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1.
Molecules ; 27(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35408684

RESUMO

As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2'-o-methyltransferase (2'OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2'-o-methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with SAM (S-Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2'OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, (1187), Calcium folinate (1913), Raltegravir (1995), Regadenoson (2176), Ertapenem (2396), Methylergometrine (2532), and Thiamine pyrophosphate hydrochloride (2612)). Out of the docked ligands, Ertapenem (2396) showed an ideal binding mode like that of the co-crystallized ligand (SAM). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, Rg, SASA, and H-bonding) have been conducted for the 2'OMTase-Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2'OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of -43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2'OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds.


Assuntos
Metiltransferases , SARS-CoV-2 , Proteínas não Estruturais Virais , Proteínas Virais Reguladoras e Acessórias , Ertapenem/farmacologia , Ligantes , Metiltransferases/antagonistas & inibidores , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , S-Adenosilmetionina/química , SARS-CoV-2/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas Virais Reguladoras e Acessórias/antagonistas & inibidores
2.
N Engl J Med ; 386(14): 1327-1338, 2022 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-35388666

RESUMO

BACKGROUND: There is a need for oral antibiotic agents that are effective against multidrug-resistant gram-negative uropathogens. Tebipenem pivoxil hydrobromide is an orally bioavailable carbapenem with activity against uropathogenic Enterobacterales, including extended-spectrum beta-lactamase-producing and fluoroquinolone-resistant strains. METHODS: In this phase 3, international, double-blind, double-dummy trial, we evaluated the efficacy and safety of orally administered tebipenem pivoxil hydrobromide as compared with intravenous ertapenem in patients with complicated urinary tract infection or acute pyelonephritis. Patients were randomly assigned, in a 1:1 ratio, to receive oral tebipenem pivoxil hydrobromide (at a dose of 600 mg every 8 hours) or intravenous ertapenem (at a dose of 1 g every 24 hours) for 7 to 10 days (or up to 14 days in patients with bacteremia). The primary efficacy end point was overall response (a composite of clinical cure and favorable microbiologic response) at a test-of-cure visit (on day 19, within a ±2-day window) in the microbiologic intention-to-treat population. The noninferiority margin was 12.5%. RESULTS: A total of 1372 hospitalized adult patients were enrolled; 868 patients (63.3%) were included in the microbiologic intention-to-treat population (50.8% of whom had complicated urinary tract infections and 49.2% of whom had pyelonephritis). An overall response was seen in 264 of 449 patients (58.8%) who received tebipenem pivoxil hydrobromide, as compared with 258 of 419 patients (61.6%) who received ertapenem (weighted difference, -3.3 percentage points; 95% confidence interval [CI], -9.7 to 3.2). Clinical cure at the test-of-cure visit was observed in 93.1% of the patients in the microbiologic intention-to-treat population who received tebipenem pivoxil hydrobromide and 93.6% of patients who received ertapenem (weighted difference, -0.6 percentage point; 95% CI, -4.0 to 2.8); the majority of patients with microbiologic response failures at the test-of-cure visit were asymptomatic patients with recurrent bacteriuria. Secondary and subgroup analyses were supportive of the primary analysis. Adverse events were observed in 25.7% of patients who received tebipenem pivoxil hydrobromide and in 25.6% of patients who received ertapenem; the most common adverse events were mild diarrhea and headache. CONCLUSIONS: Oral tebipenem pivoxil hydrobromide was noninferior to intravenous ertapenem in the treatment of complicated urinary tract infection and acute pyelonephritis and had a similar safety profile. (Funded by Spero Therapeutics and the Department of Health and Human Services; ADAPT-PO ClinicalTrials.gov number, NCT03788967.).


Assuntos
Antibacterianos , Carbapenêmicos , Pielonefrite , Infecções Urinárias , Administração Intravenosa , Administração Oral , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Carbapenêmicos/administração & dosagem , Carbapenêmicos/efeitos adversos , Carbapenêmicos/uso terapêutico , Método Duplo-Cego , Farmacorresistência Bacteriana Múltipla , Ertapenem/administração & dosagem , Ertapenem/efeitos adversos , Ertapenem/uso terapêutico , Humanos , Pielonefrite/tratamento farmacológico , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia
3.
J Clin Microbiol ; 60(4): e0218821, 2022 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-35313739

