCAI frequency in cluster 2 (20% of the study population) was initially similar to that in cluster 3 but accelerated in 2010. Cluster 4 (10% of the study population) had significantly lower estimates of nsCAI than all other clusters until 2017, when it increased drastically, reaching 85% by the end of the study period. ConclusionsWe identified highly dissimilar behavioral patterns across behavioral clusters, including drastic, atypical changes. The patterns suggest that the overall increase in the frequency of nsCAI is largely attributable to 2 clusters, accounting for a third of the population.

BackgroundIn 2011, Argentina experienced its highest pertussis incidence and mortality rates of the last decade; 60% of deaths were among infants aged <2 months. In response, a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine was recommended for all pregnant women at ≥20 weeks of gestation. Although recent studies suggest that maternal Tdap vaccination is effective at preventing infant disease, no data have come from low- or middle-income countries, nor from ones using whole-cell pertussis vaccines for primary immunization. MethodsWe conducted a matched case-control evaluation to assess the effectiveness of maternal Tdap vaccination in preventing pertussis among infants aged <2 months in Argentina. Pertussis case patients identified from September 2012 to March 2016 at 6 hospital sites and confirmed by polymerase chain reaction testing were included. Five randomly selected controls were matched to each case patient by hospital site and mother’s health district. We used multivariable conditional logistic regression to calculate odds ratios (ORs). Vaccine effectiveness (VE) was estimated as (1 – OR) × 100%. ResultsSeventy-one case patients and 300 controls were included in the analysis. Forty-nine percent of case patients and 78% of controls had mothers who were vaccinated during pregnancy. Overall Tdap VE was estimated at 80.7% (95% confidence interval, 52.1%–92.2%). We found similar VE whether Tdap was administered during the second or third trimester. ConclusionsTdap vaccination during pregnancy is effective in preventing pertussis in infants aged <2 months in Argentina, with similar effectiveness whether administered during the second or third trimester of pregnancy.

BackgroundElevated viral load (VL) early after antiretroviral therapy (ART) initiation appears frequently in pregnant and postpartum women living with human immunodeficiency virus; however the relative contributions of pre-ART drug resistance mutations (DRMs) vs nonadherence in the etiology of elevated VL are unknown. MethodsWithin a cohort of women initiating ART during pregnancy in Cape Town, South Africa, we compared women with elevated VL after initial suppression (cases, n = 80) incidence-density matched to women who maintained suppression over time (controls, n = 87). Groups were compared on pre-ART DRMs and detection of antiretrovirals in stored plasma. ResultsThe prevalence of pre-ART DRMs was 10% in cases and 5% in controls (adjusted odds ratio [aOR], 1.53 [95% confidence interval {CI}, .4–5.9]); all mutations were to nonnucleoside reverse transcriptase inhibitors. At the time of elevated VL, 19% of cases had antiretrovirals detected in plasma, compared with 87% of controls who were suppressed at a matched time point (aOR, 131.43 [95% CI, 32.8–527.4]). Based on these findings, we estimate that <10% of all elevated VL in the cohort may be attributable to pre-ART DRMs vs >90% attributable to ART nonadherence. ConclusionsDRMs account for a small proportion of all elevated VL among women occurring in the 12 months after ART initiation during pregnancy in this setting, with nonadherence appearing to drive most episodes of elevated VL. Alongside the drive for access to more robust antiretroviral agents in resource-limited settings, there is an ongoing need for effective strategies to support ART adherence in this patient population.

BackgroundThere have been concerns about reduced adherence and human immunodeficiency virus (HIV) virological suppression (VS) among clinically well people initiating antiretroviral therapy (ART) with high pre-ART CD4 cell counts. We compared virological outcomes by pre-ART CD4 count, where universal ART initiation was provided in the HIV Prevention Trials Network 071 (PopART) trial in South Africa prior to routine national and international implementation. MethodsThis prospective cohort study included adults initiating ART at facilities providing universal ART since January 2014. VS (<400 copies/mL), confirmed virological failure (VF) (2 consecutive viral loads >1000 copies/mL), and viral rebound were compared between participants in strata of baseline CD4 cell count. ResultsThe sample included 1901 participants. VS was ≥94% among participants with baseline CD4 count ≥500 cells/µL at all 6-month intervals to 30 months. The risk of an elevated viral load (≥400 copies/mL) was independently lower among participants with baseline CD4 count ≥500 cells/µL (3.3%) compared to those with CD4 count 200–499 cells/µL (9.2%) between months 18 and 30 (adjusted relative risk, 0.30 [95% confidence interval, .12–.74]; P = .010). The incidence rate of VF was 7.0, 2.0, and 0.5 per 100 person-years among participants with baseline CD4 count <200, 200–499, and ≥500 cells/µL, respectively (P < .0001). VF was independently lower among participants with baseline CD4 count ≥500 cells/µL (adjusted hazard ratio [aHR], 0.23; P = .045) and 3-fold higher among those with baseline CD4 count <200 cells/µL (aHR, 3.49; P < .0001). ConclusionsDespite previous concerns, participants initiating ART with CD4 counts ≥500 cells/µL had very good virological outcomes, being better than those with CD4 counts 200–499 cells/µL. Clinical Trials RegistrationNCT01900977.

