A 7-Year Brazilian National Perspective on Plasmid-Mediated Carbapenem Resistance in Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii Complex and the Impact of the Coronavirus Disease 2019 Pandemic on Their Occurrence.

BACKGROUND: Carbapenemase production is a global public health threat. Antimicrobial resistance (AMR) data analysis is critical to public health policy. Here we analyzed carbapenemase detection trends using the AMR Brazilian Surveillance Network. METHODS: Carbapenemase detection data from Brazilian hospitals included in the public laboratory information system dataset were evaluated. The detection rate (DR) was defined as carbapenemase detected by gene tested per isolate per year. The temporal trends were estimated using the Prais-Winsten regression model. The impact of COVID-19 on carbapenemase genes in Brazil was determined for the period 2015-2022. Detection pre- (October 2017 to March 2020) and post-pandemic onset (April 2020 to September 2022) was compared using the χ2 test. Analyses were performed with Stata 17.0 (StataCorp, College Station, TX). RESULTS: 83 282 blaKPC and 86 038 blaNDM were tested for all microorganisms. Enterobacterales DR for blaKPC and blaNDM was 68.6% (41 301/60 205) and 14.4% (8377/58 172), respectively. P. aeruginosa DR for blaNDM was 2.5% (313/12 528). An annual percent increase for blaNDM of 41.1% was observed, and a decrease for blaKPC of -4.0% in Enterobacterales, and an annual increase for blaNDM of 71.6% and for blaKPC of 22.2% in P. aeruginosa. From 2020 to 2022, overall increases of 65.2% for Enterobacterales, 77.7% for ABC, and 61.3% for P. aeruginosa were observed in the total isolates. CONCLUSIONS: This study shows the strengths of the AMR Brazilian Surveillance Network with robust data related to carbapenemases in Brazil and the impact of COVID-19 with a change in carbapenemase profiles with blaNDM rising over the years.

Clusters of preterm live births and respiratory distress syndrome-associated neonatal deaths: spatial distribution and cooccurrence patterns.

BACKGROUND: Prematurity and respiratory distress syndrome (RDS) are strongly associated. RDS continues to be an important contributor to neonatal mortality in low- and middle-income countries. This study aimed to identify clusters of preterm live births and RDS-associated neonatal deaths, and their cooccurrence pattern in São Paulo State, Brazil, between 2004 and 2015.  METHODS: Population-based study of all live births with gestational age ≥ 22 weeks, birthweight ≥ 400 g, without congenital anomalies from mothers living in São Paulo State, Brazil, during 2004-2015. RDS-associated neonatal mortality was defined as deaths < 28 days with ICD-10 codes P22.0 or P28.0. RDS-associated neonatal mortality and preterm live births rates per municipality were submitted to first- and second-order spatial analysis before and after smoothing using local Bayes estimates. Spearman test was applied to identify the correlation pattern between both rates. RESULTS: Six hundred forty-five thousand two hundred seventy-six preterm live births and 11,078 RDS-associated neonatal deaths in São Paulo State, Brazil, during the study period were analyzed. After smoothing, a non-random spatial distribution of preterm live births rate (I = 0.78; p = 0.001) and RDS-associated neonatal mortality rate (I = 0.73; p = 0.001) was identified. LISA maps confirmed clusters for both, with a negative correlation (r = -0.24; p = 0.0000). Clusters of high RDS-associated neonatal mortality rates overlapping with clusters of low preterm live births rates were detected. CONCLUSIONS: Asymmetric cluster distribution of preterm live births and RDS-associated neonatal deaths may be helpful to indicate areas for perinatal healthcare improvement.

Temporal Trend and Risk Factors for Respiratory Distress Syndrome-Associated Neonatal Mortality in Preterm Infants: A Population-Based Study in a Middle-Income Country.

