Risk factors for pulmonary tuberculosis recurrence, relapse and reinfection: a systematic review and meta-analysis.

BACKGROUND: The rate of pulmonary tuberculosis (TB) recurrence is substantial. Identifying risk factors can support the development of prevention strategies. METHODS: We retrieved studies published between 1 January 1980 and 31 December 2022 that assessed factors associated with undifferentiated TB recurrence, relapse or reinfection. For factors reported in at least four studies, we performed random-effects meta-analysis to estimate a pooled relative risk (RR). We assessed heterogeneity, risk of publication bias and certainty of evidence. RESULTS: We included 85 studies in the review; 81 documented risk factors for undifferentiated recurrence, 17 for relapse and 10 for reinfection. The scope for meta-analyses was limited given the wide variety of factors studied, inconsistency in control for confounding and the fact that only few studies employed molecular genotyping. Factors that significantly contributed to moderately or strongly increased pooled risk and scored at least moderate certainty of evidence were: for undifferentiated recurrence, multidrug resistance (MDR) (RR 3.49; 95% CI 1.86 to 6.53) and fixed-dose combination TB drugs (RR 2.29; 95% CI 1.10 to 4.75) in the previous episode; for relapse, none; and for reinfection, HIV infection (RR 4.65; 95% CI 1.71 to 12.65). Low adherence to treatment increased the pooled risk of recurrence 3.3-fold (95% CI 2.37 to 4.62), but the certainty of evidence was weak. CONCLUSION: This review emphasises the need for standardising methods for TB recurrence research. Actively pursuing MDR prevention, facilitating retention in treatment and providing integrated care for patients with HIV could curb recurrence rates. The use of fixed-dose combinations of TB drugs under field conditions merits further attention. PROSPERO REGISTRATION NUMBER: CRD42018077867.

Tuberculosis Knowledge among Persons Living with HIV Attending a Tertiary Hospital in Lima, Peru.

Tuberculosis (TB) is the leading cause of death among people living with HIV (PLWH). Limited TB knowledge has been associated with delayed TB diagnosis and low adherence to TB treatment. A cross-sectional study was conducted among PLWH at the largest HIV-referral center in Lima, Peru, to describe TB knowledge among PLWH and potential associated sociodemographic factors. Participants answered a self-administered survey on TB knowledge, which consisted of five questions about TB cure, transmission, treatment, symptoms, and prevention. Of 179 PLWH enrolled, most participants did not know that isoniazid (85%) and antiretrovirals (78%) are preventive measures for TB, and 56 (31.3%) knew that TB can be asymptomatic in PLWH. We did not find statistical differences in TB knowledge based on gender, education, marital status, and time on HIV care. We identified important gaps in TB knowledge among PLWH. Addressing these gaps could empower PLWH to reduce their TB risk.

Long-term impact on cardiopulmonary function and quality of life among patients recovered from SARS-CoV-2 infection in a 6-month follow-up period in Lima, Peru: FUNCTION cohort study protocol.

INTRODUCTION: The sequelae of COVID-19 have been described as a multisystemic condition, with a great impact on the cardiovascular and pulmonary systems with abnormalities in pulmonary function tests, such as lower diffusing capacity of the lung for carbon monoxide (DLco) levels and pathological patterns in spirometry; persistence of radiological lesions; cardiac involvement such as myocarditis and pericarditis; and an increase in mental disorders such as anxiety and depression. Several factors, such as infection severity during the acute phase as well as vaccination status, have shown some variable effects on these post-COVID-19 conditions, mainly at a clinical level such as symptoms persistence. Longitudinal assessments and reversibility of changes across the spectrum of disease severity are required to understand the long-term impact of COVID-19. METHODS AND ANALYSIS: A prospective cohort study aims to assess the impact of SARS-CoV-2 infection on cardiopulmonary function and quality of life after the acute phase of the disease over a 6-month follow-up period. Sample size was calculated to recruit 200 participants with confirmatory COVID-19 tests who will be subsequently classified according to infection severity. Four follow-up visits at baseline, month 1, month 3 and month 6 after discharge from the acute phase of the infection will be scheduled as well as procedures such as spirometry, DLco test, 6-minute walk test, chest CT scan, echocardiogram, ECG, N-terminal pro-B-type natriuretic peptide measurement and RAND-36 scale. Primary outcomes are defined as abnormal pulmonary function test considered as DLco <80%, abnormal cardiovascular function considered as left ventricular ejection fraction <50% and abnormal quality of life considered as a <40 score for each sphere in the RAND-36-Item Short Form Health Survey. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Ethics Committee of the Universidad Peruana Cayetano Heredia (SIDISI 203725) and the Ethics Committee of the Hospital Cayetano Heredia (042-2021). Protocol details were uploaded in ClinicalTrials.gov. Findings will be disseminated through peer-reviewed journals, scientific conferences and open-access social media platforms. TRIAL REGISTRATION NUMBER: NCT05386485.