RESUMO

Antibiotic resistance, particularly to carbapenems, is of increasing concern in Bacteroides fragilis. Carbapenem resistance in B. fragilis is most often mediated by the activation of chromosomally encoded metallo-ß-lactamase cfiA by the presence of an upstream insertion sequence (IS). While traditional phenotypic susceptibility methods and molecular tests to detect carbapenem resistance in B. fragilis exist, they are not available in most clinical microbiology laboratory settings. Here, we describe the development of the anaerobic carbapenem inactivation method (Ana-CIM) for predicting carbapenemase production in B. fragilis based off the principles of the well-established modified carbapenem inactivation method (mCIM) for Enterobacterales and Pseudomonas aeruginosa. We also present the clinical validation and reproducibility of the Ana-CIM at three clinical laboratory sites (with 60 clinical isolates, 45% ertapenem resistant). Compared to ertapenem susceptibility by Etest interpreted by CLSI M100 Ed30, the Ana-CIM accurately detected carbapenem resistance in B. fragilis with categorical agreement (CA) of 87% (52/60) and 0% (0/21) very major error (VME), 11% (4/36) major error (ME), and 7% (4/60) minor error (mE) rates across all sites. Additionally, the Ana-CIM demonstrated high reproducibility with 5 clinical and 3 quality control (QC) isolates tested in triplicate with 3 commercial Mueller-Hinton media across all sites, with 93% (604/648) of replicates within a 2-mm zone size of the mode for each isolate. We conclude that the Ana-CIM can be readily deployed in clinical laboratories at a low cost for detection of carbapenemase-mediated resistance in B. fragilis.


Assuntos
Infecções Bacterianas , Carbapenêmicos , Anaerobiose , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Bacteroides fragilis , Carbapenêmicos/farmacologia , Ertapenem/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Reprodutibilidade dos Testes , beta-Lactamases/metabolismo
4.
Luminescence ; 37(5): 796-802, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35274447

RESUMO

Ertapenem (EPM) has been recently approved by the United States Food and Drug Administration (US-FDA) as an antimicrobial drug. EPM has a broad spectrum of action against different bacterial strains and is most commonly prescribed in Egypt for the treatment of Klebsiella pneumonia. In this study, EPM was estimated using a sensitive and selective spectrofluorimetric method for human plasma and pharmaceutical vials. The measured fluorescence (at 540 nm) was obtained from reaction of EPM with 0.05% w/v benzofurazan (NBD-Cl) using 0.1 M borate buffer pH 8.8 after excitation at 460 nm. The fluorometric linear range was stable from 10 to 350 ng ml-1 . The lower limit of detection and the lower limit of quantitation were found to be 2.13 and 6.47 ng ml-1 respectively. Many factors such as pH, temperature, heating time, and NBD-Cl concentration were optimized. The presented work was validated according to International Council for Harmonisation guidelines and bio-analytically validated using FDA recommendations. The significant finding of this study, sensitivity, was successfully applied in Egypt for a pharmacokinetic application and commercial vials. Pharmacokinetic parameters were studied and the result, recorded as Cmax of EPM, was found to be 83.60 µg ml-1 after infusion of 0.5 g of Invanz® for 30 min. AUC0-∞ was found to be 320 ± 30.2 µ.h ml-1 .


Assuntos
Plasma , Ertapenem , Fluorometria , Humanos , Preparações Farmacêuticas , Espectrometria de Fluorescência/métodos
5.
Drugs ; 82(5): 533-557, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35294769

RESUMO

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.


Assuntos
Bacteriúria , Staphylococcus aureus Resistente à Meticilina , Pró-Fármacos , Infecções Urinárias , Monofosfato de Adenosina/farmacologia , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriúria/induzido quimicamente , Bacteriúria/tratamento farmacológico , Carbapenêmicos/farmacologia , Cefalosporinas/farmacologia , Ciprofloxacina/farmacologia , Ertapenem , Escherichia coli , Feminino , Fluoroquinolonas/farmacologia , Bactérias Gram-Negativas , Cobaias , Humanos , Imipenem/farmacologia , Lactamas , Masculino , Proteínas de Membrana/farmacologia , Meropeném/farmacologia , Camundongos , Probenecid/farmacologia , Pró-Fármacos/farmacologia , Staphylococcus aureus , Infecções Urinárias/tratamento farmacológico , beta-Lactamases/farmacologia
6.
Infect Genet Evol ; 98: 105234, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35121093