OBJECTIVE: This article aimed to report a temporal series of respiratory distress syndrome (RDS)-associated neonatal mortality rates in preterm live births in São Paulo state, Brazil, and to identify social, maternal, and neonatal characteristics associated with these deaths. STUDY DESIGN: This is a population-based study of all live births with gestational age (GA) between 22 and 36 weeks, birth weight ≥400 g, without congenital anomalies from mothers living in São Paulo state during 2004 to 2015. RDS-associated neonatal mortality was defined as death up to 27 days after birth with ICD-10 codes P22.0 or P28.0. RDS-associated neonatal mortality rate (annual percent change [APC] with 95% confidence intervals [95% CIs]) was analyzed by Prais-Winsten. Kaplan-Meier estimator identified the time after birth that the RDS-associated neonatal death occurred. Poisson's regression model compared social maternal and neonatal characteristics between preterm live births that survived the neonatal period and those with RDS-associated neonatal deaths, with results expressed in incidence rate ratio and 95% CI. RESULTS: A total of 645,276 preterm live births were included in the study, of which 612,110 survived and 11,078 had RDS-associated neonatal deaths. RDS-associated neonatal mortality rate was 17.17 per thousand preterm live births, with a decreasing annual trend (APC: -6.50%; 95% CI: -9.11 to -3.82%). The median time of these deaths was 48 hours after birth. The following risk factors for RDS-associated neonatal death were identified: maternal schooling ≤7 years (1.18; 1.09-1.29), zero to three prenatal care visits (1.25; 1.18-1.32), multiple pregnancy (1.24; 1.16-1.33), vaginal delivery (1.29; 1.22-1.36), GA 22 to 27 weeks (106.35; 98.36-114.98), GA 28 to 31 weeks (20.12; 18.62-21.73), male sex (1.16; 1.10-1.22), and 5-minute Apgar scores of 0 to 3 (6.74; 6.08-7.47) and 4 to 6 (3.97; 3.72-4.23). CONCLUSION: During the study period, RDS-associated neonatal mortality rates showed significant reduction. The relationship between RDS-associated neonatal deaths and social, maternal, and neonatal factors suggests the need for perinatal strategies to reduce prematurity and to improve the initial management of preterm infants. KEY POINTS: · RDS is associated with preterm live births.. · Impact of RDS-associated neonatal mortality in middle-income countries is scarce.. · Qualified perinatal care can reduce RDS-associated neonatal mortality..

Elevated MICs of Susceptible Antipseudomonal Cephalosporins in Non-Carbapenemase-Producing, Carbapenem-Resistant Pseudomonas aeruginosa: Implications for Dose Optimization.

The present study evaluated the in vitro potency of ceftazidime and cefepime among carbapenem-resistant Pseudomonas aeruginosa isolates collected as part of a global surveillance program and assessed the pharmacodynamic implications using previously published population pharmacokinetics. When susceptible, MICs resulted at the high end of distribution for both ceftazidime and cefepime, thus 6 g/day was required to achieve optimal pharmacodynamic profiles. These findings should be considered in the clinic and for the application of CLSI susceptibility breakpoints.

Evaluation of high-concentration EDTA-modified carbapenemase inactivation method (eCIM) for SPM-producing Pseudomonas aeruginosa.

The modified carbapenemase inactivation method (mCIM) and EDTA-modified carbapenemase inactivation method (eCIM) are simple and cost-effective detection methods used for serine- and metallo-carbapenemase determination; however, poor test performance has been reported for IMP- and SPM-producing P. aeruginosa. Recently, we reported that 40 µM EDTA concentrations improved test sensitivity for IMP-producing P. aeruginosa. Herein, we assessed standard and high-concentration EDTA eCIM against SPM-producing P. aeruginosa. Twenty-four SPM-producing P. aeruginosa were evaluated, and 3 well-characterized P. aeruginosa (wild type, n = 1; KPC, n = 1; and VIM, n = 1) were used for quality control. mCIM was conducted as described by the Clinical and Laboratory Standards Institute. Concurrently, eCIM methods were performed at standard (5 µM) and high (40 µM) EDTA concentrations. All mCIM phenotypes responded concordant with its genotype. eCIM phenotype matched its genotype for 3 and 24 SPM-producing isolates using standard and high EDTA concentrations, respectively. The eCIM sensitivity increased from 12% using standard concentrations to 100% using high EDTA concentrations. No EDTA-related adverse effects were observed on bacteria growth. The combination mCIM with 40 µM EDTA eCIM properly captured SPM-producing P. aeruginosa. This methodology should be validated in a multi-center study with various enzymatic-producing P. aeruginosa.

The ERACE-PA Global Surveillance Program: Ceftolozane/tazobactam and Ceftazidime/avibactam in vitro Activity against a Global Collection of Carbapenem-resistant Pseudomonas aeruginosa.

