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Here, we characterize the complete genome sequence of Escherichia coli isolated from a newborn affected by bacterial meningitis in Italy. Genome of E. coli strain 1455 harbored a circular chromosome and two plasmids of 167.740-bp and 4.073-bp in length, respectively. E. coli 1455 belonged to the ST3, serotype O17:H18 and carried different determinants including resistance to B-lactams, tetracyclines, and quinolones. In addition, genome of E. coli strain 1455 harbored 5 integrated pro-phage regions mainly located in the chromosome, while most of the virulence factors associated to the invasiveness and clinical severity and different antimicrobial resistance determinants (blaTEM-1, tet(A) and qnrS1) were located in the 167-Kb plasmid. Taken together, our findings suggest a possible widespread of a virulence factors-carrying plasmid worldwide and highlight the importance of genomic characterization in the diffusion of public health threats.
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We evaluated the activity of piperacillin in relation to INCREASING TAZOBACTAM CONCENTRATION against ESBL-producing Enterobacterales collected from patients with bacteraemia. Increasing tazobactam concentration (4, 12 or 24 mg/L) exerted a reduction of piperacillin MICs under the clinical breakpoint in a concentration-dependent manner (0%, 60% and 90% of clinical isolates). Also, activity of piperacillin/tazobactam based at higher achievable serum concentrations (123/14 mg/L) is needed to reduce the bacterial growth in 92% of ESBL-producers. CHANGES IN THE PIPERACILLIN MIC IN RELATION TO INCREASING TAZOBACTAM SUGGEST THAT REALTIME TDM COULD BE USED FOR DRIVEN ANTIMICROBIAL THERAPY WITH PIPERACILLIN/TAZOBACTAM IN BSI DUE TO ESBL STRAINS.
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The emergence of antimicrobial resistance represents a serious threat to public health and for infections due to multidrug-resistant (MDR) microorganisms, representing one of the most important causes of death worldwide. The renewal of old antimicrobials, such as colistin, has been proposed as a valuable therapeutic alternative to the emergence of the MDR microorganisms. Although colistin is well known to present several adverse toxic effects, its usage in clinical practice has been reconsidered due to its broad spectrum of activity against Gram-negative (GN) bacteria and its important role of "last resort" agent against MDR-GN. Despite the revolutionary perspective of treatment with this old antimicrobial molecule, many questions remain open regarding the emergence of novel phenotypic traits of resistance and the optimal usage of the colistin in clinical practice. In last years, several forward steps have been made in the understanding of the resistance determinants, clinical usage, and pharmacological dosage of this molecule; however, different points regarding the role of colistin in clinical practice and the optimal pharmacokinetic/pharmacodynamic targets are not yet well defined. In this review, we summarize the mode of action, the emerging resistance determinants, and its optimal administration in the treatment of infections that are difficult to treat due to MDR Gram-negative bacteria.
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Antibacterianos , Colistina , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Colistina/uso terapêutico , Colistina/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Testes de Sensibilidade Microbiana , AnimaisRESUMO
Listeria monocytogenes, a concerning foodborne pathogen, causes severe infections in vulnerable subjects such as pregnant women and the elderly. In this article, we present the complete genome sequence of P4_LIS, an L. monocytogenes isolated from a patient with invasive bacteria infection.
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We described the emergence of ceftazidime/avibactam and cefiderocol cross-resistance in patients with KPC-producing Klebsiella pneumoniae infections. All strains with ceftazidime/avibactam and cefiderocol cross-resistance showed point mutations on KPC Ω-loop. Taken together, our results indicate that prolonged exposure to ceftazidime/avibactam can confer cross-resistance to ceftazidime/avibactam and cefiderocol.