RESUMO

Empedobacter falsenii is an emerging opportunistic pathogen that has been occasionally implicated in various human infections. In this study, we described the genomic features of a multidrug resistant E. falsenii Q1655 obtained from a patient attending a public hospital in Sokoto, northwest Nigeria. The isolate, E. falsenii Q1655, was isolated from the stool sample of a patient in Sokoto, Nigeria. The identity of the isolate was confirmed by MALDITOF-MS. The disc diffusion test and modified Carba-NP test were used for phenotypic antibiotic susceptibility test and carbapenemase enzyme production test, respectively. The whole genome of the strain was sequenced using the Illumina MiSeq technique. Resistome analysis was done by annotation of the WGS against the ARG-ANNOT database. The isolate was resistant to all ß-lactam antibiotics with the exception of cefepime. The MICs of imipenem and ertapenem as determined by E-test were 12 µg/ml and 2 µg/ml, respectively. Modified Carba NP test showed that the strain was carbapenemase producing. Resistome analysis revealed the presence of a novel metallo-ß-lactamase, a chromosomal blaEBR-4, which exhibited 94.92% and 97.02% nucleotide and protein sequence identities respectively with blaEBR-3 gene of E. falsenii 174,820. Seven and eight amino-acid substitutions were observed with the blaEBR-1 and blaEBR-2, respectively. We reported the first isolation and genomic description of an extensively drug resistant isolate of Empedobacter falsenii in Nigeria. This report broadens our knowledge of carbapenem resistance in E. falsenii and it will serve as a useful guide in the development of antibiotic use policy.


Assuntos
Antibacterianos/farmacologia , Ertapenem/farmacologia , Flavobacteriaceae/genética , Genoma Bacteriano , Imipenem/farmacologia , beta-Lactamases/genética , Flavobacteriaceae/enzimologia , Testes de Sensibilidade Microbiana , beta-Lactamases/metabolismo
7.
Lancet Infect Dis ; 22(5): 706-717, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35065063

RESUMO

BACKGROUND: Neisseria gonorrhoeae causes gonorrhoea, a common sexually transmitted infection. Emerging strains resistant to first-line ceftriaxone threaten N gonorrhoeae management. Hence, alternative treatments are needed. We aimed to evaluate the efficacy of ertapenem, gentamicin, and fosfomycin as alternative treatments for anogenital N gonorrhoeae. METHODS: In a randomised, controlled, double-blind, non-inferiority trial (three experimental groups and one control group) at the Centre for Sexual Health in Amsterdam, Netherlands, we included adults aged 18 years or older, with anorectal or urogenital gonorrhoea. With random permuted blocks, participants were randomly assigned (1:1:1:1) to receive intramuscular 500 mg ceftriaxone (control group), intramuscular 1000 mg ertapenem, intramuscular 5 mg/kg gentamicin (maximum 400 mg), or oral 6 g fosfomycin. The primary outcome was the proportion of participants with a negative nucleic acid amplification test of the predefined primary infected site, 7-14 days after treatment. The primary analysis was per protocol (ie, excluding those lost to follow-up). The modified intention-to-treat analysis included all randomly assigned patients with anogenital gonorrhoea considering those lost-to-follow-up as treatment failure. Non-inferiority was established if the lower Hochberg-corrected 95% CI for difference between the experimental and control groups was greater than -10%. For the analysis of adverse events, we included all participants who received medication. The trial was registered at ClinicalTrials.gov (NCT03294395) and is complete. FINDINGS: Between Sept 18, 2017, and June 5, 2020, from 2160 patients invited to participate, we assigned 346 (16%) participants to receive either ceftriaxone (n=103), ertapenem (n=103), gentamicin (n=102), or fosfomycin (n=38). The fosfomycin group was terminated early after interim analysis revealed less than 60% efficacy. In the primary per-protocol analysis, 93 (100%) of 93 patients in the ceftriaxone group, 86 (99%) of 87 patients in the ertapenem group, 79 (93%) of 85 patients in the gentamicin group, and four (12%) of 33 patients in the fosfomycin group cleared N gonorrhoeae (risk difference vs ceftriaxone -0·01 [95% CI -0·08 to 0·05] for ertapenem and -0·07 [-0·16 to -0·01] for gentamicin). Thus, ertapenem proved non-inferior to ceftriaxone. In mITT analysis, risk differences versus ceftriaxone were -0·08 (-0·17 to 0·003) for ertapenem and -0·11 (-0·21 to -0·04) for gentamicin. We observed a higher proportion of patients with at least one adverse event in the ertapenem group (58 [56%] of 103) and fosfomycin group (36 [95%] of 38) versus the ceftriaxone group (24 [23%] of 103). INTERPRETATION: Single-dose 1000 mg ertapenem is non-inferior to single-dose 500 mg ceftriaxone in gonorrhoea treatment. Yet, 5 mg/kg gentamicin (maximum 400 mg) is not non-inferior to ceftriaxone. Ertapenem is a potential effective alternative for anogenital N gonorrhoeae infections and merits evaluation for ceftriaxone-resistant infections. FUNDING: ZonMw and GGD-Amsterdam. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.