The cephalosporin-ß-lactamase-inhibitor-combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have revolutionized treatment of carbapenem-resistant Pseudomonas aeruginosa (CR-PA). A contemporary assessment of their in vitro potency against a global CR-PA collection and an assessment of carbapenemase diversity are warranted. Isolates determined as CR-PA by the submitting site were collected from 2019-2021 (17 centers in 12 countries) during the ERACE-PA Global Surveillance Program. Broth microdilution MICs were assessed per CLSI standards for ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime, and cefepime. Phenotypic carbapenemase testing was conducted (modified carbapenem inactivation method (mCIM)). mCIM positive isolates underwent genotypic carbapenemase testing using the CarbaR, the CarbaR NxG, or whole genome sequencing. The MIC50/90 was reported as well as percent susceptible (CLSI and EUCAST interpretation). Of the 807 isolates, 265 (33%) tested carbapenemase-positive phenotypically. Of these, 228 (86%) were genotypically positive for a carbapenemase with the most common being VIM followed by GES. In the entire cohort of CR-PA, ceftolozane/tazobactam and ceftazidime/avibactam had MIC50/90 values of 2/ > 64 and 4/64 mg/L, respectively. Ceftazidime/avibactam was the most active agent with 72% susceptibility per CLSI compared with 63% for ceftolozane/tazobactam. For comparison, 46% of CR-PA were susceptible to ceftazidime and cefepime. Against carbapenemase-negative isolates, 88 and 91% of isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against carbapenem-resistant P. aeruginosa, particularly in the absence of carbapenemases. The contemporary ERACE-PA Global Program cohort with 33% carbapenemase positivity including diverse enzymology will be useful to assess therapeutic options in these clinically challenging organisms with limited therapies.

Annual trend of neonatal mortality and its underlying causes: population-based study - São Paulo State, Brazil, 2004-2013.

BACKGROUND: Population-based studies analyzing neonatal deaths in middle-income countries may contribute to design interventions to achieve the Sustainable Development Goals, established by United Nations. This study goal is to analyze the annual trend of neonatal mortality in São Paulo State, Brazil, over a 10-year period and its underlying causes and to identify maternal and neonatal characteristics at birth associated with neonatal mortality. METHOD: A population-based study of births and deaths from 0 to 27 days between 2004 and 2013 in São Paulo State, Brazil, was performed. The annual trend of neonatal mortality rate according to gestational age was analyzed by Poisson or by Negative Binomial Regression models. Basic causes of neonatal death were classified according to ICD-10. Association of maternal demographic variables (block 1), prenatal and delivery care variables (block 2), and neonatal characteristics at birth (block 3) with neonatal mortality was evaluated by Poisson regression analysis adjusted by year of birth. RESULTS: Among 6,056,883 live births in São Paulo State during the study period, 48,309 died from 0 to 27 days (neonatal mortality rate: 8.0/1,000 live births). For the whole group and for infants with gestational age 22-27, 28-31, 32-36, 37-41 and ≥ 42 weeks, reduction of neonatal mortality rate was, respectively, 18 %, 15 %, 38 %, 53 %, 31 %, and 58 %. Median time until 50 % of deaths occurred was 3 days. Main basic causes of death were respiratory disorders (25 %), malformations (20 %), infections (17 %), and perinatal asphyxia (7 %). Variables independently associated with neonatal deaths were maternal schooling, prenatal care, parity, newborn sex, 1st minute Apgar, and malformations. Cesarean delivery, compared to vaginal, was protective against neonatal mortality for infants at 22-31 weeks, but it was a risk factor for those with 32-41 weeks. CONCLUSIONS: Despite the significant decrease in neonatal mortality rate over the 10-year period in São Paulo State, improved access to qualified health care is needed in order to avoid preventable neonatal deaths and increase survival of infants that need more complex levels of assistance.

In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin or aztreonam against MDR Pseudomonas aeruginosa.

OBJECTIVES: Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-ß-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. METHODS: MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n = 13), blaIMP (n = 4), blaVIM (n = 3), blaGES-1 (n = 2) and blaCTX-M-like (n = 2), and 3 isolates with no acquired ß-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time-kill analysis (TKA). RESULTS: All CR-PSA isolates harbouring blaSPM-1, blaGES-1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. CONCLUSIONS: In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.