Multiomics characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolates with heterogeneous intermediate resistance to vancomycin (hVISA) in Latin America.

BACKGROUND: Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms. OBJECTIVE: To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches. METHODS: 39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and hydrophilic interaction in six CC5-MRSA. RESULTS: Genomic relatedness of MRSA associated to hVISA phenotype was not detected. The change Try38 → His in Atl (autolysin) was identified in 92% of the hVISA. We identified SNPs and k-mers associated to hVISA in 11 coding regions with predicted functions in virulence, transport systems, carbohydrate metabolism and tRNA synthesis. Further, capABCDE, sdrD, esaA, esaD, essA and ssaA genes were overexpressed in hVISA, while lacABCDEFG genes were downregulated. Additionally, valine, threonine, leucine tyrosine, FAD and NADH were more abundant in VSSA, while arginine, glycine and betaine were more abundant in hVISA. Finally, we observed altered metabolic pathways in hVISA, including purine and pyrimidine pathway, CoA biosynthesis, amino acid metabolism and aminoacyl tRNA biosynthesis. CONCLUSIONS: Our results show that the mechanism of hVISA involves major changes in regulatory systems, expression of virulence factors and reduction in glycolysis via TCA cycle. This work contributes to the understanding of the development of this complex resistance mechanism in regional strains.

Mycetoma, chromoblastomycosis and other deep fungal infections: diagnostic and treatment approach.

PURPOSE OF REVIEW: to review recent advances in the epidemiology, diagnosis, and treatment of deep fungal infections. RECENT FINDINGS: Mycetoma and chromoblastomycosis are the only deep fungal infections incorporated in the list of neglected tropical diseases. These infections start in the skin but progress to deep tissues if not recognized early. A wide array of fungal pathogens are the causative agents. Molecular methods allow for early and accurate identification of the pathogens, but are unfortunately not available in endemic areas. Treatment options are mostly based upon clinical experience rather than on well-designed clinical trials. SUMMARY: Deep fungal infections of the skin and soft tissues are rare conditions of wide world distribution but mostly reported from tropical countries. Urgent need for affordable and easily accessible molecular methods and well-conducted studies to allow for accurate diagnosis and to provide evidence to guide proper therapy are urgently needed.

Recurrent TB: a systematic review and meta-analysis of the incidence rates and the proportions of relapses and reinfections.

BACKGROUND: A recurrent tuberculosis (TB) episode results from exogenous reinfection or relapse after cure. The use of genotyping allows the distinction between both. METHODS: We did a systematic review and meta-analysis, using four databases to search for studies in English, French and Spanish published between 1 January 1980 and 30 September 2020 that assessed recurrences after TB treatment success and/or differentiated relapses from reinfections using genotyping. We calculated person years of follow-up and performed random-effects model meta-analysis for estimating pooled recurrent TB incidence rates and proportions of relapses and reinfections. We performed subgroup analyses by clinical-epidemiological factors and by methodological study characteristics. FINDINGS: The pooled recurrent TB incidence rate was 2.26 per 100 person years at risk (95% CI 1.87 to 2.73; 145 studies). Heterogeneity was high (I2=98%). Stratified pooled recurrence rates increased from 1.47 (95% CI 0.87 to 2.46) to 4.10 (95% CI 2.67 to 6.28) per 100 person years for studies conducted in low versus high TB incidence settings. Background HIV prevalence, treatment drug regimen, sample size and duration of follow-up contributed too. The pooled proportion of relapses was 70% (95% CI 63% to 77%; I²=85%; 48 studies). Heterogeneity was determined by background TB incidence, as demonstrated by pooled proportions of 83% (95% CI 75% to 89%) versus 59% (95% CI 42% to 74%) relapse for studies from settings with low versus high TB incidence, respectively. INTERPRETATION: The risk of recurrent TB is substantial and relapse is consistently the most frequent form of recurrence. Notwithstanding, with increasing background TB incidence the proportion of reinfections increases and the predominance of relapses among recurrences decreases. PROSPERO REGISTRATION NUMBER: CRD42018077867.