BackgroundWhile antibiotics are life-saving drugs, their use is not without risk, including adverse events and antibiotic resistance. The majority of US antibiotic prescriptions are prescribed in outpatient settings, making outpatient antibiotic prescribing an important antibiotic stewardship target. The primary objective of this study was to describe trends in US outpatient oral antibiotic prescriptions from 2011–2016. MethodsWe estimated annual oral antibiotic prescription rates using national prescription dispensing count data from IQVIA Xponent, divided by census estimates for 2011–2016. We calculated the ratio of broad- to narrow-spectrum prescriptions by dividing broad-spectrum prescription rates by narrow-spectrum prescription rates. We used Poisson models to estimate prevalence rate ratios, comparing 2011 and 2016 antibiotic prescription rates, and linear models to evaluate temporal trends throughout the study period. ResultsOral antibiotic prescription rates decreased 5%, from 877 prescriptions per 1000 persons in 2011 to 836 per 1000 persons in 2016. During this period, rates of prescriptions dispensed to children decreased 13%, while adult rates increased 2%. The ratio of broad- to narrow-spectrum antibiotics decreased from 1.62 in 2011 to 1.49 in 2016, driven by decreases in macrolides and fluoroquinolones. The proportion of prescriptions written by nurse practitioners and physician assistants increased during the study period; in 2016, these providers prescribed over one-quarter of all antibiotic prescriptions. ConclusionsOutpatient antibiotic prescription rates, especially of broad-spectrum agents, have decreased in recent years. Clinicians who prescribe to adults, including nurse practitioners and physician assistants, are important targets for antibiotic stewardship.

antibiotic stewardshiprespiratory tract infection

BackgroundLarge norovirus (NoV) outbreaks are explosive in nature and vary widely in final size and duration, suggesting that superspreading combined with heterogeneous contact may explain these dynamics. Modeling tools that can capture heterogeneity in infectiousness and contact are important for NoV outbreak prevention and control, yet they remain limited. MethodsData from a large NoV outbreak at a Dutch scout jamboree, which resulted in illness among 326 (of 4500 total) individuals from 7 separate camps, were used to examine the contributions of individual variation in infectiousness and clustered contact patterns to the transmission dynamics. A Bayesian hierarchical model of heterogeneous, clustered outbreak transmission was applied to represent (1) between-individual heterogeneity in infectiousness and (2) heterogeneous patterns of contact. ResultsWe found wide heterogeneity in infectiousness across individuals, suggestive of superspreading. Nearly 50% of individual infectiousness was concentrated in the individual’s subcamp of residence, with the remainder distributed over other subcamps. This suggests a source-and-sink dynamic in which subcamps with greater average infectiousness fed cases to those with a lower transmission rate. Although the per capita transmission rate within camps was significantly greater than that between camps, the large pool of susceptible individuals across camps enabled similar numbers of secondary cases generated between versus within camps. ConclusionsThe consideration of clustered transmission and heterogeneous infectiousness is important for understanding NoV transmission dynamics. Models including these mechanisms may be useful for providing early warning and guiding outbreak response.

Plasmodium knowlesiSabahepidemiology

BackgroundMalaysia aims to eliminate malaria by 2020. However, while cases of Plasmodium falciparum and Plasmodium vivax have decreased substantially, the incidence of zoonotic malaria from Plasmodium knowlesi continues to increase, presenting a major challenge to regional malaria control efforts. Here we report incidence of all Plasmodium species in Sabah, including zoonotic P. knowlesi, during 2015–2017. MethodsMicroscopy-based malaria notification data and polymerase chain reaction (PCR) results were obtained from the Sabah Department of Health and State Public Health Laboratory, respectively, from January 2015 to December 2017. From January 2016 this was complemented by a statewide prospective hospital surveillance study. Databases were matched, and species was determined by PCR, or microscopy if PCR was not available. ResultsA total of 3867 malaria cases were recorded between 2015 and 2017, with PCR performed in 93%. Using PCR results, and microscopy if PCR was unavailable, P. knowlesi accounted for 817 (80%), 677 (88%), and 2030 (98%) malaria cases in 2015, 2016, and 2017, respectively. P. falciparum accounted for 110 (11%), 45 (6%), and 23 (1%) cases and P. vivax accounted for 61 (6%), 17 (2%), and 8 (0.4%) cases, respectively. Of those with P. knowlesi, the median age was 35 (interquartile range: 24–47) years, and 85% were male. ConclusionsMalaysia is approaching elimination of the human-only Plasmodium species. However, the ongoing increase in P. knowlesi incidence presents a major challenge to malaria control and warrants increased focus on knowlesi-specific prevention activities. Wider molecular surveillance in surrounding countries is required.

