Person: Munita, Jose M.
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Jose M.
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Publication Trends in Inpatient Antibiotic Use Among Adults Hospitalized During the Coronavirus Disease 2019 Pandemic in Argentina, Brazil, and Chile, 2018-2021(2023) Patel, Twisha; McGovern, Olivia; Mahon, Garrett; Osuka, Hanako; Boszczowski, Icaro; Munita, Jose M.; Garzon, Maria; Salomao, Matias; Marssola, Giovanna; Tavares, Bruno; Francisco, Debora; Gurgel, Alessandra; Arantes, Tiago; Bori, Andrea; Nogueira, Cassimiro; Peters, Anne Sophie; Spencer, Maria; Orellana, Cristian; Barbe, Mario; Lopez, Constanza; Stender, Stacie; Lessa, FernandaBackground: High rates of antibiotic use (AU) among inpatients with coronavirus disease 2019 (COVID-19) despite low rates of bacterial coinfection and secondary infection have been reported. We evaluated the impact of the COVID-19 pandemic on AU in healthcare facilities (HCFs) in South America. Methods: We conducted an ecologic evaluation of AU in inpatient adult acute care wards in 2 HCFs each in Argentina, Brazil, and Chile. The AU rates for intravenous antibiotics were calculated as the defined daily dose per 1000 patient-days, using pharmacy dispensing records and hospitalization data from March 2018-February 2020 (prepandemic) and March 2020-February 2021 (pandemic). Differences in median AU were compared between the prepandemic and pandemic periods, using the Wilcoxon rank sum test to determine significance. Interrupted time series analysis was used to analyze changes in AU during the COVID-19 pandemic. Results: Compared with the prepandemic period, the median difference in AU rates for all antibiotics combined increased in 4 of 6 HCFs (percentage change, 6.7%-35.1%; P < .05). In the interrupted time series models, 5 of 6 HCFs had significant increases in use of all antibiotics combined immediately at the onset of the pandemic (immediate effect estimate range, 15.4-268), but only 1 of these 5 HCFs experienced a sustained increase over time (change in slope, +8.13; P < .01). The effect of the pandemic onset varied by antibiotic group and HCF. Conclusions: Substantial increases in AU were observed at the beginning of the COVID-19 pandemic, suggesting the need to maintain or strengthen antibiotic stewardship activities as part of pandemic or emergency HCF responses.Publication Creación del primer biorrepositorio nacional de bacterias multirresistentes disponible para el estudio de la resistencia bacteriana en Chile(2022) García, Patricia; Rivas Jiménez, Lina María; Peters, Anne Sophie; Henríquez, Paola; Castillo, Loriana; Illesca, Vijna; Maripani, Andrea; Moreno, Juan; Mühlhause, Margareta; Porte, Lorena; Rioseco, María Luisa; Rojas, Pamela; Silva, Francisco; Suazo, Patricio; Munita, Jose M.La disponibilidad de cepas bacteriana para el estudio de la resis tencia bacteriana es clave para los avances en la investigación básica y clínica respecto del tema. Existen pocos biorrepositorios o bancos de bacterias con mecanismos de resistencia conocidos, aisladas de infecciones clínicamente significativas. Una revisión de la literatura revela que sólo en los Estados Unidos de América existe un biobanco de aislados resistentes disponibles para estudios. En esta publicación se cuenta cómo se creó el primer biorrepositorio de bacterias resistentes en Chile asociados a la Red de Laboratorios MICROB-R, con la participación de 11 centros distribuidos a lo largo del país, que a la fecha cuenta con más de 3.500 aislados bacterianos estudiados fenotípica y genotípicamente, disponibles para la comunidad científica chilenaPublication Ceftazidime/avibactam resistance is associated with PER-3-producing ST309 lineage in Chilean clinical isolates of non-carbapenemase producing Pseudomonas