The COVID-19 Pandemic in Peru: What Went Wrong?

Despite the early adoption of a national lockdown and other restrictions, Peru has been severely impacted by the COVID-19 pandemic. Having reached a milestone of more than 1,200 deaths per one million inhabitants by February 2021, important messages can be learned from how the pandemic was handled. Possible explanations for poor outcomes are a fragmented and already overwhelmed public health sector, lack of infrastructure and specialized personnel to tackle the pandemic, and deficient leadership from health authorities.

A pragmatic stepped-wedge cluster randomized trial to evaluate the effectiveness and cost-effectiveness of active case finding for household contacts within a routine tuberculosis program, San Juan de Lurigancho, Lima, Peru.

BACKGROUND: Active case finding (ACF) in household contacts of tuberculosis (TB) patients is now recommended for National TB Programs (NTP) in low- and middle-income countries. However, evidence supporting these recommendations remains limited. This study evaluates the effectiveness and cost-effectiveness of ACF for household contacts of TB cases in a large TB endemic district of Lima, Peru. METHODS: A pragmatic stepped-wedge cluster randomized controlled trial was conducted in 34 health centers of San Juan de Lurigancho district. Centers were stratified by TB rate and randomly allocated to initiate ACF in groups of eight or nine centers at four-month intervals. In the intervention arm, NTP providers visited households of index patients to screen contacts for active TB. The control arm was routine passive case finding (PCF) of symptomatic TB cases. The primary outcomes were the crude and adjusted active TB case rates among household contacts. Program costs were directly measured, and the cost-effectiveness of the ACF intervention was determined. FINDINGS: 3222 index TB cases and 12,566 household contacts were included in the study. ACF identified more household contact TB cases than PCF, 199.29/10,000 contacts/year vs. 132.13 (incidence rate ratio of 1.51 (95% CI 1.21-1.88)). ACF was associated with an incremental cost-effectiveness ratio of US $16,400 per disability-adjusted life year averted and not cost-effective assuming a willingness-to-pay threshold for Peru of US $6360. CONCLUSION: ACF of TB case household contacts detected significantly more secondary TB cases than PCF alone, but was not cost-effective in this setting. In threshold analyses, ACF becomes cost-effective if associated with case detection rates 2.5 times higher than existing PCF programs.

Detection of heterogeneous vancomycin intermediate resistance in MRSA isolates from Latin America.

BACKGROUND: Vancomycin is a common first-line option for MRSA infections. The heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) phenotype is associated with therapeutic failure. However, hVISA isolates are usually reported as vancomycin susceptible by routine susceptibility testing procedures. OBJECTIVES: To detect and characterize the hVISA phenotype in MRSA isolates causing infections in nine Latin American countries. METHODS: We evaluated a total of 1189 vancomycin-susceptible MRSA isolates recovered during 2006-08 and 2011-14. After an initial screening of hVISA using glycopeptide-supplemented agar strategies, the detection of hVISA was performed by Etest (GRD) and Macro-method (MET). Isolates deemed to be hVISA were subjected to population analysis profile/AUC (PAP/AUC) and WGS for further characterization. Finally, we interrogated alterations in predicted proteins associated with the development of the VISA phenotype in both hVISA and vancomycin-susceptible S. aureus (VSSA) genomes. RESULTS: A total of 39 MRSA isolates (3.3%) were classified as hVISA (1.4% and 5.6% in MRSA recovered from 2006-08 and 2011-14, respectively). Most of the hVISA strains (95%) belonged to clonal complex (CC) 5. Only 6/39 hVISA isolates were categorized as hVISA by PAP/AUC, with 6 other isolates close (0.87-0.89) to the cut-off (0.9). The majority of the 39 hVISA isolates exhibited the Leu-14→Ile (90%) and VraT Glu-156→Gly (90%) amino acid substitutions in WalK. Additionally, we identified 10 substitutions present only in hVISA isolates, involving WalK, VraS, RpoB and RpoC proteins. CONCLUSIONS: The hVISA phenotype exhibits low frequency in Latin America. Amino acid substitutions in proteins involved in cell envelope homeostasis and RNA synthesis were commonly identified. Our results suggest that Etest-based methods are an important alternative for the detection of hVISA clinical isolates.