Assuntos
Fosfomicina , Gonorreia , Adulto , Antibacterianos , Ceftriaxona , Ertapenem/farmacologia , Ertapenem/uso terapêutico , Fosfomicina/farmacologia , Fosfomicina/uso terapêutico , Gentamicinas/efeitos adversos , Gentamicinas/uso terapêutico , Gonorreia/tratamento farmacológico , Humanos , Neisseria gonorrhoeae , Resultado do Tratamento
8.
Antimicrob Agents Chemother ; 66(2): e0216621, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34978891

RESUMO

Cefazolin and ertapenem have been shown to be an effective salvage regimen for refractory methicillin-susceptible Staphylococcus aureus bacteremia. Our findings suggest cefazolin plus ertapenem in vitro stimulates interleukin-1ß release from peripheral blood monocytes both with and without S. aureus presence. This IL-1ß augmentation was primarily driven by ertapenem. These findings support further exploration of cefazolin plus ertapenem in MSSA bacteremia and may partially explain its marked potency in vivo despite modest synergy in vitro.


Assuntos
Bacteriemia , Infecções Estafilocócicas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Cefazolina/farmacologia , Cefazolina/uso terapêutico , Ertapenem , Humanos , Interleucina-1beta , Meticilina/farmacologia , Meticilina/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus
9.
Antimicrob Agents Chemother ; 66(1): e0132521, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-34694873

RESUMO

The objective of this study was to compare the rate of pneumonia resolution in obese (body mass index [BMI], ≥30 kg/m2) and nonobese (BMI, <30 kg/m2) patients treated with 1 gram ertapenem daily. In this retrospective cohort study, we evaluated patients treated at The Ohio State University Wexner Medical Center between 1 January 2015 and 31 August 2020. Patients were included if they were between 18 and 89 years old and received ertapenem for at least 48 hours for pneumonia treatment. Patients were excluded if they were pregnant, were incarcerated, had renal impairment, received antibiotics with Gram-negative activity for a significant period prior to or in addition to ertapenem, and had other concomitant deep-seated infections. The primary outcome of clinical resolution was defined as meeting any of the following three criteria in order of evaluations: discontinuation of antibiotics by day 8 of therapy, afebrile while on ertapenem in addition to a decrease in white blood cell count, or improvement on chest radiograph at day 7 of therapy. A multivariable logistic regression analysis was performed to examine the association between obesity and clinical resolution, while adjusting for proven confounders. There were 76 nonobese and 65 obese patients included. The median patient BMI was 23.7 kg/m2 (21.0 to 26.9) and 35.0 kg/m2 (32.8 to 39.8) for the nonobese and obese cohorts, respectively. Clinical resolution was achieved in 78% (59/76) of nonobese and 75% (49/65) of obese patients (P = 0.75) without an observed difference in the regression model. Outcomes were similar in obese and nonobese patients treated with 1 gram of ertapenem daily for pneumonia.


Assuntos
Obesidade , Pneumonia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Ertapenem/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/tratamento farmacológico , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Gravidez , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
10.
J Microbiol Immunol Infect ; 55(2): 215-224, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34219043

RESUMO

BACKGROUND/PURPOSE: Streptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial resistance and epidemiological profiles of S. pneumoniae infections in Taiwan. METHODS: A total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed. RESULTS: Among the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid. CONCLUSION: Empirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan.


Assuntos
Meningite Pneumocócica , Infecções Pneumocócicas , Idoso , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Ceftriaxona/farmacologia , Doripenem/uso terapêutico , Farmacorresistência Bacteriana , Ertapenem/uso terapêutico , Humanos , Levofloxacino/uso terapêutico , Linezolida/uso terapêutico , Meningite Pneumocócica/tratamento farmacológico , Testes de Sensibilidade Microbiana , Penicilinas/farmacologia , Penicilinas/uso terapêutico , Infecções Pneumocócicas/tratamento farmacológico , Infecções Pneumocócicas/epidemiologia , Streptococcus pneumoniae , Taiwan/epidemiologia , Vancomicina/farmacologia
11.
Rev Esp Enferm Dig ; 114(4): 240-241, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34933565

RESUMO

Carbapenems are antibiotics of the cephalosporin family with a good penetrance into the central nervous system. Neurotoxicity is a rare adverse effect, most often associated with imipenem (0.4-10 %) and unusual with ertapenem. It usually presents as seizures, although encephalopathy or hallucinations may develop. However, a recent large study (n = 544) found neurotoxicity associated to the use of ertapenem with an incidence of 4.6 %. There were associated factors such as advanced age or renal dysfunction (ertapenem has a renal metabolism level of 80 %).