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Antibacterianos , Compostos Azabicíclicos , Cefiderocol , Ceftazidima , Cefalosporinas , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Infecções por Klebsiella , Klebsiella pneumoniae , Testes de Sensibilidade Microbiana , beta-Lactamases , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Ceftazidima/farmacologia , Ceftazidima/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Humanos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Cefalosporinas/uso terapêutico , Cefalosporinas/farmacologia , Farmacorresistência Bacteriana Múltipla/genética , beta-Lactamases/genética , beta-Lactamases/metabolismo , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Mutação PuntualRESUMO
BACKGROUND: Klebsiella pneumoniae is a concerning pathogen, responsible for hospital-associated outbreaks. Multi drug resistant (MDR) strains are especially hard to treat. We conducted whole-genome sequencing on a MDR K. pneumoniae strain in order to identify genomic features potentially linked to its phenotype. METHODS: DNA sequencing was performed on the Illumina iSeq 100 platform. Genome assembly was carried out with SPAdes. The genome was annotated with RASTtk. Typing was performed with MLST and Kaptive. Antibiotic resistance genes were detected with AMRFinderPlus and Abricate, and further verified with BLAST. RESULTS: The strain exhibited resistance to ceftazidime/avibactam and cefiderocol, but remained susceptible to carbapenems. The strain belonged to sequence type ST101, serotype O1:K17. The analysis of antibiotic resistance genes indicated that the strain carried a novel KPC variant, designated as KPC-203, featuring a EL deletion at amino acid position 166-167, within the Ω-loop, and a nine-amino-acid insertion (LAVYTRAPM) at position 259. Sequence alterations were found in porin genes ompK35 and ompK36. Unlike molecular testing, which was able to detect the KPC-203 variant, all phenotypic carbapenemase detection methods achieved negative results. CONCLUSIONS: KPC-203, a novel KPC variant, showed a sequence modification in a cephalosporin resistance-associated hotspot. Interestingly, such alterations typically correlate with the restoration of carbapenem susceptibility. We hypothesize that KPC-203 likely led to resistance to ceftazidime/avibactam and cefiderocol, while maintaining susceptibility to carbapenems.
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Streptococcus pneumoniae is a major global health concern, being a common cause of meningitis in both children and adults. Here, we report the complete genome sequence of P10_PNE_LCR, a S. pneumoniae 11A strain isolated in Northern Italy from an adult patient diagnosed with meningitis.
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Ceftazidima , Infecções por Klebsiella , Humanos , Ceftazidima/farmacologia , Ceftazidima/uso terapêutico , Cefiderocol , Klebsiella pneumoniae/genética , Estado Terminal , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Compostos Azabicíclicos/uso terapêutico , Combinação de Medicamentos , Testes de Sensibilidade Microbiana , beta-Lactamases , Infecções por Klebsiella/tratamento farmacológico , Proteínas de BactériasRESUMO
PURPOSE: Cefiderocol susceptibility testing (AST) represents an open challenge for clinical microbiology. Herein, we evaluated the performance of the UMIC® Cefiderocol broth microdilution (BMD) test and disc diffusion on Gram-negative species. METHODS: UMIC® Cefiderocol BMD test, disc diffusion and reference BMD were in parallel performed on a collection of 256 clinical isolates. Categorical agreement (CA), essential agreement (EA), bias, major errors (MEs) and very major errors (VMEs) were calculated for both AST methods. RESULTS: The UMIC® Cefiderocol BMD strip exhibited an EA < 90% (85.5%), a CA higher than 90% (93.7%) and a low number of VMEs (n = 4, 4.2%) and MEs (n = 12, 7.4%). UMIC® Cefiderocol identified 96.2% of the resistant isolates [Enterobacterales, (39/40); P. aeruginosa (19/19); A. xylosoxidans (5/6); S. maltophilia (5/6); Burkholderia spp. (8/8)]. Disc diffusion showed a high CA (from 94.9 to 100%) regardless of disc manufacturer in Enterobacterales, P. aeuroginosa, A. baumannii and S. maltophilia. However, high rates of results falling in the area of technical uncertainty (ATU) were observed in Enterobacterales (34/90, 37.8%) and P. aeruginosa (16/40, 40%). Disc diffusion showed a poor performance in A. xylosoxidans and Burkholderia spp. if PK/PD breakpoint was used (overall, 5/9 VMEs; in contrast, the use of P. aeruginosa-specific breakpoints resulted in 100% of CA with 24.6% of results in the ATU). CONCLUSION: In conclusion, disc diffusion and UMIC® Cefiderocol are valid methods for the determination of cefiderocol susceptibility. Given the high number of results in the ATU by disc diffusion, a combined use of both AST methods may represent a solution to overcome the challenge of cefiderocol susceptibility testing in routine microbiology laboratories.