Adherence to standards of care and mortality in the management of Staphylococcus aureus bacteraemia in Peru: A prospective cohort study.

BACKGROUND: Despite high mortality rates, physicians can alter the course of the Staphylococcus aureus bacteraemia (SAB) by following recommended standards of care. We aim to assess the adherence of these guidelines and their impact on mortality. METHODS: Substudy from a prospective cohort of hospitalized patients with SAB from three hospitals from Peru. Hazard ratios were calculated using Cox proportional regression to evaluate the association between 30-day mortality and the performance of standards of care: removal of central venous catheters (CVC), follow-up blood cultures, echocardiography, correct duration, and appropriate definitive antibiotic therapy. RESULTS: 150 cases of SAB were evaluated; 61.33% were MRSA. 30-day attributable mortality was 22.39%. CVC removal was done in 42.86% of patients. Follow-up blood cultures and echocardiograms were performed in 8% and 29.33% of cases, respectively. 81.33% of cases had appropriate empirical treatment, however, only 22.41% of MSSA cases were given appropriate definitive treatment, compared to 93.47% of MRSA. The adjusted regression for all-cause mortality found a substantial decrease in hazards when removing CVC (aHR 0.28, 95% CI: 0.10 - 0.74) and instituting appropriate definitive treatment (aHR 0.27, 95% CI: 0.08 - 0.86), while adjusting for standards of care, qPitt bacteraemia score, comorbidities, and methicillin susceptibility; similar results were found in the attributable mortality model (aHR 0.24, 95% CI: 0.08 - 0.70 and aHR 0.21, 95% CI: 0.06 - 0.71, respectively). CONCLUSIONS: Deficient adherence to standards of care was observed, especially definitive treatment for MSSA. CVC removal and the use of appropriate definitive antibiotic therapy reduced the hazard mortality of SAB.

Prevalence of positive TST among healthcare workers in high-burden TB setting in Peru.

BACKGROUND: Tuberculosis (TB) transmission has long been recognized as an important occupational hazard for healthcare workers (HCWs). HCWs have a 5.8% annual risk of exposure and three times greater risk of developing active TB than the general population. METHODS: We conducted an observational cross-sectional study between September 2014 and March 2015 among HCWs in a high-burden TB setting in Lima to estimate the prevalence of positive Tuberculin Skin Test (TST) and to investigate factors associated with a positive TST. RESULTS: Two hundred forty participants were included in the analysis; TST was administered to 190 (79.2%) while the rest were exempt due to a previous positive TST result, history of TB, or test refusal. A positive TST result was found among 56.2% of participants to whom the TST was applied (95% CI: 49.22-63.55%). When considering those who had a previous positive TST result and those with a history of TB, the prevalence of a positive TST result was 64.3% (95% CI: 57.8-70.3%). No significant differences were observed between clinical/paramedical and administrative staff in the health center. The use of N95 masks during work hours was reported by 142 (69.9%) participants. Prevalence ratios (PR) show that workers with more than 120 months as a HCW were 1.44 times more likely to be TST positive. The multivariate analysis found that HCWs with over 10 years of service were 1.52 times more likely to be TST positive. CONCLUSION: This study supports previous reports that TB infection is an occupational hazard for HCWs. Prevention of TB transmission through control measures, as well as timely diagnosis of LTBI in this particular high-risk group, is critical for individual and public health.

Novel Insights into the Classification of Staphylococcal ß-Lactamases in Relation to the Cefazolin Inoculum Effect.