Pharmacodynamic comparison of different antimicrobial regimens against Staphylococcus aureus bloodstream infections with elevated vancomycin minimum inhibitory concentration.

BACKGROUND: Staphylococcus aureus is one of the major causes of bloodstream infections (BSI) worldwide, representing a major challenge for public health due to its resistance profile. Higher vancomycin minimum inhibitory concentrations (MIC) in S. aureus are associated with treatment failure and defining optimal empiric options for BSIs in settings where these isolates are prevalent is rather challenging. In silico pharmacodynamic models based on stochastic simulations (Monte Carlo) are important tools to estimate best antimicrobial regimens in different scenarios. We aimed to compare the pharmacodynamic profiles of different antimicrobials regimens for the treatment of S. aureus BSI in an environment with high vancomycin MIC. METHODS: Steady-state drug area under the curve ratio to MIC (AUC/MIC) or the percent time above MIC (fT > MIC) were modeled using a 5000-patient Monte Carlo simulation to achieve pharmacodynamic exposures against 110 consecutive S. aureus isolates associated with BSI. RESULTS: Cumulative fractions of response (CFRs) against all S. aureus isolates were 98% for ceftaroline; 79% and 92% for daptomycin 6 mg/kg q24h and for the high dose of 10 mg/kg q24h, respectively; 77% for linezolid 600 mg q12h when MIC was read according to CLSI M100-S26 instructions, and 64% when MIC was considered at the total growth inhibition; 65% and 86% for teicoplanin, three loading doses of 400 mg q12 h followed by 400 mg q24 h and for teicoplanin 400 mg q12 h, respectively; 61% and 76% for vancomycin 1000 mg q12 h and q8 h, respectively. CONCLUSIONS: Based on this model, ceftaroline and high-dose daptomycin regimens delivered best pharmacodynamic exposures against S. aureus BSIs. Teicoplanin higher dose regimen achieved the best CFR (86%) among glycopeptides, although optimal threshold was not achieved, and vancomycin performance was critically affected by the S. aureus vancomycin MIC ≥2 mg/L. Linezolid effectiveness (CFR of 73%) is also affected by high prevalence of isolates with linezolid MIC ≥2 mg/L. These data show the need to continually evaluate the pharmacodynamic profiles of antimicrobials for empiric treatment of these infections.

NDM-producing Enterobacterales prevalence associated to COVID-19 in a tertiary hospital.

Colonizations/Infections caused by carbapenem-resistant Enterobacterales are of great clinical and epidemiological importance due to their rapid dissemination and high mortality rates. In this scenario, the use of antibiotics intensified by the COVID-19 pandemic has brought about a great warning on the real impact that this pandemic could have on antimicrobial management programs and long-term antimicrobial resistance rates. The objective of this study was to evaluate the increase of New Delhi Metallo ß-Lactamase (NDM)-producing Enterobacterales cases in COVID-19 units of a complex Brazilian tertiary hospital. This retrospective observational study included all patients admitted to the hospital identified as colonized or infected by NDM-producing Gram negative bacilli (GNB), from January 2017 to April 2021. Forty-two NDM-producing Enterobacterales were identified in 39 patients. The rate of NDM cases per total surveillance cultures increased progressively between 2017 and 2021 (chi-2 for trend, p < 0.0001) and was associated with a higher occurrence specifically in COVID units (Fisher exact, p < 0.0001). The molecular investigation of the NDM-producing Klebsiella pneumoniae strains revealed the emergence of diverse clones during the COVID-19 period, also with possible evidence of horizontal transmission among patients within COVID units. NDM-producing Enterobacterales with multiple and different clonalities in the COVID-19 units also raised questions about the importance of other factors besides horizontal clonal transfer, including the increase of antimicrobial consumption by these patients.

Underreporting of unfavorable outcomes of congenital syphilis on the Notifiable Health Conditions Information System in the state of São Paulo, Brazil, 2007-2018.