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Achromobacter denitrificans , Acinetobacter baumannii , Stenotrophomonas maltophilia , Humanos , Cefiderocol , Antibacterianos/farmacologia , Pseudomonas aeruginosa , Testes de Sensibilidade MicrobianaRESUMO
Candida auris is a concerning pathogen in health care due to its ability to spread in medical settings. In this study, we characterized the genome of three C. auris clinical isolates collected in the Emilia-Romagna region of Northeastern Italy from January 2020 to May 2021. Whole-genome sequencing was performed using Illumina iSeq 100 and Oxford Nanopore MinION systems. Genomes were assembled with Flye. Phylogenetic analysis was carried out with RaxML. The ERG11, TAC1b, and FKS1 genes were examined for known substitutions associated with resistance to azoles and caspofungin using Diamond. All three C. auris isolates belonged to clade I (South Asian lineage) and showed high minimum inhibitory concentrations for fluconazole. Two of the three isolates were closely related to the first Italian index case of C. auris occurred in the 2019 and carried similar mutations associated to azole resistance. The third isolate showed a greater phylogenetic distance from these strains and had a different genetic determinant not previously seen in Italy. Our data suggest that two C. auris clinical isolates may have been epidemiologically related to the first outbreak previously observed in Italy, while the remaining isolate may have originated from a different source. Further research is needed to understand C. auris transmission and resistance and to control its spread.
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Antifúngicos , Candidíase , Humanos , Antifúngicos/farmacologia , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Candida , Candida auris , Filogenia , Farmacorresistência Fúngica/genética , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , AzóisRESUMO
The novel ß-lactam/ß-lactamase inhibitor combinations (ßL-ßLICs) are one of the last-line resources available against multidrug-resistant (MDR) Gram-negative bacteria. Among ßL-ßLICs, ceftazidime/avibactam (CAZ-AVI) demonstrated strong activity against carbapenem-resistant Enterobacterales (CRE). Avibactam was proven to restore bactericidal activity of ceftazidime, inhibiting both KPC and OXA-48-like ß-lactamases. Despite this, emergence of CAZ-AVI-resistant strains in Enterobacterales has been reported. Herein, we evaluated the in vitro ceftazidime activity in the presence of increasing concentrations of avibactam by the broth microdilution method against CAZ-AVI-susceptible and resistant genome-characterized KPC-producing K. pneumoniae (KPC-Kp) clinical isolates. Strains expressing KPC and co-expressing KPC/OXA-181 carbapenemase were selected on the basis of the different phenotypic traits for novel ßL-ßLICs and cefiderocol. Notably, avibactam at 8 mg/L maintained the MIC of ceftazidime above the clinical breakpoint in 14 out of 15 (93%) KPC-Kp resistant to CAZ-AVI. A high concentration of avibactam (i.e., 64 mg/L) is required to observe a bactericidal activity of ceftazidime against 9 out of 15 (60%) CAZ-AVI-resistant isolates. In vitro evaluation showed that with the increase in the concentration of avibactam, ceftazidime showed high activity against CAZ-AVI-susceptible strains. High concentrations of avibactam in vivo are required for ceftazidime to be active against CAZ-AVI-resistant KPC-Kp.