Cefazolin has become a prominent therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections. However, an important concern is the cefazolin inoculum effect (CzIE), a phenomenon mediated by staphylococcal ß-lactamases. Four variants of staphylococcal ß-lactamases have been described based on serological methodologies and limited sequence information. Here, we sought to reassess the classification of staphylococcal ß-lactamases and their correlation with the CzIE. We included a large collection of 690 contemporary bloodstream MSSA isolates recovered from Latin America, a region with a high prevalence of the CzIE. We determined cefazolin MICs at standard and high inoculums by broth microdilution. Whole-genome sequencing was performed to classify the ß-lactamase in each isolate based on the predicted full sequence of BlaZ. We used the classical schemes for ß-lactamase classification and compared it to BlaZ allotypes found in unique sequences using the genomic information. Phylogenetic analyses were performed based on the BlaZ and core-genome sequences. The overall prevalence of the CzIE was 40%. Among 641 genomes, type C was the most predominant ß-lactamase (37%), followed by type A (33%). We found 29 allotypes and 43 different substitutions in BlaZ. A single allotype, designated BlaZ-2, showed a robust and statistically significant association with the CzIE. Two other allotypes (BlaZ-3 and BlaZ-5) were associated with a lack of the CzIE. Three amino acid substitutions (A9V, E112A, and G145E) showed statistically significant association with the CzIE (P = <0.01). CC30 was the predominant clone among isolates displaying the CzIE. Thus, we provide a novel approach to the classification of the staphylococcal ß-lactamases with the potential to more accurately identify MSSA strains exhibiting the CzIE.

Contact evaluation and isoniazid preventive therapy among close and household contacts of tuberculosis patients in Lima, Peru: an analysis of routine data.

OBJECTIVE: Contacts of pulmonary tuberculosis (TB) cases are at high risk of TB infection and progression to disease. Close and household contacts and those <5 years old have the highest risk. Isoniazid preventive therapy (IPT) can largely prevent TB disease among infected individuals. International and Peruvian recommendations include TB contact investigation and IPT prescription to eligible contacts. We conducted a study in Lima, Peru, to determine the number of close and household contacts who were evaluated, started on IPT, and who completed it, and the factors associated to compliance with national guidelines. METHODS: We conducted a longitudinal retrospective study including all TB cases diagnosed between January 2015 and July 2016 in 13 health facilities in south Lima. Treatment cards, TB registers and clinical files were reviewed and data on index cases (sex, age, smear status, TB treatment outcome), contact investigation (sex, age, kinship to the index case, evaluations at month 0, 2 and 6) and health facility (number of TB cases notified per year, proportion of TB cases with treatment success) were extracted. We tabulated frequencies of contact evaluation by contact and index case characteristics. To investigate determinants of IPT initiation and completion, we used generalised linear mixed models. RESULTS: A total of 2323 contacts were reported by 662 index cases; the median number of contacts per case was four (IQR, 2-5). Evaluation at month 0 was completed by 99.2% (255/257) of contacts <5 and 98.1% (558/569) of contacts aged 5-19 years. Of 191 eligible contacts <5 years old, 70.2% (134) started IPT and 31.4% (42) completed it. Of 395 contacts 5-19 years old, 36.7% (145) started IPT and 32.4% (47) completed it. Factors associated to not starting IPT among contacts <5 years old were being a second-degree relative to the index case (OR 6.6 95CI% 2.6-16.5), not having received a tuberculin skin test (TST) (OR 3.9 95%CI 1.4-10.8), being contact of a smear-negative index case (OR 5.5 95%CI 2.0-15.1) and attending a low-caseload health facility (OR 2.8 95%CI 1.3-6.2). Factors associated to not starting IPT among 5-19 year-olds were age (OR 13.7 95%CI 5.9-32.0 for 16-19 vs. 5-7 years old), being a second-degree relative (OR 3.0 95%CI 1.6-5.6), not having received a TST (OR 5.4, 95%CI 2.5-11.8), being contact of a male index case (OR 2.1 95CI% 1.2-3.5), with smear-negative TB (OR 1.9 95%CI 1.0-3.6), and attending a high-caseload health facility (OR 2.1 95%CI 1.2-3.6). Factors associated to not completing IPT, among contacts who started, were not having received a TST (OR 3.4 95%CI 1.5-7.9 for <5 year-olds, and OR 4.3 95%CI 1.7-10.8 for those 5-19 years old), being contact of an index case with TB treatment outcome other than success (OR 9.3 95%CI 2.6-33.8 for <5 year-olds and OR 15.3 95%CI 1.9-125.8 for those 5-19 years old), and, only for those 5-19 years old, attending a health facility with high caseload (OR 3.2 95%CI 1.4-7.7) and a health facility with low proportion of TB cases with treatment success (OR 4.4 95%CI 1.9-10.2). CONCLUSIONS: We found partial compliance to TB contact investigation, and identified contact, index case and health facility-related factors associated to IPT start and completion that can guide the TB programme in increasing coverage and quality of this fundamental activity.