BackgroundEndemic outbreaks of hantaviruses pose a critical public health threat worldwide. Hantaan orthohantavirus (HTNV) causes hemorrhagic fever with renal syndrome (HFRS) in humans. Using comparative genomic analyses of partial and nearly complete sequences of HTNV from humans and rodents, we were able to localize, with limitations, the putative infection locations for HFRS patients. Partial sequences might not reflect precise phylogenetic positions over the whole-genome sequences; finer granularity of rodent sampling reflects more precisely the circulation of strains. MethodsFive HFRS specimens were collected. Epidemiological surveys were conducted with the patients during hospitalization. We conducted active surveillance at suspected HFRS outbreak areas. We performed multiplex polymerase chain reaction–based next-generation sequencing to obtain the genomic sequence of HTNV from patients and rodents. The phylogeny of human- and rodent-derived HTNV was generated using the maximum likelihood method. For phylogeographic analyses, the tracing of HTNV genomes from HFRS patients was defined on the bases of epidemiological interviews, phylogenetic patterns of the viruses, and geographic locations of HTNV-positive rodents. ResultsThe phylogeographic analyses demonstrated genetic clusters of HTNV strains from clinical specimens, with HTNV circulating in rodents at suspected sites of patient infections. ConclusionsThis study demonstrates a major shift in molecular epidemiological surveillance of HTNV. Active targeted surveillance was performed at sites of suspected infections, allowing the high-resolution phylogeographic analysis to reveal the site of emergence of HTNV. We posit that this novel approach will make it possible to identify infectious sources, perform disease risk assessment, and implement preparedness against vector-borne viruses.

(See the Major Article by Githinji et al on pages 483–90.)

BackgroundHousehold contacts (HHCs) of individuals with multidrug-resistant tuberculosis (MDR-TB) are at high risk of infection and subsequent disease. There is limited evidence on the willingness of MDR-TB HHCs to take MDR-TB preventive therapy (MDR TPT) to decrease their risk of TB disease. MethodsIn this cross-sectional study of HHCs of MDR-TB and rifampicin-resistant tuberculosis (RR-TB) index cases from 16 clinical research sites in 8 countries, enrollees were interviewed to assess willingness to take a hypothetical, newly developed MDR TPT if offered. To identify factors associated with willingness to take MDR TPT, a marginal logistic model was fitted using generalized estimating equations to account for household-level clustering. ResultsFrom 278 MDR-TB/RR-TB index case households, 743 HHCs were enrolled; the median age of HHCs was 33 (interquartile range, 22–49) years, and 62% were women. HHC willingness to take hypothetical MDR TPT was high (79%) and remained high even with the potential for mild side effects (70%). Increased willingness was significantly associated with current employment or schooling (adjusted odds ratio [aOR], 1.83 [95% confidence interval {CI}, 1.07–3.13]), appropriate TB-related knowledge (aOR, 2.22 [95% CI, 1.23–3.99]), confidence in taking MDR TPT (aOR, 7.16 [95% CI, 3.33–15.42]), and being comfortable telling others about taking MDR TPT (aOR, 2.29 [95% CI, 1.29–4.06]). ConclusionsThe high percentage of HHCs of MDR-TB/RR-TB index cases willing to take hypothetical MDR TPT provides important evidence for the potential uptake of effective MDR TPT when implemented. Identified HHC-level variables associated with willingness may inform education and counseling efforts to increase HHC confidence in and uptake of MDR TPT.

BackgroundIn human immunodeficiency virus (HIV)–positive adults, low CD4 cell counts despite fully suppressed HIV-1 RNA on antiretroviral therapy (ART) have been associated with increased risk of morbidity and mortality. We assessed the prevalence and outcomes of poor immune response (PIR) in children receiving suppressive ART. MethodsSixteen cohorts from the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) contributed data. Children <18 years at ART initiation, with sustained viral suppression (VS) (≤400 copies/mL) for ≥1 year were included. The prevalence of PIR (defined as World Health Organization advanced/severe immunosuppression for age) at 1 year of VS was described. Factors associated with PIR were assessed using logistic regression. Rates of acquired immunodeficiency syndrome (AIDS) or death on suppressive ART were calculated by PIR status. ResultsOf 2318 children included, median age was 6.4 years and 68% had advanced/severe immunosuppression at ART initiation. At 1 year of VS, 12% had PIR. In multivariable analysis, PIR was associated with older age and worse immunological stage at ART start, hepatitis B coinfection, and residing in Thailand (all P ≤ .03). Rates of AIDS/death (95% confidence interval) per 100 000 person-years were 1052 (547, 2022) among PIR versus 261 (166, 409) among immune responders; rate ratio of 4.04 (1.83, 8.92; P < .001). ConclusionsOne in eight children in our cohort experienced PIR despite sustained VS. While the overall rate of AIDS/death was low, children with PIR had a 4-fold increase in risk of event as compared with immune responders.