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Infecções por Klebsiella , Pneumonia Associada à Ventilação Mecânica , Humanos , Meropeném/farmacologia , Klebsiella pneumoniae , Estado Terminal , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Antibacterianos/farmacologia , Combinação de Medicamentos , beta-Lactamases , Testes de Sensibilidade Microbiana , Proteínas de Bactérias , Infecções por Klebsiella/tratamento farmacológicoRESUMO
The objective of this study was to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome of documented difficult-to-treat resistant (DTR) Gram-negative infections. A 2-year retrospective cohort study was performed in patients receiving CI ceftazidime-avibactam mono- or combo therapy for documented DTR Gram-negative infections and undergoing therapeutic drug monitoring of both ceftazidime and avibactam. The free fractions of steady-state concentrations (fCss) of ceftazidime and avibactam were calculated. The joint PK/PD target was considered optimal when both the fCss/MIC ratio for ceftazidime ≥4 (equivalent to 100% fT>4xMIC) and the fCss/CT ratio for avibactam >1 (equivalent to 100% fT >CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two and suboptimal if neither of the two was achieved). Multivariate logistic regression analysis was applied for testing potential variables associated with microbiological failure. Fifty-eight patients were treated with CI ceftazidime-avibactam mono- (36) or combo therapy (22) for documented DTR Gram-negative infections [74.2% for primary or secondary bloodstream infections (BSIs)]. Combo therapy was administered more frequently to intensive care unit (ICU) patients (P = 0.023) or for pneumonia (P = 0.001) and less frequently for intra-abdominal infections and BSIs (P = 0.04). Microbiological failure occurred in five cases (8.6%, three in mono- and two in combo therapy). In the multivariate analysis, the suboptimal/quasi-optimal joint PK/PD target emerged as the only independent predictor of microbiological failure (odds ratio [OR] 11.11; 95% confidence interval [CI] 1.31-93.98; P = 0.023), whereas monotherapy was not (P = 0.99). Optimized joint PK/PD target attainment of CI ceftazidime-avibactam monotherapy could represent a way forward for allowing microbiological eradication of DTR Gram-negative infections and could render unnecessary combo therapy.
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Antibacterianos , Ceftazidima , Humanos , Ceftazidima/farmacologia , Antibacterianos/farmacologia , Estudos Retrospectivos , Compostos Azabicíclicos/farmacologia , Combinação de Medicamentos , Testes de Sensibilidade MicrobianaRESUMO
Objectives: Herein, we describe the epidemiology of carbapenemase-producing Enterobacterales (CPE) before and during the COVID-19 pandemic. Also, we report the emergence of an outbreak of Klebsiella pneumoniae strains co-producing KPC and OXA-181 carbapenemase, resistant to novel ß-lactam/ß-lactamase inhibitors (ßL-ßLICs) and cefiderocol. Methods: CPE were collected during a period of 3â years from 2019 to 2021. Antimicrobial susceptibility testing for novel ßL-ßLICs and cefiderocol was performed by MIC test strips and microdilution with iron-depleted broth. WGS was performed on 10 selected isolates using the Illumina platform, and resistome analysis was carried out by a web-based pipeline. Results: Between January 2019 and December 2021, we collected 1430 carbapenemase producers from 957 patients with infections due to CPE. KPC was the most common carbapenemase, followed by VIM, OXA-48 and NDM. During 2021, we identified 78 K. pneumoniae co-producing KPC and OXA-181 carbapenemases in 60 patients, resistant to meropenem/vaborbactam and imipenem/relebactam. Resistance to ceftazidime/avibactam and cefiderocol was observed respectively in 7 and 8 out of the 10 sequenced K. pneumoniae. Genome analysis showed that all isolates were clonally related, shared a common porin and plasmid content, and carried blaOXA-181 and blaKPC carbapenemases. Specifically, 4 out of 10 isolates carried blaKPC-3, while 6 harboured mutated blaKPC. Of note, KPC producers resistant to ceftazidime/avibactam and harbouring mutated blaKPC exhibited higher MICs of cefiderocol (median MIC 16â mg/L, IQR 16-16) than strains harbouring WT blaKPC-3 (cefiderocol 9â mg/L, IQR 1.5-16). Conclusions: Our results highlight the need for continuous monitoring of CPE to limit widespread MDR pathogens carrying multiple mechanisms conferring resistance to novel antimicrobial molecules.