OBJECTIF: Les contacts des cas de tuberculose (TB) pulmonaire présentent un risque élevé d'infection à la TB et d'évolution vers la maladie. Les contacts étroits et familiaux et ceux de moins de 5 ans sont les plus à risque. Le traitement préventif à l'isoniazide (TPI) peut largement prévenir la maladie TB chez les personnes infectées. Nous avons mené une étude à Lima, au Pérou, pour déterminer le nombre de contacts proches et familiaux qui ont été évalués, qui ont commencé le TPI et qui l'ont achevé, ainsi que les facteurs associés au respect des directives nationales. MÉTHODES: Etude longitudinal rétrospective de tous les cas de TB diagnostiqués entre janvier 2015 et juillet 2016 dans 13 établissements de santé dans le sud de Lima. Les cartes de traitement, les registres de TB et les dossiers cliniques ont été examinés et des données sur les cas indice, l'investigation des contacts et les établissements de santé ont été extraites. Nous avons tabulé les fréquences d'évaluation des contacts par les caractéristiques des contacts et des cas indice. Pour étudier les déterminants de l'initiation et de l'achèvement du TPI, nous avons utilisé des modèles linéaires mixtes généralisés. RÉSULTATS: Au total, 2.323 contacts ont été rapportés par 662 cas indice; 70,2% des contacts âgés de moins de 5 ans ont commencé le TPI et 31,4% l'ont terminé, tandis que 36,7% des contacts âgés de 5 à 19 ans ont commencé le TPI et 32,4% l'ont terminé. Les facteurs associés au fait de ne pas commencer ou de terminer le TPI étaient: être un parent de second degré du cas indice, ne pas avoir reçu le test tuberculinique, être le contact d'un cas indice à frottis négatif et fréquenter un établissement de santé à faible charge de travail pour les moins de cinq ans contre fréquenter un établissement de santé à charge de travail élevée pour les contacts plus âgés. CONCLUSIONS: Nous avons constaté une compliance partielle à l'enquête sur les contacts de la TB, et avons identifié les facteurs liés aux contacts, aux cas indice et aux établissements de santé associés au début et à la fin du TPI qui peuvent guider le programme de TB dans l'augmentation de sa couverture et de sa qualité.

Mycobacterium tuberculosis-specific cytokine biomarkers for the diagnosis of childhood TB in a TB-endemic setting.

The tuberculin skin test and interferon-gamma release assays have limitations in diagnosing tuberculosis (TB), particularly in children. This study investigated the performance of candidate M. tuberculosis-specific cytokine biomarkers for TB in children in a TB-endemic setting. A total of 237 children with a household contact with smear-positive pulmonary TB were recruited. Importantly, a group of children with illnesses other than TB (sick controls) was included to assess specificity. Median IFN-É£, IL-1ra, IL-2, IL-13, IP-10, MIP-1ß and TNF-α responses were significantly higher in children with active TB and latent TB infection (LTBI) than in both healthy and sick control children. Three of these cytokines - IL-2, IL-13 and IP-10 - showed better performance characteristics than IFN-É£, with IL-2 achieving positive and negative predictive values of 97.7% and 90.7%, respectively. Furthermore, IL-1ra and TNF-α responses differed significantly between active TB and LTBI cases, suggesting that they may be stage-specific biomarkers. Our data indicate that incorporating these biomarkers into future blood-based TB assays could result in substantial performance gains.