OBJECTIVE: to describe the frequency of underreporting of unfavorable outcomes of congenital syphilis in the state of São Paulo, Brazil, 2007-2018. METHODS: this was a descriptive study of cases of abortion, fetal and non-fetal deaths due to congenital syphilis reported on the Notifiable Health Conditions Information System (Sistema de Informação de Agravos de Notificação - SINAN), and those of congenital syphilis registered in any line in the Death Certificate, on the Mortality Information System (Sistema de Informações sobre Mortalidade - SIM), by means of probabilistic and deterministic linkage. RESULTS: of the 27,713 cases of congenital syphilis reported, 1,320 progressed to death (871 fetal deaths, 449 infant deaths) and were matched to the SIM; 355 deaths (259 fetal deaths, 96 infant deaths) were not included on SINAN; there was an increase in unfavorable outcomes,11.4% for infant deaths due to congenital syphilis, 3.0% for fetal deaths and 1.9% for abortions. CONCLUSION: the use of different relationship techniques proved to be adequate to identify the frequency of underreporting of unfavorable outcomes of congenital syphilis in the state of São Paulo.

Congenital diaphragmatic hernia in a middle-income country: Persistent high lethality during a 12-year period.

BACKGROUND: In high- and middle-income countries, mortality associated to congenital diaphragmatic hernia (CDH) is high and variable. In Brazil, data is scarce regarding the prevalence, mortality, and lethality of CDH. This study aimed to analyze, in São Paulo state of Brazil, the temporal trends of prevalence, neonatal mortality and lethality of CDH and identify the time to CDH-associated neonatal death. METHODS: Population-based study of all live births with gestational age ≥ 22 weeks, birthweight ≥400g, from mothers residing in São Paulo State, Brazil, during 2004-2015. CDH definition and its subgroups classification were based on ICD-10 codes reported in the death and/or live birth certificates. CDH-associated neonatal death was defined as death up to 27 days after birth of infants with CDH. CDH prevalence, neonatal mortality and lethality were calculated and their annual percent change (APC) with 95% confidence intervals (95%CI) was analyzed by Prais-Winsten. Kaplan-Meier estimator identified the time after birth that CDH-associated neonatal death occurred. RESULTS: CDH prevalence was 1.67 per 10,000 live births, with a significant increase throughout the period (APC 2.55; 95%CI 1.30 to 3.83). CDH neonatal mortality also increased over the time (APC 2.09; 95%CI 0.27 to 3.94), while the lethality was 78.78% and remained stationary. For isolated CDH, CDH associated to non-chromosomal anomalies and CDH associated to chromosomal anomalies the lethality was, respectively, 72.25%, 91.06% and 97.96%, during the study period. For CDH as a whole and for all subgroups, 50% of deaths occurred within the first day after birth. CONCLUSIONS: During a 12-year period in São Paulo State, Brazil, CDH prevalence and neonatal mortality showed a significant increase, while lethality remained stable, yet very high, compared to rates reported in high income countries.

Temporal Trend, Causes, and Timing of Neonatal Mortality of Moderate and Late Preterm Infants in São Paulo State, Brazil: A Population-Based Study.

Moderate and late preterm newborns comprise around 85% of live births < 37 weeks gestation. Data on their neonatal mortality in middle-income countries is limited. This study aims to analyze the temporal trend, causes and timing of neonatal mortality of infants with 320/7-366/7 weeks gestation without congenital anomalies from 2004-2015 in the population of São Paulo State, Brazil. A database was built by deterministic linkage of birth and death certificates. Causes of death were classified by ICD-10 codes. Among 7,317,611 live births in the period, there were 545,606 infants with 320/7-366/7 weeks gestation without congenital anomalies, and 5782 of them died between 0 and 27 days. The neonatal mortality rate decreased from 16.4 in 2004 to 7.6 per thousand live births in 2015 (7.47% annual decrease by Prais-Winsten model). Perinatal asphyxia, respiratory disorders and infections were responsible, respectively, for 14%, 27% and 44% of the 5782 deaths. Median time to death was 24, 53 and 168 h, respectively, for perinatal asphyxia, respiratory disorders, and infections. Bottlenecks in perinatal health care are probably associated with the results that indicate the need for policies to reduce preventable neonatal deaths of moderate and late preterm infants in the most developed state of Brazil.

Epidemiological trends of isolated and non-isolated central nervous system congenital malformations in live births in a middle-income setting.