aeruginosa(2024) Soto, Katherine; Alcalde, Manuel; Ugalde, Juan; Olivares, Jorge; Quiroz, Valeria; Brito, Bárbara; Rivas Jiménez, Lina María; Munita, Jose M.; García, Patricia; Wozniak, AnielaIntroduction: Ceftazidime/avibactam (CZA) is indicated against multidrug-resistant Pseudomonas aeruginosa, particularly those that are carbapenem resistant. CZA resistance in P. aeruginosa producing PER, a class A extended-spectrum β-lactamase, has been well documented in vitro. However, data regarding clinical isolates are scarce. Our aim was to analyze the contribution of PER to CZA resistance in non-carbapenemase-producing P. aeruginosa clinical isolates that were ceftazidime and/or carbapenem non-susceptible. Methods: Antimicrobial susceptibility was determined through agar dilution and broth microdilution, while bla PER gene was screened through PCR. All PER-positive isolates and five PER-negative isolates were analyzed through Whole Genome Sequencing. The mutational resistome associated to CZA resistance was determined through sequence analysis of genes coding for PBPs 1b, 3 and 4, MexAB-OprM regulators MexZ, MexR, NalC and NalD, AmpC regulators AmpD and AmpR, and OprD porin. Loss of bla PER-3 gene was induced in a PER-positive isolate by successive passages at 43°C without antibiotics. Results: Twenty-six of 287 isolates studied (9.1%) were CZA-resistant. Thirteen of 26 CZA-resistant isolates (50%) carried bla PER. One isolate carried bla PER but was CZA-susceptible. PER-producing isolates had significantly higher MICs for CZA, amikacin, gentamicin, ceftazidime, meropenem and ciprofloxacin than non-PER-producing isolates. All PER-producing isolates were ST309 and their bla PER-3 gene was associated to ISCR1, an insertion sequence known to mobilize adjacent DNA. PER-negative isolates were classified as ST41, ST235 (two isolates), ST395 and ST253. PER-negative isolates carried genes for narrow-spectrum β-lactamases and the mutational resistome showed that all isolates had one major alteration in at least one of the genes analyzed. Loss of bla PER-3 gene restored susceptibility to CZA, ceftolozane/tazobactam and other β-lactamsin the in vitro evolved isolate. Discussion: PER-3-producing ST309 P. aeruginosa is a successful multidrug-resistant clone with blaPER-3 gene implicated in resistance to CZA and other β-lactams.Publication Excess burden of antibiotic-resistant bloodstream infections: evidence from a multicentre retrospective cohort study in Chile, 2018–2022(2024) Allel, Kasim; Peters, Anne Sophie; Haghparast-Bidgoli, Hassan; Spencer-Sandino, Maria; Conejeros, Jose; Garcia, Patricia; Pouwels, Koen B.; Yakob, Laith; Munita, Jose M.; Undurraga, Eduardo A.Background Antibiotic-resistant bloodstream infections (ARB BSI) cause an enormous disease and economic burden. We assessed the impact of ARB BSI caused by high- and critical-priority pathogens in hospitalised Chilean patients compared to BSI caused by susceptible bacteria. Methods We conducted a retrospective cohort study from 2018 to 2022 in three Chilean hospitals and measured the association of ARB BSI with in-hospital mortality, length of hospitalisation (LOS), and intensive care unit (ICU) admission. We focused on BSI caused by Acinetobacter baumannii, Enterobacterales, Staphylococcus aureus, Enterococcus species, and Pseudomonas aeruginosa. We addressed confounding using propensity scores, inverse probability weighting, and multivariate regressions. We stratified by community- and hospital-acquired BSI and assessed total hospital and productivity costs. Findings We studied 1218 adult patients experiencing 1349 BSI episodes, with 47.3% attributed to ARB. Predominant pathogens were Staphylococcus aureus (33% Methicillin-resistant ‘MRSA’), Enterobacterales (50% Carbapenem-resistant ‘CRE’), and