BackgroundThe Centers for Disease Control and Prevention (CDC) recently published interim guidance for a public health response to contain novel or targeted multidrug-resistant organisms (MDROs). We assessed the impact of implementing the strategy in a US state using a mathematical model. MethodsWe used a deterministic compartmental model, parametrized via a novel analysis of carbapenem-resistant Enterobacteriaceae data reported to the National Healthcare Safety Network and patient transfer data from the Centers for Medicare and Medicaid Services. The simulations assumed that after the importation of the MDRO and its initial detection by clinical culture at an index hospital, fortnightly prevalence surveys for colonization and additional infection control interventions were implemented at the index facility; similar surveys were then also implemented at those facilities known to be connected most strongly to it as measured by patient transfer data; and prevalence surveys were discontinued after 2 consecutive negative surveys. ResultsIf additional infection-control interventions are assumed to lead to a 20% reduction in transmissibility in intervention facilities, prevalent case count in the state 3 years after importation would be reduced by 76% (interquartile range: 73–77%). During the third year, these additional infection-control measures would be applied in facilities accounting for 42% (37–46%) of inpatient days. ConclusionsCDC guidance for containing MDROs, when used in combination with information on transfer of patients among hospitals, is predicted to be effective, enabling targeted and efficient use of prevention resources during an outbreak response. Even modestly effective infection-control measures may lead to a substantial reduction in transmission events.

BackgroundCertain vaccines, such as Bacille Calmette-Guérin (BCG), have nonspecific effects, which modulate innate immune responses and lead to protection against mortality from unrelated infections (trained immunity). In contrast, in spite of the disease-specific effects, an enhanced overall mortality has been described after diphtheria-tetanus-pertussis (DTP) vaccination in females. This randomized trial aimed to investigate the nonspecific immunological effects of BCG and DTP-containing vaccines on the immune response to unrelated pathogens. MethodsWe randomized 75 healthy, female, adult volunteers to receive either BCG, followed by a booster dose of tetanus-diphtheria-pertussis inactivated polio vaccine (Tdap) 3 months later; BCG and Tdap combined; or Tdap followed by BCG 3 months later. Blood was collected before vaccination, as well as at 1 day, 4 days, 2 weeks, and 3 months after the first vaccination(s), plus 2 weeks after the second vaccination. Ex vivo leukocyte responses to unrelated stimuli and pathogens were assessed. ResultsTdap vaccination led to short-term potentiation and long-term repression of monocyte-derived cytokine responses, and short-term as well as long-term repression of T-cell reactivity to unrelated pathogens. BCG led to short-term and long-term potentiation of monocyte-derived cytokine responses. When given together with Tdap or after Tdap, BCG abrogated the immunosuppressive effects of Tdap vaccination. ConclusionsTdap induces immunotolerance to unrelated antigens, which is partially restored by concurrent or subsequent BCG vaccination. These data indicate that the modulation of heterologous immune responses is induced by vaccination with Tdap and BCG, and more studies are warranted to investigate whether this is involved in the nonspecific effects of vaccines on mortality. Clinical Trials RegistrationNCT02771782.

BackgroundWe assessed multidrug-resistant tuberculosis (MDR-TB) cases and their household contacts (HHCs) to inform the development of an interventional clinical trial. MethodsWe conducted a cross-sectional study of adult MDR-TB cases and their HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings, chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing (tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human immunodeficiency virus (HIV) testing. ResultsFrom October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli sputum smears and 43% had cavitary disease; at study entry, 35% remained smear positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs that were diagnosed with TB prior to entry and excluded. Of the remaining 1007 HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable, and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775 (77%) were considered high-risk per these mutually exclusive groups: 102 (10%) were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610 (61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and were TBI positive. Only 21 (2%) HHCs were on preventive therapy. ConclusionsThe majority of HHCs in these high-burden countries were at high risk of TB disease and infection, yet few were receiving routine preventive therapy. Trials of novel, preventive therapies are urgently needed to inform treatment policy and practice.

BackgroundDespite increased access to highly active antiretroviral therapy (HAART), lung disease remains common in human immunodeficiency virus (HIV)–infected (HIV+) adolescents. There is limited information on changes in lung function over time in perinatally HIV+ adolescents on HAART. The objective was to investigate the progression of spirometry findings over 2 years in HIV+ adolescents on HAART in a prospective cohort, the Cape Town Adolescent Antiretroviral Cohort (CTAAC). MethodsHIV+ adolescents aged 9–14 years, with at least 6 months of HAART, and a comparator group of healthy HIV-uninfected (HIV–), age-matched controls were enrolled in CTAAC. Spirometry and bronchodilator testing were done at baseline, 12 months, and 24 months. Mixed-effect models were used to compute longitudinal changes in lung function. ResultsFive hundred fifteen HIV+ adolescents, mean age 12 (standard deviation [SD], 1.6) years, 50.4% male, and 110 HIV– adolescents, mean age 11.8 (SD, 1.8) years, 45.6% male, were tested at baseline; 477 (93%) HIV+ and 102 (93%) HIV– adolescents at 12 months; and 473 (92%) HIV+ and 97 (88%) HIV– adolescents at 24 months. Only 5.4% of the HIV+ adolescents had HIV viral load >10 000 copies/mL at baseline. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were lower in the HIV+ compared to the HIV– adolescents and tracked with no deterioration or catch-up over 2 years. Previous pulmonary tuberculosis (PTB) or lower respiratory tract infection (LRTI) was significantly associated with reduced FEV1 and FVC (P < .05 for both). ConclusionsHIV+ adolescents had lower lung function over 2 years than HIV– adolescents. This study highlights the need for lung function surveillance and prevention of LRTIs and PTB in HIV+ adolescents.