OBJECTIVES: This study aimed to analyze, in the São Paulo state of Brazil, time trends in prevalence, neonatal mortality, and neonatal lethality of central nervous system congenital malformations (CNS-CM) between 2004 and 2015. METHODS: Population-based study of all live births with gestational age ≥22 weeks and/or birthweight ≥400 g from mothers living in São Paulo State, during 2004-2015. CNS-CM was defined by the presence of International Classification Disease 10th edition codes Q00-Q07 in the death and/or live birth certificates. CNS-CM was classified as isolated (only Q00-Q07 codes), and non-isolated (with congenital anomalies codes nonrelated to CNS-CM). CNS-CM associated neonatal death was defined as death between 0 and 27 days after birth in infants with CNS-CM. CNS-CM prevalence, neonatal mortality, and lethality rates were calculated, and their annual trends were analyzed by Prais-Winsten Model. The annual percent change (APC) with 95% confidence interval (95%CI) was obtained. RESULTS: 7,237,628 live births were included in the study and CNS-CM were reported in 7526 (0.1%). CNS-CM associated neonatal deaths occurred in 2935 (39.0%). Isolated CNS-CM and non-isolated CNS-CM were found respectively in 5475 and 2051 livebirths, with 1525 (28%) and 1410 (69%) neonatal deaths. CNS-CM prevalence and neonatal lethality were stationary, however neonatal mortality decreased (APC -1.66; 95%CI -3.09 to -0.21) during the study. For isolated CNS-CM, prevalence, neonatal mortality, and lethality decreased over the period. For non-isolated CNS-CM, the prevalence increased, neonatal mortality was stationary, and lethality decreased during the period. The median time of CNS-CM associated neonatal deaths was 18 h after birth. CONCLUSIONS: During a 12-year period in São Paulo State, Brazil, neonatal mortality of infants with CNS-CM in general and with isolated CNS-CM showed a decreasing pattern. Nevertheless CNS-CM mortality remained elevated, mostly in the first day after birth.

The burden of inappropriate birth weight on neonatal survival in term newborns: a population-based study in a middle-income setting.

Introduction: Premature birth, perinatal asphyxia, and infections are the main causes of neonatal death. Growth deviations at birth also affect neonatal survival according to week of gestation at birth, particularly in developing countries. The purpose of this study was to verify the association between inappropriate birth weight and neonatal death in term live births. Methods: This is an observational follow-up study with all term live births from 2004 to 2013 in Sao Paulo State, Brazil. Data were retrieved with the deterministic linkage of death and birth certificates. The definition of very small for gestational age (VSGA) and very large for gestational age (VLGA) used the 10th percentile of 37 weeks and the 90th percentile of 41 weeks + 6 days, respectively, based on the Intergrowth-21st. We measured the outcome in terms of time to death and the status of each subject (death or censorship) in the neonatal period (0-27 days). Survival functions were calculated using the Kaplan-Meier method stratified according to the adequacy of birth weight into three groups (normal, very small, or very large). We used multivariate Cox regression to adjust for proportional hazard ratios (HRs). Results: The neonatal death rate during the study period was 12.03/10,000 live births. We found 1.8% newborns with VSGA and 2.7% with VLGA. The adjusted analysis showed a significant increase in mortality risk for VSGA infants (HR = 4.25; 95% CI: 3.89-4.65), independent of sex, 1-min Apgar score, and five maternal factors. Discussion: The risk of neonatal death in full-term live births was approximately four times greater in those with birth weight restriction. The development of strategies to control the factors that determine fetal growth restriction through planned and structured prenatal care can substantially reduce the risk of neonatal death in full-term live births, especially in developing countries such as Brazil.

Broad-spectrum antimicrobial consumption trends and correlation with bacterial infections and antimicrobial resistance over 5 years.