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Infecções por Klebsiella , Inibidores de beta-Lactamases , Humanos , Inibidores de beta-Lactamases/farmacologia , Klebsiella pneumoniae , Lactamas , Cefalosporinas/farmacologia , Antibacterianos/farmacologia , beta-Lactamases , Testes de Sensibilidade Microbiana , Combinação de Medicamentos , Proteínas de Bactérias , CefiderocolAssuntos
Infecções Intra-Abdominais , Transplante de Fígado , Humanos , Klebsiella pneumoniae , Líquido Ascítico , Ceftazidima/farmacologia , Combinação de Medicamentos , Compostos Azabicíclicos/uso terapêutico , Compostos Azabicíclicos/farmacologia , Infecções Intra-Abdominais/tratamento farmacológicoRESUMO
OBJECTIVES: To assess the pharmacokinetics/pharmacodynamics (PK/PD) of cefiderocol administered by continuous infusion (CI) in a case series of critically ill patients with carbapenem-resistant Acinetobacter baumannii (CRAB) infections undergoing continuous venovenous haemodiafiltration (CVVHDF). METHODS: Critically ill patients receiving cefiderocol by CI during CVVHDF for documented bloodstream infections (BSIs), ventilator-associated pneumonia (VAP), and/or complicated intrabdominal infections (cIAIs) caused by CRAB and undergoing therapeutic drug monitoring (TDM) from February 2022 to January 2023 were retrospectively assessed. Cefiderocol concentrations were determined at steady-state, and the free fraction (fCss) was calculated. Cefiderocol total clearance (CLtot) was determined at each TDM assessment. fCss/MIC ratio was selected as a PD determinant of cefiderocol efficacy and defined as optimal (>4), quasi-optimal (1-4), and suboptimal (<1). RESULTS: Five patients with documented CRAB infections (two BSI+VAP, two VAP, and one BSI+cIAI) were included. The maintenance dose of cefiderocol was 2 g q8h over 8 h by CI. Median average fCss was 26.5 mg/L (21.7-33.6 mg/L). Median CLtot was 4.84 L/h (2.04-5.22 L/h). Median CVVHDF dose was 41.1 mL/kg/h (35.5-44.9 mL/kg/h), and residual diuresis was reported in 4/5 cases. Optimal PK/PD target was attained in all cases, with a median cefiderocol fCss/MIC ratio of 14.9 (6.6-33.6). CONCLUSION: CI of full doses of cefiderocol could be a useful strategy to attain aggressive PK/PD targets for the treatment of severe CRAB infections in critically ill patients undergoing high-intensity CVVHDF and who have residual diuresis.