To the Editor—We thank Drs Yates and Barr for their valuable comments. In our article [1], we were not attempting to assess the extent to which dysglycemia is causally associated with tuberculosis (TB). A number of prospective studies exist, among a body of evidence, supporting probabilistic causation between diabetes mellitus (DM) and TB [2, 3]. Rather, the aim of our study was to identify age-adjusted prevalence and clinical characteristics of DM and intermediate hyperglycemia among those with newly diagnosed TB across 4 TB-endemic settings. In our South African population, the prevalence of DM (10.9% [95% confidence interval, 7%–14.9%]) was the lowest across all 4 study sites. However, as the smallest site, uncertainty around this estimate is greatest and the prevalence estimate was shown to increase after age standardization.

To the Editor—We appreciate Dr MacDonald and colleagues’ [1] interest in our study [2] describing the limited coverage of hepatitis C virus (HCV) testing in the noninstitutionalized US civilian population, even among Baby Boomers, for whom there is a 1-time HCV testing recommendation. Our study was conducted using data from the 2013–2017 National Health Interview Survey. Using the same data source, the authors make an important point that, even in 2017, there were missed opportunities for HCV testing [1]. In particular, the authors highlight that 78% of untested Baby Boomers interacted with a primary care provider in the past year. We agree with MacDonald et al [1] that interventions to improve the uptake of HCV testing recommendations should be implemented in primary care settings (eg, provider and patient education programs, in combination with targeted electronic medical record best practice alerts for providers [3]).

To the Editor—We read with interest the study by Patel et al [1], in which they used 2013–2017 National Health Interview Survey (NHIS) data to assess hepatitis C virus (HCV) testing coverage for the 1945–1965 birth cohort in the United States. The authors reported that HCV testing for this birth cohort was low, with a peak of only 17% in 2017. An overall improvement in HCV testing is needed, and a settings-based perspective may be useful for guiding interventions [2].

To the Editor—In our opinion, the extent to which dysglycemia is causally associated with tuberculosis (TB) remains unanswered. Ugarte-Gil and colleagues, with no control group, cannot answer that question [1]. We note that the prevalence of diabetes in, for example, their South African TB patients is not dissimilar to that reported in the general population of South Africans aged >30 years [2]. In fairness, their TB cohort is at the lower end of this age distribution.

To the Editor—We read with interest the impressive study by Hong et al [1] that developed a new clinical prediction model of aminoglycoside (AG)-induced hearing loss among patients initiating drug-resistant tuberculosis (DR-TB) treatment. The results showed reasonable discrimination (area under curve [AUC] = 0.71) and calibration (χ2[8] = 6.10; P = .636) in the development cohort, and satisfied discrimination (AUC = 0.81) and calibration (χ2[8] = 6.48; P = .593) in the validation (ultrahigh-frequency hearing loss) cohort. According to these results, we agree that the authors built a simple model for the identification of patients with DR-TB who are at the highest risk of developing AG-induced ototoxicity. However, we think this model should be improved before its clinical application.

To the Editor—Chen and colleagues [1] suggest that our prediction model of hearing loss among patients receiving aminoglycosides for the treatment of multidrug-resistant tuberculosis (MDR-TB) [2] should undergo validation in other cohorts, achieve a higher level of accuracy, and undergo additional analyses prior to clinical application. We agree with this assessment, but would like to clarify these concerns further.

Because of the diverse etiologies of community-acquired pneumonia (CAP) and the limitations of current diagnostic modalities, serum procalcitonin levels have been proposed as a novel tool to guide antibiotic therapy. Outcome data from procalcitonin-guided therapy trials have shown similar mortality, but the essential question is whether the sensitivity and specificity of procalcitonin levels enable the practitioner to distinguish bacterial pneumonia, which requires antibiotic therapy, from viral pneumonia, which does not. In this meta-analysis of 12 studies in 2408 patients with CAP that included etiologic diagnoses and sufficient data to enable analysis, the sensitivity and specificity of serum procalcitonin were 0.55 (95% confidence interval [CI], .37–.71; I2 = 95.5%) and 0.76 (95% CI, .62–.86; I2 = 94.1%), respectively. Thus, a procalcitonin level is unlikely to provide reliable evidence either to mandate administration of antibiotics or to enable withholding such treatment in patients with CAP.