Assuntos
Transplante de Fígado , Síndromes Neurotóxicas , Antibacterianos/efeitos adversos , Ertapenem/efeitos adversos , Humanos , Transplante de Fígado/efeitos adversos , Testes de Sensibilidade Microbiana , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , beta-Lactamas/efeitos adversos
12.
Ann Clin Microbiol Antimicrob ; 20(1): 76, 2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34732199

RESUMO

BACKGROUND: The emergence of carbapenem-resistant Pseudomonas aeruginosa is one of the most important challenges in a healthcare setting. The aim of this study is double-locus sequence typing (DLST) typing of blaNDM-1 positive P. aeruginosa isolates. METHODS: Twenty-nine blaNDM-1 positive isolates were collected during three years of study from different cities in Iran. Modified hodge test (MHT), double-disk synergy test (DDST) and double-disk potentiation test (DDPT) was performed for detection of carbapenemase and metallo-beta-lactamase (MBL) producing blaNDM-1 positive P. aeruginosa isolates. The antibiotic resistance genes were considered by PCR method. Clonal relationship of blaNDM-1 positive was also characterized using DLST method. RESULTS: Antibiotic susceptibility pattern showed that all isolates were resistant to imipenem and ertapenem. DDST and DDPT revealed that 15/29 (51.8%) and 26 (89.7%) of blaNDM-1 positive isolates were MBL producing isolates, respectively. The presence of blaOXA-10, blaVIM-2, blaIMP-1 and blaSPM genes were detected in 86.2%, 41.4%, 34.5% and 3.5% isolates, respectively. DLST typing results revealed the main cluster were DLST 25-11 with 13 infected or colonized patients. CONCLUSIONS: The presence of blaNDM-1 gene with other MBLs encoding genes in P. aeruginosa is a potential challenge in the treatment of microorganism infections. DLST showed partial diversity among 29 blaNDM-1 positive isolates.


Assuntos
Antibacterianos/farmacologia , Infecção Hospitalar/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , beta-Lactamases/genética , Farmacorresistência Bacteriana Múltipla , Ertapenem/farmacologia , Humanos , Imipenem/farmacologia , Pacientes Internados , Irã (Geográfico)/epidemiologia , Testes de Sensibilidade Microbiana , Tipagem Molecular , Reação em Cadeia da Polimerase , Pseudomonas aeruginosa/isolamento & purificação
13.
Farm Hosp ; 45(6): 335-339, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34806574

RESUMO

OBJECTIVE: The literature has described the interaction between valproic acid  and carbapenems. This interaction leads to decreases in plasma concentrations  of valproic acid. The main objectives of this study were  to assess its relevance in clinical practice, to identify variables associated with  increased seizure episode rates, and to analyse the impact of pharmaceutical intervention on avoiding the effects of this interaction. METHOD: An observational retrospective study of inpatients with epilepsy  admitted between 2016 and 2020. Their pharmacological treatment throughout  admission was recorded, and the presence of other interactions  leading to decreased plasma concentrations of valproic acid was reviewed. The  seizure rate during the year prior to admission was compared to that during  the interaction period. For every episode in which the interaction was detected, an intervention was conducted by providing the prescriber with information on  the interaction and suggesting a change of antibiotherapy as well as the  pharmacokinetic monitoring of valproic acid. RESULTS: 37 episodes were included. 58.1% of the patients were male and  median age was 70 years. In total, 56.8% of the patients received meropenem  and 43.2% received ertapenem. The median duration of  concomitant treatment with valproic acid and carbapenem was 4 days. The  incidence rate ratio was 2.60 (95% confidence interval: 1.61-4.21). Thus, this  interaction was associated with a higher seizure rate. A statistically significant  association was found between higher seizure rates and patients treated with  more than one anti-epileptic drug. Hospital pharmacists detected 24 episodes  (64.9%). In total, 17 interventions (70.8%) were accepted and 13  combinations were discontinued. Pharmacokinetic monitoring was conducted in  13 episodes (35.1%) and infratherapeutic levels were found in all of them. CONCLUSIONS: The interaction between valproic acid and meropenem or ertapenem is clinically relevant. It is recommended that this combination should be avoided provided that a viable alternative is available.  Pharmaceutical intervention may contribute to preventing seizures associated with this combination.