OBJECTIVES: Consumption trends of four broad-spectrum antimicrobials and their correlation with antimicrobial resistance in Gram-negative bacilli (GNB) from 2013-2017 within intensive care units (ICUs) were explored. METHODS: Consumption of meropenem (MEM), polymyxin B (PMB), piperacillin/tazobactam (TZP) and cefepime (FEP) in defined daily doses per 1000 patient-days (DDD/1000PD) was measured. Infection-related GNB isolates were grouped according to specific resistance profiles. Time series of antimicrobial consumption and their parametric correlation with each grouped resistant GNB were explored. RESULTS: A total of 1423 GNB were evaluated. A significant linear decline in consumption was observed for MEM [slope -3.88, 95% confidence interval (CI) -4.96 to -2.81; P < 0.0001] and PMB (slope -3.51, 95% CI -5.528 to -1.495; P = 0.0009). A significant decline in MEM-non-susceptible Acinetobacter spp. (R2 = 0.476; P = 0.006) and an increase in FEP-non-susceptible Escherichia coli (R2 = 0.124; P = 0.006) was observed. A significant correlation between MEM consumption and MEM-non-susceptible Acinetobacter spp. (r = 0.43; P = 0.001) was observed. MEM consumption and MEM-non-susceptible Acinetobacter spp. showed a positive correlation. CONCLUSION: Reduction in the consumption of broad-spectrum antimicrobials may alter the frequency of infection-related isolates and their antimicrobial resistance profiles.

Multicenter, Prospective Validation of a Phenotypic Algorithm to Guide Carbapenemase Testing in Carbapenem-Resistant Pseudomonas aeruginosa Using the ERACE-PA Global Surveillance Program.

BACKGROUND: Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) is a global challenge. However, detection efforts can be laborious because numerous mechanisms produce carbapenem resistance. A minimum inhibitory concentration-based algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) was proposed to identify the isolates most likely to harbor a carbapenemase; however, prospective validation in geographies displaying genotypic diversity and varied carbapenemase prevalence is warranted. METHODS: CRPA isolates were collected during the Enhancing Rational Antimicrobials for P. aeruginosa (ERACE-PA) global surveillance program from 17 sites in 12 countries. Isolates underwent susceptibility testing following local standards to ceftazidime, cefepime, and ceftolozane/tazobactam. Isolates underwent initial phenotypic carbapenemase screening followed by molecular testing if positive. The primary algorithm criteria were applied, and results were compared with phenotypic carbapenemase results to assess the performance of the algorithm. A secondary criterion, the algorithm criterion or imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible, was assessed. RESULTS: A total of 807 CRPA were assessed, and 464 isolates met the algorithm criteria described above. Overall, testing was reduced by 43% compared with testing all CRPA. Carbapenemase-positive isolates missed by the algorithm were largely driven by Guiana extended spectrum (GES). Addition of the criterion of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible decreased the number of CP-CRPA missed by the algorithm (21 vs 40 isolates, respectively), reducing number of isolates tested by 39%. CONCLUSIONS: Application of the initial algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) performed well in a global cohort, with 33% phenotypically carbapenemase-positive isolates. The addition of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible reduced the number of phenotypically carbapenemase-positive isolates missed and may be useful in areas with a prominence of GES.

Large Scale Genome-Centric Metagenomic Data from the Gut Microbiome of Food-Producing Animals and Humans.

The One Health concept is a global strategy to study the relationship between human and animal health and the transfer of pathogenic and non-pathogenic species between these systems. However, to the best of our knowledge, no data based on One Health genome-centric metagenomics are available in public repositories. Here, we present a dataset based on a pilot-study of 2,915 metagenome-assembled genomes (MAGs) of 107 samples from the human (N = 34), cattle (N = 28), swine (N = 15) and poultry (N = 30) gut microbiomes. Samples were collected from the five Brazilian geographical regions. Of the draft genomes, 1,273 were high-quality drafts (≥90% of completeness and ≤5% of contamination), and 1,642 were medium-quality drafts (≥50% of completeness and ≤10% of contamination). Taxonomic predictions were based on the alignment and concatenation of single-marker genes, and the most representative phyla were Bacteroidota, Firmicutes, and Proteobacteria. Many of these species represent potential pathogens that have already been described or potential new families, genera, and species with potential biotechnological applications. Analyses of this dataset will highlight discoveries about the ecology and functional role of pathogens and uncultivated Archaea and Bacteria from food-producing animals and humans. Furthermore, it also represents an opportunity to describe new species from underrepresented taxonomic groups.

Exploring the Bacteriome and Resistome of Humans and Food-Producing Animals in Brazil.