Pseudomonas aeruginosa (65% Carbapenem-resistant ‘CRPA’). Approximately 80% of BSI were hospital-acquired. ARB was associated with extended LOS (incidence risk ratio IRR = 1.14, 95% CI = 1.05–1.24), increased ICU admissions (odds ratio OR = 1.25; 1.07–1.46), and higher mortality (OR = 1.42, 1.20–1.68) following index blood culture across all BSI episodes. In-hospital mortality risk, adjusted for time-varying and fixed confounders, was 1.35-fold higher (1.16–1.58) for ARB patients, with higher hazard ratios for hospital-acquired MRSA and CRE at 1.37 and 1.48, respectively. Using a societal perspective and a 5% discount rate, we estimated excess costs for ARB at $12,600 per patient, with an estimated annual excess burden of 2270 disability-adjusted life years (DALYs) and $9.6 (5.0–16.4) million. Interpretation It is urgent to develop and implement interventions to reduce the burden of ARB BSIs, particularly from MRSA and CRE.Publication Clinical characteristics, microbiology and outcomes of a cohort of patients treated with ceftolozane/tazobactam in acute care inpatient facilities, Houston, Texas, USA(2023) Tran, Truc; Cabrera, Nicolo; Gonzales, Anne; Carlson, Travis; Alnezary, Faris; Miller, William; Sakurai, Aki; Dinh, An; Rydell, Kirsten; Rios, Rafael; Diaz, Lorena; Hanson, Blake; Munita, Jose M.; Pedroza, Claudia; Shelburne, Samuel; Aitken, Samuel; Garey, Kevin; Dillon, Ryan; Puzniak, Laura; Arias, CesarBackground: Ceftolozane/tazobactam is a β-lactam/β-lactamase inhibitor combination with activity against a variety of Gram-negative bacteria, including MDR Pseudomonas aeruginosa. This agent is approved for hospital-acquired and ventilator-associated bacterial pneumonia. However, most real-world outcome data come from small observational cohorts. Thus, we sought to evaluate the utilization of ceftolozane/tazobactam at multiple tertiary hospitals in Houston, TX, USA. Methods: We conducted a multicentre retrospective study of patients receiving at least 48 h of ceftolozane/tazobactam therapy from January 2016 through to September 2019 at two hospital systems in Houston. Demographic, clinical and microbiological data were collected, including the infecting bacterial isolate, when available. The primary outcome was composite clinical success at hospital discharge. Secondary outcomes included in-hospital mortality and clinical disposition at 14 and 30 days post ceftolozane/tazobactam initiation. Multivariable logistic regression analysis was used to identify predictors of the primary outcome and mortality. Recovered isolates were tested for susceptibility to ceftolozane/tazobactam and underwent WGS. Results: A total of 263 patients were enrolled, and composite clinical success was achieved in 185 patients (70.3%). Severity of illness was the most consistent predictor of clinical success. Combination therapy with ceftolozane/tazobactam and another Gram-negative-active agent was associated with reduced odds of clinical success (OR 0.32, 95% CI 0.16-0.63). Resistance to ceftolozane/tazobactam was noted in 15.4% of isolates available for WGS; mutations in ampC and ftsI were common but did not cluster with a particular ST. Conclusions: Clinical success rate among this patient cohort treated with ceftolozane/tazobactam was similar compared with previous experiences. Ceftolozane/tazobactam remains an alternative agent for treatment of susceptible isolates of P. aeruginosa.Publication Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review(2023) Doernberg, Sarah; Arias, Cesar; Altman, Deena; Babiker, Ahmed; Boucher, Helen; Creech, C Buddy; Cosgrove, Sara; Evans, Scott; Fowler, Vance; Fritz, Stephanie; Hamasaki, Toshimitsu; Kelly, Brendan; Leal, Sixto; Liu, Catherine; Lodise, Thomas; Miller, Loren; Munita, Jose