Objetivo: La interacción entre ácido valproico y carbapenems está descrita en  la literatura y conlleva una disminución de los niveles plasmáticos de ácido  valproico. Los objetivos son evaluar su relevancia en la práctica clínica, conocer  las variables que se asocian a un incremento de crisis epilépticas y  analizar el impacto de la intervención farmacéutica para evitar las  consecuencias de dicha interacción.Método: En este estudio observacional retrospectivo se estudiaron pacientes  con epilepsia hospitalizados entre 2016 y 2020. Se registró el tratamiento  farmacológico prescrito en el ingreso y se revisó la presencia de otras  interacciones que redujeran la concentración plasmática de ácido valproico. La  frecuencia de crisis epilépticas durante el año previo al ingreso se comparó con  la correspondiente al periodo de interacción. Se realizó una intervención  en todos los episodios con la interacción detectada informando al prescriptor  sobre la interacción y proponiendo sustitución de la antibioterapia, así como  monitorización farmacocinética de ácido valproico.Resultados: Se incluyeron 37 episodios. El 58,1% eran varones y la mediana  de edad fue de 70 años. El 56,8% de los pacientes recibió meropenem y el  43,2% restante, ertapenem. Para la duración del tratamiento concomitante  entre ácido valproico y el carbapenem prescrito  se obtuvo una mediana de 4  días. Se halló una razón de tasas de incidencia de 2,60 (intervalo de confianza  del 95%: 1,61-4,21), por lo que esta interacción se asocia a una mayor  frecuencia de crisis epilépticas. Se asoció una mayor frecuencia de crisis  estadísticamente significativa en los pacientes tratados con más de un fármaco  antiepiléptico. Los farmacéuticos hospitalarios detectaron 24  episodios (64,9%). Se aceptaron 17 intervenciones farmacéuticas (70,8%) y  se suprimieron 13 combinaciones. Se realizó monitorización farmacocinética en  13 episodios (35,1%) y en todos se hallaron niveles infraterapéuticos. Conclusiones: La interacción entre ácido valproico y meropenem o ertapenem  es clínicamente relevante y se recomienda evitarla siempre que  existan alternativas viables. La intervención farmacéutica puede contribuir a  prevenir las crisis epilépticas favorecidas por esta combinación.


Assuntos
Epilepsia , Preparações Farmacêuticas , Idoso , Antibacterianos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Interações Medicamentosas , Epilepsia/tratamento farmacológico , Ertapenem/uso terapêutico , Humanos , Masculino , Meropeném/uso terapêutico , Estudos Retrospectivos , Ácido Valproico/uso terapêutico
14.
Microbiol Spectr ; 9(2): e0018121, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34668731

RESUMO

This study was conducted to determine the in vitro activities of gentamicin alone and in combination with ceftriaxone, ertapenem, and azithromycin against multidrug-resistant (MDR) Neisseria gonorrhoeae isolates. A total of 407 clinical isolates from Nanjing, China, obtained in 2016 to 2017, had MICs determined for gentamicin using the agar dilution method. MDR status was ascribed to 97 strains that displayed decreased susceptibility or resistance to extended-spectrum cephalosporins (ESCs) (ceftriaxone [MIC, ≥0.125 mg/liter] and cefixime [MIC, ≥0.25 mg/liter]), plus resistance to at least two of the following antimicrobials: penicillin (MIC, ≥2 mg/liter), ciprofloxacin (MIC, ≥1 mg/liter), and azithromycin (MIC, ≥1 mg/liter). MDR strains underwent MIC determinations for antimicrobial combinations using the antimicrobial gradient epsilometer test (Etest). Results that ranged from synergy to antagonism were interpreted using the fractional inhibitory concentration (FICI). All 407 gonococcal isolates were susceptible to gentamicin; MICs ranged from 2 mg/liter to 16 mg/liter. Synergy was demonstrated in 16.5% (16/97), 27.8% (27/97), and 8.2% (8/97) of MDR strains when gentamicin was combined with ceftriaxone (geometric mean [GM] FICI, 0.747), ertapenem (GM FICI, 0.662), and azithromycin (GM FICI, 1.021), respectively. No antimicrobial antagonism was observed with any combination tested against MDR strains; overall, antimicrobial combinations were indifferent. The GM MICs of gentamicin were reduced by 2.63-, 3.80-, and 1.98-fold when tested in combination with ceftriaxone, ertapenem, and azithromycin, respectively. The GM MICs of the three additional antimicrobials individually were reduced by 3-, 2.57-, and 1.98-fold, respectively, when each was tested in combination with gentamicin. Gentamicin alone was effective in vitro against N. gonorrhoeae, including MDR isolates. Combination testing of MDR strains showed lower MICs against gentamicin and each of three antimicrobials (ceftriaxone, ertapenem, and azithromycin) when used in combination. IMPORTANCE Antimicrobial-resistant Neisseria gonorrhoeae is a major global public health concern. New treatment options are urgently needed to successfully treat multidrug-resistant (MDR) Neisseria gonorrhoeae infections. This study showed that gentamicin maintained excellent in vitro susceptibility against clinical gonococcal isolates collected in 2016 and 2017, including MDR isolates. Combinations of gentamicin plus ertapenem, ceftriaxone, and azithromycin produced synergistic effects against certain MDR isolates. No antagonism was observed in any of the antimicrobial combinations, which may prove useful to guide clinical testing of combination therapies.