We find that patients <40 years old with a first invasive encapsulated bacterial infection have a high likelihood of death or readmission within 23 months. It is imperative to highlight them for immunological screening and initiate prophylactic interventions and treatment.

In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality (27.5% [95% confidence interval, 16.3 to 44.1]).

We evaluated the effect of systemic antibiotics (azithromycin, amoxicillin, cotrimoxazole, or placebo) on the gut resistome in children aged 6 to 59 months. Azithromycin and cotrimoxazole led to an increase in macrolide and sulfonamide resistance determinants. Resistome expansion can be induced with a single course of antibiotics.

We describe a second case of human infection caused by Thelazia gulosa (the cattle eye worm), likely acquired in California. For epidemiologic purposes, it is important to identify all Thelazia recovered from humans in North America to the species level.

A 67-year-old Caucasian man, an avid traveler with a history of hypertension, depression, and previous morbid obesity treated with bariatric surgery, presented with low-grade fever and recurrent left-ankle painful rash (Figure 1A). The patient noted the first episode 2 months prior to presentation when he presented with a poorly defined painful erythematous patch over his left ankle and leukocytosis. He was treated with cefazolin for suspected cellulitis and discharged on cephalexin with partial improvement. Infectious workup, including blood cultures, echocardiogram, and x-ray, was negative. Over the next few weeks he developed similar discrete episodes with new, noncontiguous rashes to other body parts, such as the abdomen, left shoulder (Figure 1B), right gluteal region, right elbow, and left knee that spontaneously resolved within a few days, sometimes without antibiotic treatment. A partial response to antihistamines, leg elevation, and doxycycline was noted, but rash and pain worsened with a short trial of steroids after initial improvement. Two days prior to admission, he again developed left-ankle painful erythematous rash spreading up to his knee, associated with fever. He had an extensive travel history with trips to China, India, South Asia, Canada, and Brazil in the last decade. Five months previously he had visited Hong Kong where he had a diarrheal illness consisting of 4–5 loose but not watery stools for 2 days that self-resolved. Three months previously he visited Morocco where he rode a camel. He lives in Missouri and has retired but volunteers with refugees hailing from the developing world receiving treatment for tuberculosis. He is a former sushi chef and eats raw seafood often. On presentation, he was febrile to 38.3°C but otherwise had stable vital signs. Laboratory data revealed leukocytosis (12 300 cells/μL) and elevated erythrocyte sedimentation rate (49 mm/h) and C-reactive protein (103 mg/L). Blood cultures were collected, and the patient was started on vancomycin and cefepime. Rheumatologic testing was negative, as was testing for syphilis, human immunodeficiency virus, tuberculosis, and Lyme disease. Left lower extremity computed tomography showed superficial soft tissue edema without osteomyelitis or abscess. Echocardiogram showed normal ventricular function without vegetations. Skin biopsy revealed sparse perivascular and interstitial inflammatory infiltrate consistent with cellulitis with negative tissue bacterial cultures. The aerobic bottle from 2 sets of blood cultures obtained on the day of admission yielded a pathogen whose microscopic features are shown in Figures 2 and 3.

The One Health approach has received widespread international endorsements from professional, academic, and governmental organizations as the way forward in tackling complex interdisciplinary problems, such as emerging zoonotic diseases, antimicrobial resistance, and food safety. Yet conspicuously absent from US One Health training or research activities are the animal agricultural industries. Their absence is likely due to multiple factors, including the lack of appreciation for their potential problem-solving roles, as well as the industries’ business-oriented fears that such engagement could cause them to suffer economic damage. As demands on the swine, poultry, egg, beef, and dairy production industries are closely linked to the above-mentioned complex problems, we must find new, nonthreatening ways to better engage and win animal agriculture’s collaboration into One Health training and research partnerships for successful health problem solving. Without animal agricultural industries’ improved cooperation, One Health’s efforts to control these complex problems are not likely to succeed.

Preexposure prophylaxisPrEPHIVretention

Guidance regarding indications for initial or follow-up (FU) blood cultures (BCx) is limited. We conducted a scoping review of articles published between 1/2004-6/2019 that reported the yield of BCx and/or their impact in the clinical management of fever and common infectious syndromes in non-neutropenic adult inpatients. 2,893 articles were screened; 51 were included. Based on the reported incidence of bacteremia, syndromes were categorized into low, moderate and high pre-test probability of bacteremia. Routine BCx are recommended in syndromes with a high likelihood of bacteremia (e.g., endovascular infections) and those with moderate likelihood when cultures from the primary source of infection are unavailable or prompt initiation of antibiotics is needed prior to obtaining primary source cultures. In syndromes where BCx are low-yield, BCx can be considered for patients at risk of adverse events if a bacteremia is missed (e.g., patient with pacemaker and severe purulent cellulitis). If a patient has adequate source control and risk factors or concern for endovascular infection are not present, most Streptococci or Enterobacterales bacteremias do not require routine FUBCx.