M.; Murray, Barbara; Pettigrew, Melinda; Ruffin, Felicia; Scheetz, Marc; Shopsin, Bo; Tran, Truc; Turne, Nicholas; Williams, Derek; Zaharoff, Smitha; Holland, Thomas; Antibacterial Resistance Leadership GroupThe Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.Publication Global epidemiology and clinical outcomes of carbapenem-resistant Pseudomonas aeruginosa and associated carbapenemases (POP): a prospective cohort study(2023) Reyes, Jinnethe; Komarow, Lauren; Chen, Liang; Ge, Lizhao; Hanson, Blake; Cober, Eric; Herc, Erica; Alenazi, Thamer; Kaye, Keith; Garcia, Julia; Li, Lanjuan; Kanj, Souha; Liu, Zhengyin; Oñate, Jose; Salata, Robert; Marimuthu, Kalisvar; Gao, Hainv; Zong, Zhiyong; Valderrama, Sandra; Yu, Yunsong; Tambyah, Paul; Weston, Gregory; Salcedo, Soraya; Abbo, Lillian; Xie, Qing; Ordoñez, Karen; Wang, Minggui; Stryjewski, Martin; Munita, Jose M.; Paterson, David; Evans, Scott; Hill, Carol; Baum, Keri; Bonomo, Robert; Kreiswirth, Barry; Virginia, Maria; Pate, Robin; Arias, Cesar; Chambers, Henry; Fowler,Vance; Doi, Yohei; Van Duin, David; Satlin, Michael; Antibacterial Resistance Leadership Group and Multi-Drug Resistant Organism Network InvestigatorsBackground: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA. Methods: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality. Findings: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses.Interpretation: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms. Funding: National Institutes of Health.Publication Role of the multi-drug efflux systems on the baseline susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam in clinical isolates of non-carbapenemase-producing carbapenem-resistant Pseudomonas aeruginosa(2022) Contreras-Gómez, María José; Martínez, José Rodrigo Waldemar; Rivas Jiménez, Lina María; Riquelme-Neira, Roberto; Ugalde, Juan A.; Wozniak, Aniela; García, Patricia; Munita, Jose M.; Olivares-Pacheco, Jorge; Alcalde-Rico, ManuelCarbapenem-resistant Pseudomonas aeruginosa (CRPA) is one of the pathogens that urgently needs new drugs and new alternatives for its control. The primary strategy to combat this bacterium is combining treatments of beta-lactam with a beta-lactamase inhibitor. The most used combinations against P. aeruginosa are ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T). Although mechanisms leading to CZA and C/T resistance have already been described, among which are the resistance-nodulation-division (RND) efflux pumps, the role that these extrusion systems may play in CZA, and C/T baseline susceptibility of clinical isolates remains unknown. For this purpose, 161 isolates of non-carbapenemase-producing (Non-CP) CRPA were selected, and susceptibility tests to CZA and C/T were performed in the presence and absence of the RND efflux pumps inhibitor, Phenylalanine-arginine β-naphthylamide (PAβN). In the absence of PAβN, C/T showed markedly higher activity against Non-CP-CRPA isolates than observed for CZA. These results were even more evident in isolates classified as extremely-drug resistant (XDR) or with difficult-to-treat resistance (DTR), where CZA decreased its activity up to 55.2% and 20.0%, respectively, whereas C/T did it up to 82.8% (XDR), and 73.3% (DTR). The presence of PAβN showed an increase in both CZA (37.6%) and C/T (44.6%) activity, and 25.5% of Non-CP-CRPA isolates increased their susceptibility to these two combined antibiotics. However, statistical analysis showed that only the C/T susceptibility of Non-CP-CRPA isolates was significantly increased. Although the contribution of RND activity to CZA and C/T baseline susceptibility was generally low (two-fold decrease of minimal inhibitory concentrations [MIC]), a more evident contribution was observed in a non-minor proportion of the Non-CP-CRPA isolates affected by PAβN [CZA: 25.4% (15/59); C/T: 30% (21/70)]. These