Assuntos
Antibacterianos/farmacologia , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Ertapenem/farmacologia , Gentamicinas/farmacologia , Neisseria gonorrhoeae/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/genética , Sinergismo Farmacológico , Quimioterapia Combinada , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/isolamento & purificação
15.
Intern Med J ; 51(10): 1717-1721, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34664365

RESUMO

Subcutaneous (SC) administration of ertapenem in outpatient parenteral antimicrobial therapy (OPAT) services may be a practical alternative to intravenous delivery for complicated infections. The clinical features and outcomes according to route of administration were compared from a large Australian OPAT service. Chronic renal impairment was more common in the SC group, reflecting an opportunity for route of administration as a vein preservation strategy. Adverse events were uncommon and successful outcomes were not different between the groups.


Assuntos
Anti-Infecciosos , Pacientes Ambulatoriais , Assistência Ambulatorial , Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Austrália/epidemiologia , Ertapenem , Humanos , Infusões Parenterais , Estudos Retrospectivos
16.
J Card Surg ; 36(12): 4786-4788, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34599521

RESUMO

The use of left ventricular assist devices (LVADs) is increasingly more common as the availability of donor organs in relation to failing hearts is outstandingly limited. Infections are the most common complications in LVAD recipients, particularly those caused by Staphylococcus spp. Refractory LVAD-related infections are not uncommon as achieving adequate source control is often not feasible before heart transplantation. Evidence suggest that cefazolin plus ertapenem is effective in refractory methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, but this approach has not been described in LVAD recipients. In this article, we report two cases of refractory MSSA bacteremia in LVAD recipients that were successfully treated with salvage therapy with cefazolin plus ertapenem and subsequent heart transplantation. This treatment strategy should be considered in patients with refractory LVAD-associated infection due to MSSA that are not responding to standard treatment.


Assuntos
Bacteriemia , Transplante de Coração , Coração Auxiliar , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Cefazolina , Ertapenem , Humanos , Meticilina , Terapia de Salvação , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus
17.
Int J Antimicrob Agents ; 58(4): 106417, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34391903

RESUMO

Gonococcal infections represent an urgent public-health threat as >50% of cases caused by Neisseria gonorrhoeae strains display reduced susceptibility to at least one antimicrobial agent. We evaluated the pharmacodynamics of a number of antimicrobials against N. gonorrhoeae in order to assess the likelihood of mutant selection by these agents. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, doxycycline, ertapenem, gentamicin, ciprofloxacin, levofloxacin and moxifloxacin against a wild-type strain of N. gonorrhoeae (ATCC 49226) and a gyrA mutant of ATCC 49226. Pharmacokinetic parameters, including peak concentration (Cmax), half-life (t1/2) and area under the plasma concentration-time curve over 24 h (AUC), associated with each agent were used to calculate the time within the MSW (TMSW, percentage of the dosing interval that antimicrobial concentrations fall within the MSW), Cmax/MPC ratio and AUC/MPC ratio for each antimicrobial agent. Concentrations of ceftriaxone (500 mg), ertapenem, ciprofloxacin, levofloxacin and moxifloxacin surpass the MPC for both strains. Results of pharmacodynamic analyses suggest that ertapenem, ciprofloxacin, levofloxacin and moxifloxacin may be most likely to prevent mutant selection in N. gonorrhoeae. Use of ceftriaxone, azithromycin, doxycycline or gentamicin for gonorrhoea is expected to lead to the ongoing emergence of resistance to these agents. There is a clear need to develop novel treatment regimens for gonococcal infections in order to limit the dissemination of resistance in N. gonorrhoeae.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , Gonorreia/tratamento farmacológico , Neisseria gonorrhoeae/efeitos dos fármacos , Azitromicina/farmacologia , Ceftriaxona/farmacologia , Ciprofloxacina/farmacologia , Doxiciclina/farmacologia , Ertapenem/farmacologia , Gentamicinas/farmacologia , Humanos , Levofloxacino/farmacologia , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologia , Neisseria gonorrhoeae/genética
18.
BMC Infect Dis ; 21(1): 823, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399680