The epidemiology of antimicrobial resistance (AMR) is complex, with multiple interfaces (human-animal-environment). In this context, One Health surveillance is essential for understanding the distribution of microorganisms and antimicrobial resistance genes (ARGs). This report describes a multicentric study undertaken to evaluate the bacterial communities and resistomes of food-producing animals (cattle, poultry, and swine) and healthy humans sampled simultaneously from five Brazilian regions. Metagenomic analysis showed that a total of 21,029 unique species were identified in 107 rectal swabs collected from distinct hosts, the highest numbers of which belonged to the domain Bacteria, mainly Ruminiclostridium spp. and Bacteroides spp., and the order Enterobacterales. We detected 405 ARGs for 12 distinct antimicrobial classes. Genes encoding antibiotic-modifying enzymes were the most frequent, followed by genes related to target alteration and efflux systems. Interestingly, carbapenemase-encoding genes such as blaAIM-1, blaCAM-1, blaGIM-2, and blaHMB-1 were identified in distinct hosts. Our results revealed that, in general, the bacterial communities from humans were present in isolated clusters, except for the Northeastern region, where an overlap of the bacterial species from humans and food-producing animals was observed. Additionally, a large resistome was observed among all analyzed hosts, with emphasis on the presence of carbapenemase-encoding genes not previously reported in Latin America. IMPORTANCE Humans and food production animals have been reported to be important reservoirs of antimicrobial resistance (AMR) genes (ARGs). The frequency of these multidrug-resistant (MDR) bacteria tends to be higher in low- and middle-income countries (LMICs), due mainly to a lack of public health policies. Although studies on AMR in humans or animals have been carried out in Brazil, this is the first multicenter study that simultaneously collected rectal swabs from humans and food-producing animals for metagenomics. Our results indicate high microbial diversity among all analyzed hosts, and several ARGs for different antimicrobial classes were also found. As far as we know, we have detected for the first time ARGs encoding carbapenemases, such as blaAIM-1, blaCAM-1, blaGIM-2, and blaHMB-1, in Latin America. Thus, our results support the importance of metagenomics as a tool to track the colonization of food-producing animals and humans by antimicrobial-resistant bacteria. In addition, a network surveillance system called GUARANI, created for this study, is ready to be expanded and to collect additional data.

Pharmacodynamic evaluation of commonly prescribed oral antibiotics against respiratory bacterial pathogens.

BACKGROUND: Upper and lower respiratory tract infections (RTIs) account for a substantial portion of outpatient antibiotic utilization. However, the pharmacodynamic activity of commonly used oral antibiotic regimens has not been studied against clinically relevant pathogens. The objective of this study was to assess the probability of achieving the requisite pharmacodynamic exposure for oral antibacterial regimens commonly prescribed for RTIs in adults against bacterial isolates frequently involved in these processes (S. pneumoniae, H. influenzae, and M. catharralis). METHODS: Using a 5000-subject Monte Carlo simulation, the cumulative fractions of response (CFR), (i.e., probabilities of achieving requisite pharmacodynamic targets) for the most commonly prescribed oral antibiotic regimens, as determined by a structured survey of medical prescription patterns, were assessed against local respiratory bacterial isolates from adults in São Paulo collected during the same time period. Minimal inhibitory concentration (MIC) of 230 isolates of Streptococcus pneumoniae (103), Haemophilus influenzae (98), and Moraxella catharralis (29) from a previous local surveillance were used. RESULTS: The most commonly prescribed antibiotic regimens were azithromycin 500 mg QD, amoxicillin 500 mg TID, and levofloxacin 500 mg QD, accounting for 58% of the prescriptions. Varied doses of these agents, plus gatifloxacin, amoxicillin-clavulanate, moxifloxacin, and cefaclor made up the remaining regimens. Utilizing aggressive pharmacodynamic exposure targets, the only regimens to achieve greater than 90% CFR against all three pathogens were amoxicillin/amoxicillin-clavulanate 500 mg TID (> 91%), gatifloxacin 400 mg QD (100%), and moxifloxacin 400 mg QD (100%). Considering S. pneumoniae isolates alone, azithromycin 1000 mg QD also achieved greater than 90% CFR (91.3%). CONCLUSIONS: The only regimens to achieve high CFR against all three pathogen populations in both scenarios were gatifloxacin 400 mg QD, moxifloxacin 400 mg QD, and amoxicillin-clavulanate 500 mg TID. These data suggest the need for reconsideration of empiric antibiotic regimen selection among adult patients with RTIs in the São Paulo area. Additionally, this type of study could be used to optimize prescribing patterns in specific regions in light of emerging resistance.