isolates presented significantly higher MIC values for C/T. Therefore, we conclude that RND efflux pumps are participating in the phenomenon of baseline susceptibility to CZA and, even more, to C/T. However, the genomic diversity of clinical isolates is so great that deeper analyzes are necessary to determine which elements are directly involved in this phenomenon.Publication Multisite Detection of Tn 1549-Mediated vanB Vancomycin Resistance in Multidrug-Resistant Enterococcus faecalis ST6 in Texas and Florida(2023) Simar, Shelby; Tran, Truc; Rydell, Kirsten; Panesso, Diana; Contreras, German; Munita, Jose M.; Cifuentes. Renzo; Abbo, Lilian; Sahasrabhojane, Pranoti; Dinh, An; Axell-House, Dierdre; Savidge, Tor; Shelburne, Samuel; Hanson, Blake; Arias, CesarIn the United States, vanB-mediated resistance in enterococci is rare. We characterized three sequence type (ST) 6, vancomycin-resistant Enterococcus faecalis isolates causing bacteremia in unique patients in spatiotemporally distinct settings. Isolates were recovered between 2018 and 2020 in two cities in the United States (Houston, TX; Miami, FL). The isolates harbored the vanB operon on a chromosomally located Tn1549 transposon, and epidemiological data suggested multiple introductions of the vanB gene cluster into ST6 E. faecalis.Publication Antibiotic Consumption During the Coronavirus Disease 2019 Pandemic and Emergence of Carbapenemase-Producing Klebsiella pneumoniae Lineages Among Inpatients in a Chilean Hospital: A Time-Series Study and Phylogenomic Analysis(2023) Allel, Kasim; Peters, Anne Sophie; Conejeros, José; Martínez, José; Spencer, Maria; Riquelme, Roberto; Rivas Jiménez, Lina María; Rojas, Pamela; Orellana, Cristian; García, Patricia; Araos Bralic, Rafael Ignacio; McGovern, Olivia; Patel, Twisha; Arias, Cesar; Lessa, Fernanda; Undurraga, Eduardo; Munita, Jose M.Background: The impact of coronavirus disease 2019 (COVID-19) on antimicrobial use (AU) and resistance has not been well evaluated in South America. These data are critical to inform national policies and clinical care. Methods: At a tertiary hospital in Santiago, Chile, between 2018 and 2022, subdivided into pre- (3/2018-2/2020) and post-COVID-19 onset (3/2020-2/2022), we evaluated intravenous AU and frequency of carbapenem-resistant Enterobacterales (CRE). We grouped monthly AU (defined daily doses [DDD]/1000 patient-days) into broad-spectrum β-lactams, carbapenems, and colistin and used interrupted time-series analysis to compare AU during pre- and post-pandemic onset. We studied the frequency of carbapenemase-producing (CP) CRE and performed whole-genome sequencing analyses of all carbapenem-resistant (CR) Klebsiella pneumoniae (CRKpn) isolates collected during the study period. Results: Compared with pre-pandemic, AU (DDD/1000 patient-days) significantly increased after the pandemic onset, from 78.1 to 142.5 (P < .001), 50.9 to 110.1 (P < .001), and 4.1 to 13.3 (P < .001) for broad-spectrum β-lactams, carbapenems, and colistin, respectively. The frequency of CP-CRE increased from 12.8% pre-COVID-19 to 51.9% after pandemic onset (P < .001). The most frequent CRE species in both periods was CRKpn (79.5% and 76.5%, respectively). The expansion of CP-CRE harboring blaNDM was particularly noticeable, increasing from 40% (n = 4/10) before to 73.6% (n = 39/53) after pandemic onset (P < .001). Our phylogenomic analyses revealed the emergence of two distinct genomic lineages of CP-CRKpn: ST45, harboring blaNDM, and ST1161, which carried blaKPC. Conclusions: AU and the frequency of CP-CRE increased after COVID-19 onset. The increase in CP-CRKpn was driven by the emergence of novel genomic lineages. Our observations highlight the need to strengthen infection prevention and control and antimicrobial stewardship efforts.