BackgroundDaily oral preexposure prophylaxis (PrEP) is highly effective in preventing HIV infection if used adherently throughout periods of HIV risk. We estimated PrEP persistence among cohorts of persons with commercial or Medicaid insurance. MethodsWe analyzed data from the IBM MarketScan Research Database to identify persons aged 18-64 years who initiated PrEP between 2012−2017. We assessed PrEP persistence by calculating the time period that each person continued filling PrEP prescriptions until there was a gap in prescription fills >30 days. We used Kaplan-Meier time-to-event methods to estimate the proportion of PrEP users who persisted with PrEP at 3, 6, and 12 months after initiation, and constructed Cox proportional hazards models to determine patient characteristics associated with non-persistence. ResultsWe studied 11,807 commercially insured and 647 Medicaid insured persons with PrEP prescriptions. Commercially insured patients persisted for median time of 13.7 months (95% CI 13.3−14.1), compared to 6.8 months (95% CI 6.1−7.6) among Medicaid patients. Additionally, female sex, younger age, residence in rural location, and black race were associated with shorter persistence. After adjusting for covariates, we found that female sex (Hazard Ratio [HR]=1.81; 95% CI 1.56−2.11) and younger age (18-24 years: HR=2.38; 95% CI 2.11−2.69) predicted non-persistence. ConclusionsMore than half of commercially insured persons who initiated PrEP persisted with it for 12 months, compared to a third of those with Medicaid. A better understanding of reasons for non-persistence is important to support persistent PrEP use, and to develop interventions designed for the diverse needs of at-risk populations.

BackgroundMetagenomic next-generation sequencing (mNGS) of plasma cell-free DNA has emerged as an attractive diagnostic modality allowing broad-range pathogen detection, noninvasive sampling, and earlier diagnosis. However, little is known about its real-world clinical impact as used in routine practice. MethodsWe performed a retrospective cohort study of all patients for whom plasma mNGS (Karius test) was performed for all indications at 5 U.S. institutions over 1.5 years. Comprehensive chart review was performed, and standardized assessment of clinical impact of the mNGS based on the treating team’s interpretation of Karius results and patient management was established. ResultsA total of 82 Karius tests were evaluated, from 39 (47.6%) adults and 43 (52.4%) children and a total of 53 (64.6%) immunocompromised patients. Karius positivity rate was 50/82 (61.0%), with 25 (50.0%) showing two or more organisms (range, 2-8). The Karius test results led to positive impact in 6 (7.3%), negative impact in 3 (3.7%), no impact in 71 (86.6%), and was indeterminate in 2 (2.4%). Cases with positive Karius result and clinical impact involved bacteria and/or fungi but not DNA viruses or parasites. In 10 patients who underwent 16 additional repeated tests, only one was associated with clinical impact. ConclusionsThe real-world impact of the Karius test as currently used in routine clinical practice is limited. Further studies are needed to identify high-yield patient populations, define the complementary role of mNGS to conventional microbiological methods and how best to integrate mNGS into current testing algorithms.

BackgroundDrug-drug interactions (DDI) between feminizing hormone therapy (FHT) and antiretroviral therapy (ART) is a major concern among transgender women (TGW) that may lead to sub-optimal ART adherence and inappropriate FHT dosage. To evaluate potential DDI between FHT and ART, we measured intensive pharmacokinetic parameters (PK) of blood tenofovir (TFV), efavirenz (EFV), and estradiol (E2). MethodsTwenty newly-diagnosed HIV-positive TGW were enrolled. FHT (estradiol valerate 2 mg and cyproterone acetate 25 mg) were prescribed at baseline until week 5 and restarted at week 8. ART (tenofovir disoproxil fumarate/emtricitabine/efavirenz 300/200/600 mg) was initiated at week 3. Intensive E2 PK were measured at weeks 3 (without ART) and 5 (with ART), and intensive TFV and EFV PK were measured at weeks 5 (with FHT) and 8 (without FHT). ResultsMedian (IQR) age and body mass index were 25.5 (22.5-31.0) years and 20.6 (19.3-23.1) kg/m2, respectively. The differences in GMR (90%CI) of E2 AUC, Cmax, and C24 at week 5 versus week 3 were 0.72 (0.64-0.81), p<0.001; 0.81 (0.72-0.92), p=0.006; and 0.64 (0.50-0.83), p=0.004, respectively. The differences in GMR (90%CI) of TFV AUC, C24, and EFV C24 at week 5 versus week 8 were 0.86 (0.80-0.93), p=0.002; 0.83 (0.75-0.93), p=0.006; and EFV C24 was 0.91 (0.85-0.97), p=0.02, respectively. ConclusionsE2 PK was significantly lowered in the presence of TDF/FTC/EFV, and some lower TFV and EFV PK in the presence of FHT among HIV-positive TGW. Further studies should determine whether these reductions are clinically significant and evidenced when other FHT or ART regimens are used.