Health literacy and knowledge related to tuberculosis among outpatients at a referral hospital in Lima, Peru.

BACKGROUND: Tuberculosis (TB) case detection in Peru relies on passive case finding. This strategy relies on the assumption that the community is aware that a persistent cough or contact with a TB patient is an indication to seek formal health care. This study evaluated health literacy and TB knowledge among outpatients at Hospital Cayetano Heredia in Lima, Peru. METHODS: A cross-sectional survey was performed between June and August 2017. Data on sociodemographic factors, TB knowledge, and health literacy were collected, and bivariate and multivariate logistic regressions were performed to study the associations between variables. RESULTS: The analysis included 272 participants; 57.7% knew someone who had TB and 9% had TB in the past. A 2-week cough was reported as a TB symptom by 66 (24%) participants. High TB knowledge was found among 149 (54.8%) participants and high health literacy was found among 193 (71.0%) participants. Health literacy and TB knowledge were not significantly associated (OR=0.9; 95% CI 0.5-1.5). After controlling for sex, age, district, education, health insurance, frequency of hospital visits, and previous TB diagnosis, high TB knowledge was associated with knowing someone with TB (aOR=2.7; 95% CI 1.6-4.7) and inversely associated with being a public transport driver (aOR=0.2; 95% CI 0.05-0.9). Not living in poverty was the single factor associated with high health literacy (aOR=3.8; 95% CI 1.6-8.9). CONCLUSION: Although TB knowledge was fair, 30% did not know that cough is a symptom of TB and >70% did not know being in contact with a TB patient is a risk factor for TB. Tailoring educational strategies to at-risk groups may enhance passive case detection especially among transport workers and TB contacts in Lima, Peru.

Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis.

Patients with multidrug-resistant tuberculosis in Peru and South Africa were randomized to a weight-banded nominal dose of 11, 14, 17, or 20 mg/kg/day levofloxacin (minimum, 750 mg) in combination with other second-line agents. A total of 101 patients were included in noncompartmental pharmacokinetic analyses. Respective median areas under the concentration-time curve from 0 to 24 h (AUC0-24) were 109.49, 97.86, 145.33, and 207.04 µg · h/ml. Median maximum plasma concentration (Cmax) were 11.90, 12.02, 14.86, and 19.17 µg/ml, respectively. Higher levofloxacin doses, up to 1,500 mg daily, resulted in higher exposures. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.).

The Cefazolin Inoculum Effect Is Associated With Increased Mortality in Methicillin-Susceptible Staphylococcus aureus Bacteremia.

BACKGROUND: Recent studies have favored the use of cefazolin over nafcillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia. The clinical influence of the cefazolin inoculum effect (CzIE) in the effectiveness of cephalosporins for severe MSSA infections has not been evaluated. METHODS: We prospectively included patients from 3 Argentinian hospitals with S. aureus bacteremia. Cefazolin minimum inhibitory concentrations (MICs) were determined at standard (105 colony-forming units [CFU]/mL) and high (107 CFU/mL) inoculum. The CzIE was defined as an increase of MIC to ≥16 µg/mL when tested at high inoculum. Whole-genome sequencing was performed in all isolates. RESULTS: A total of 77 patients, contributing 89 MSSA isolates, were included in the study; 42 patients (54.5%) had isolates with the CzIE. In univariate analysis, patients with MSSA exhibiting the CzIE had increased 30-day mortality (P = .034) and were more likely to have catheter-associated or unknown source of bacteremia (P = .033) compared with patients infected with MSSA isolates without the CzIE. No statistically significant difference between the groups was observed in age, clinical illness severity, place of acquisition (community vs hospital), or presence of endocarditis. The CzIE remained associated with increased 30-day mortality in multivariate analysis (risk ratio, 2.65; 95% confidence interval, 1.10-6.42; P = .03). MSSA genomes displayed a high degree of heterogeneity, and the CzIE was not associated with a specific lineage. CONCLUSIONS: In patients with MSSA bacteremia where cephalosporins are used as firstline therapy, the CzIE was associated with increased 30-day mortality. Clinicians should be cautious when using cefazolin as firstline therapy for these infections.