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Acinetobacter baumannii , Terapia de Substituição Renal Contínua , Hemodiafiltração , Humanos , Antibacterianos/uso terapêutico , Estado Terminal , Estudos Retrospectivos , Carbapenêmicos/farmacologia , Carbapenêmicos/uso terapêutico , CefiderocolRESUMO
Limited treatment options are among the main reasons why antimicrobial resistance has become a leading major public health problem. In particular, carbapenem-resistant Enterobacteriales (CRE), Pseudomonas aeruginosa and Acinetobacter baumannii have been included by the World Health Organization (WHO) among the pathogens for which new therapeutic agents are needed. The combination of antibiotics represents an effective strategy to treat multidrug-resistant (MDR) pathogen infections. In this context, the aim of this study is to evaluate the in vitro activity of cefiderocol (CFD) in combination with different antimicrobial molecules against a collection of well-characterized clinical strains, exhibiting different patterns of antimicrobial susceptibility. Clinical strains were genomically characterized using Illumina iSeq100 platform. Synergy analyses were performed by combining CFD with piperacillin-tazobactam (PIP-TAZ), fosfomycin (FOS), ampicillin-sulbactam (AMP-SULB), ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MER-VAB) and imipenem-relebactam (IMI-REL). Our results demonstrated the synergistic effect of CFD in combination with FOS and CAZ-AVI against CRE and carbapenem-resistant Acinetobacter baumannii (CR-Ab) clinical strains owing CFD-resistant profile, while the CFD and AMP-SULB combination was effective against CR-Pa strain displaying AMP-SULB-resistant profile. Moreover, the combination of CAZ-AVI/SULB showed synergistic activity in CAZ-AVI-resistant CRE strain. In conclusion, although further analyses are needed to confirm these results, our work showed the efficacy of CFD when used for synergistic formulations.
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Usutu virus (USUV) is an arthropod-borne flavivirus emerged in Africa in 1950s and in Eruope in 1990s causing a massive number of birds' deaths. The role of USUV as human pathogen has been only recently hypothesized and cases of USUV infection in humans remain limited and often related to immunocompromised subjects. Herein, we report a case of USUV meningoencephalitis infection in an immunocompromised patient with no history of previous flavivirus infection. The infection due to USUV evolved rapidly since hospital admission thus resulting fatal in few days after symptoms onset and, although not proven, a suspected bacteria co-infection has been hypothesized. Based on these findings, we suggested that when USUV meningoencephalitis is suspected in countries endemic, careful attention should be applied to neurological syndromes during summer months especially among immunocompromised patients.
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Infecções por Flavivirus , Flavivirus , Humanos , Flavivirus/genética , Infecções por Flavivirus/epidemiologia , Itália , Hospedeiro ImunocomprometidoRESUMO
PURPOSE: To explore pharmacokinetic/pharmacodynamic (PK/PD) profile of continuous infusion (CI) ceftazidime-avibactam for treating difficult-to-treat resistant Gram-negative (DTR-GN) infections in critical patients undergoing continuous venovenous haemodiafiltration (CVVHDF). MATERIALS AND METHODS: Patients treated with CI ceftazidime-avibactam for DTR-GN infections during CVVHDF were retrospectively assessed. Ceftazidime and avibactam concentrations were measured at steady-state and the free fraction (fCss) was calculated. Total clearance (CLtot) of both agents were calculated and the impact of CVVHDF intensity was assessed by linear regression. The joint PK/PD target of ceftazidime-avibactam was defined as optimal when both fCss/MIC≥4 for ceftazidime and fCss/CT > 1 for avibactam were achieved. Relationship between ceftazidime-avibactam PK/PD targets and microbiological outcome was assessed. RESULTS: Eight patients with DTR-GN infections were retrieved. Median fCss were 84.5 (73.7-87.7 mg/L) for ceftazidime and 24.8 mg/L (20.7-25.8 mg/L) for avibactam. Median CLtot was 2.39 L/h (2.05-2.96 L/h) for ceftazidime and 2.56 L/h (2.12-2.98 L/h) for avibactam. Median CVVHDF dose was 38.6 mL/h/kg (35.9-40.0 mL/kg/h). CLtot were linearly correlated with CVVHDF dose (r = 0.53;p = 0.03, and r = 0.64;p = 0.006, respectively). The joint PK/PD targets were optimal granting microbiological eradication in all the assessable cases. CONCLUSION: CI administration of 1.25-2.5 g q8h ceftazidime-avibactam may allow prompt attainment and maintenance of optimal joint PK/PD targets during high-intensity CVVHDF.