The online publication of this article [Tagbo BN, Bancroft RE, Fajolu I et al. Pediatric Bacterial Meningitis Surveillance in Nigeria From 2010 to 2016, Prior to and During the Phased Introduction of the 10-Valent Pneumococcal Conjugate Vaccine. Clin Infect Dis. https://doi.org/10.1093/cid/ciz474] was inadvertently listed with Volume 69, Issue Supplement 3, resulting in an incorrect citation line. The article is now listed in the correct issue online, and the citation line has since been corrected to “Clinical Infectious Diseases, Volume 69, Issue Supplement_2, 15 September 2019, Pages S81–S88, https://doi.org/10.1093/cid/ciz474.”

BackgroundSusceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with HIV (PLWH), but remains unexplored in African-ancestry populations. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and β-cell function (HOMA-B), insulin resistance (HOMA-IR), and incident diabetes mellitus (DM) among black women with or at risk for HIV. MethodsWomen without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI. Incident DM was defined by a combination of FG ≥126 mg/dL, use of DM medication, DM diagnosis, or HbA1c ≥6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the association between HOMA-B and HOMA-IR and DM by haplogroup. ResultsOf 1288 women (933 HIV+, 355 HIV-), PLWH had higher initial HOMA-B and HOMA-IR than people without HIV (PWOH). PLWH with haplogroup L2 had slower decline in HOMA-B per year (Pinteraction=0.02) and lower risk of incident DM (Hazard Ratio [HR]: 0.51, 95% CI: 0.32, 0.82) than PLWH with other haplogroups after adjustment for age, body mass index, cART use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2 compared to non-L2 (HR 1.28 [95% CI: 0.70, 2.38] vs 4.13 [95% CI: 3.28, 5.22], pinteraction<0.01) among PLWH. ConclusionsMitochondrial genetic variation is associated with β-cell function, and incident DM in non-Hispanic Black women with HIV and alters the relationship between insulin resistance and DM.

BackgroundEarly antiretroviral treatment (ART) is recommended for HIV-infected infants. However, few antiretroviral options are available for neonates. MethodsThe Early Infant Treatment Study in Botswana tested HIV-exposed infants using DNA PCR within 96 hours of birth, and HIV-infected infants started nevirapine (NVP) 6mg/kg BID, zidovudine (ZDV), and lamivudine (3TC) at age <7 days. Nevirapine trough concentrations were tested at 1 and 2 weeks. NVP was switched to lopinavir-ritonavir (LPV-r) at week 2, 3, 4, or 5 according to delivery gestational age (≥38, 37, 36, 35 weeks). ResultsForty HIV-infected infants started ART at median age 2 days (range 1-5). Nevirapine trough concentrations were highly variable and below therapeutic target (3000ng/mL) for 50% of 2-week measurements; concentrations did not correlate with viral decline at weeks 2, 4, or 12. Two deaths unrelated to ART occurred through 24 weeks. Only one unscheduled treatment modification was required. Within 4 weeks of transition to LPV-r, 9 (22.5%) had transient HIV RNA increases, likely due to poor LPV-r palatability. At 12 weeks, HIV-1 RNA was <40 copies/mL for 22 (55%) of 40 (93% <400 copies/mL); by 24 weeks, 27 (71%) of 38 were <40 copies/mL (84% <400 copies/mL). HIV-1 RNA response at 12 and 24 weeks did not differ by baseline HIV RNA, or other factors. ConclusionsNVP/ZDV/3TC started in the first week of life was safe and effective, even when trough NVP levels were below target. Transient viral increases occurred following transition to LPV-r, but by 12 and 24 weeks most children achieved and maintained viral suppression.

Reports of antibiotic stewardship (AS) integration into the >1000 U.S. internal medicine and family practice residency core curricula are scarce, but residents value such training. To help address this gap, and the projected shortage of physicians with training for establishing and leading an AS program (ASP), we describe the rationale for, and the output and shortcomings of, a dedicated AS rotation. Residents critically review, in real-time, inpatient antibiotic orders, provide feedback to the prescribers, learn the mechanics and requirements of an ASP, and complete a preliminary quality improvement project. Program evaluations are uniformly positive, noting limited opportunities otherwise to clarify optimal antibiotic choices or discuss antibiotics in depth. Nine posters at national conferences and one publication have roots in this rotation. Three alumni matriculated to accredited U.S. infectious diseases fellowships. We invite others to join us in calling for more AS training opportunities during residency.

In hematopoietic stem cell transplant recipients, the incidence of tuberculosis in positive interferon-gamma-releasing-assay (IGRA) without isoniazid prophylaxis (3.58/100 person-years) was higher than in negative-or-indeterminate IGRA (1.15/100 person-years)(P=.01) and in positive IGRA with isoniazid prophylaxis (0/100 person-years)(P=.09). The number needed to treat was 22 (95% CI 12-99) with positive IGRA results.