RESUMO

BACKGROUND: Urinary tract infections (UTI) are often over-diagnosed and over-treated, which can induce and select for resistant pathogens. After observing wide-spread outpatient use of ertapenem, a broad-spectrum antibiotic, a structured antimicrobial stewardship initiative (ASI) to improve appropriate antimicrobial prescribing was undertaken. ASI objectives were to achieve a goal of reducing ertapenem utilization for extended spectrum beta lactamase Enterobacteriaceae (ESBL-EB) UTI by 10% and evaluate the clinical outcomes associated with the ASI. METHODS: A pre-to-post cohort study was conducted at a single-center integrated healthcare system between November 1, 2014 and February 26, 2017. An intensive, 90-day, pharmacist-driven, structured ASI was implemented between November 1, 2015 and January 29, 2016. Female patients aged ≥18 years who were treated for an uncomplicated, ESBL-EB urinary tract infection (UTI) were included. Primary outcome was clinical resolution defined as cure, persistence, relapse and recurrence. Secondary outcome measured was monthly ertapenem use expressed as number of days of therapy (DOT)/1000 adjusted patient days (APD). Segmented regression analysis for interrupted time series was performed to estimate ASI intervention effect. RESULTS: A total of 184 patients were included in the study. Ertapenem utilization decreased from 0.0145 DOT/1000 APD in Nov. 2014 to 0.0078 DOT/1000 APD Feb. 2017(p < 0.01). The mean ertapenem DOT declined 19% overall from the pre vs. post intervention periods (32 vs 26, p < 0.01). Frequency of recurrent UTIs between treatments did not significantly differ and no adverse effects were reported in patients treated with aminoglycosides. CONCLUSIONS: A structured ASI for uncomplicated ESBL-EB UTI was associated with a clinically meaningful decrease in ertapenem utilization and once-daily, 5-day aminoglycoside treatment was well-tolerated.


Assuntos
Aminoglicosídeos/uso terapêutico , Antibacterianos/uso terapêutico , Gestão de Antimicrobianos , Infecções por Enterobacteriaceae/tratamento farmacológico , Enterobacteriaceae/efeitos dos fármacos , Ertapenem/uso terapêutico , Infecções Urinárias/tratamento farmacológico , Adolescente , Adulto , Estudos de Coortes , Enterobacteriaceae/isolamento & purificação , Feminino , Humanos , Pacientes Ambulatoriais , Melhoria de Qualidade , Estudos Retrospectivos , Resultado do Tratamento , Infecções Urinárias/microbiologia , beta-Lactamases
19.
Antimicrob Agents Chemother ; 65(11): e0110221, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34370578

RESUMO

There are scarce data on the efficacy of ertapenem in the treatment of bacteremia due to extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-E) in kidney transplant (KT) recipients. We evaluated the association between treatment with ertapenem or meropenem and clinical cure in KT recipients with nonsevere bacteremic urinary tract infections (B-UTI) caused by ESBL-E. We performed a registered, retrospective, international (29 centers in 14 countries) cohort study (INCREMENT-SOT, NCT02852902). The association between targeted therapy with ertapenem versus meropenem and clinical cure at day 14 (the principal outcome) was studied by logistic regression. Propensity score matching and desirability of outcome ranking (DOOR) analyses were also performed. A total of 201 patients were included; only 1 patient (treated with meropenem) in the cohort died. Clinical cure at day 14 was reached in 45/100 (45%) and 51/101 (50.5%) of patients treated with ertapenem and meropenem, respectively (adjusted OR 1.29; 95% CI 0.51 to 3.22; P = 0.76); the propensity score-matched cohort included 55 pairs (adjusted OR for clinical cure at day 14, 1.18; 95% CI 0.43 to 3.29; P = 0.74). In this cohort, the proportion of cases treated with ertapenem with better DOOR than with meropenem was 49.7% (95% CI, 40.4 to 59.1%) when hospital stay was considered. It ranged from 59 to 67% in different scenarios of a modified (weights-based) DOOR sensitivity analysis when potential ecological advantage or cost was considered in addition to outcome. In conclusion, targeted therapy with ertapenem appears as effective as meropenem to treat nonsevere B-UTI due to ESBL-E in KT recipients and may have some advantages.


Assuntos
Bacteriemia , Transplante de Rim , Infecções Urinárias , Antibacterianos/uso terapêutico , Bacteriemia/tratamento farmacológico , Estudos de Coortes , Ertapenem , Humanos , Pontuação de Propensão , Estudos Retrospectivos , Infecções Urinárias/tratamento farmacológico , beta-Lactamases
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