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Background: The increase in carbapenem-resistant Klebsiella pneumoniae (CRKP) infections is of great concern because of limited treatment options. New antimicrobials were recently approved for clinical therapy. This study evaluated the epidemiology of carbapenemase-producing K. pneumoniae isolates collected at a Greek university hospital during 2017–2020, and their susceptibilities to ceftazidime–avibactam (CAZ/AVI), meropenem–vaborbactam (M/V), imipenem–relebactam (I/R), eravacycline, plazomicin, and comparators. Methods: Minimum inhibitory concentrations (MICs) were evaluated by Etest. Only colistin MICs were determined by the broth microdilution method. Carbapenemase genes were detected by PCR. Selected isolates were typed by multilocus sequence typing (MLST). Results: A total of 266 carbapenemase-producing K. pneumoniae strains were isolated during the 4-year study period. Among them, KPC was the most prevalent (75.6%), followed by NDM (11.7%), VIM (5.6%), and OXA-48 (4.1%). KPC-producing isolates belonged mainly to ST258 and NDM producers belonged to ST11, whereas OXA-48- and VIM producers were polyclonal. Susceptibility to tigecycline, fosfomycin, and colistin was 80.5%, 83.8%, and 65.8%, respectively. Of the novel agents tested, plazomicin was the most active inhibiting 94% of the isolates at ≤ 1.5 μg/ml. CAZ/AVI and M/V inhibited all KPC producers and I/R 98.5% of them. All OXA-48 producers were susceptible to CAZ/AVI and plazomicin. The novel β-lactam/β-lactamase inhibitors (BLBLIs) tested were inactive against MBL-positive isolates, while eravacycline inhibited 61.3% and 66.7% of the NDM and VIM producers, respectively. Conclusions: KPC remains the predominant carbapenemase among K. pneumoniae, followed by NDM. Novel BLBLIs, eravacycline, and plazomicin are promising agents for combating infections by carbapenemase-producing K. pneumoniae. However, the emergence of resistance to these agents highlights the need for continuous surveillance and application of enhanced antimicrobial stewardship. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to determine the epidemiology of bloodstream infections (BSIs) by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) after the introduction of ceftazidime/avibactam in January 2018 among ICU patients.Patients and Methods: All patients hospitalized at the ICU of the University General Hospital of Patras, Greece with CP-Kp BSI during 2015-18 were included. MICs of meropenem, fosfomycin, tigecycline and ceftazidime/avibactam (only for isolates from 2018) were determined by Etest, whereas for colistin, the broth microdilution method was applied. All isolates were tested by PCR for the presence of blaKPC, blaVIM, blaNDM and blaOXA-48 genes.Results: Among 170 BSIs due to CP-Kp (2015-18), 132 (78%) were caused by isolates carrying blaKPC (4 ceftazidime/avibactam-resistant), 17 blaVIM (10%), 16 blaNDM (9%) and 5 carrying both blaKPC and blaVIM (3%). From 2015 to 2017 (125 BSIs), KPC-producing strains (110; 88%) predominated, followed by NDM-producing strains (15; 12%), whereas no VIM-producing strain was isolated. Among the 45 BSIs in 2018, 22 (49%) were due to isolates carrying blaKPC (4 ceftazidime/avibactam resistant), followed by 17 (38%) carrying blaVIM, 5 (11%) carrying both blaKPC and blaVIM, and 1 isolate carrying blaNDM (2%). MBLs were more frequent in 2018 compared with 2015-17 (51% versus 12%; P < 0.001). Multivariate analysis found that prior administration of ceftazidime/avibactam (P = 0.014; OR 16.7, 95% CI 1.8-158.6) was independently associated with the development of BSI due to ceftazidime/avibactam-resistant isolates.Conclusions: Widespread ceftazidime/avibactam use may lead to a change in the palette of carbapenemases by replacing KPC with MBL-producing isolates. [ABSTRACT FROM AUTHOR]

Antimicrobial susceptibilities of 4973 Bacteroides spp. isolates recovered from various sources of patients from 12 countries (99.6% from European countries) in the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme, 2007–2020, were investigated. The minimum inhibitory concentrations (MICs) of the isolates with six commonly used agents were determined using the agar dilution method. Among the isolates, 10 Bacteroides spp. were included: B. fragilis (n =3180, 64.0%) was encountered most frequently, followed by B. thetaiotaomicron (n =675) and B. ovatus (n =409). During the 14 years, the proportion of B. fragilis declined, but the proportion of non- fragilis Bacteroides spp. increased. More than 90% of the isolates tested were susceptible to piperacillin-tazobactam, meropenem and tigecycline. Significantly lower susceptibility rates to cefoxitin (P <0.001), clindamycin (P <0.001), piperacillin/tazobactam (P <0.001) and tigecycline (P =0.006) were observed among non- fragilis Bacteroides spp. isolates than among B. fragilis isolates. Moreover, the susceptibility rates to clindamycin (P =0.003) and tigecycline (P =0.044) decreased significantly among non- fragilis Bacteroides spp. over time. Clindamycin susceptibility rates >80% were found in Greece (100%), Sweden (86.3%) and the UK (80.7%), and the lowest susceptibility rates were found in the USA (42.9%) and Japan (53.9%). In conclusion, the susceptibility of Bacteroides spp. to commonly used antibiotics varied geographically. Empirical antibiotic therapy for suspected anaerobic infections with clindamycin and cefoxitin should be avoided due to high resistance rates. Piperacillin-tazobactam, meropenem, metronidazole and tigecycline could be considered favourable options for the treatment of infections caused by Bacteroides spp. [ABSTRACT FROM AUTHOR]

Summary: Starting in May 2007, an ongoing outbreak of infections due to carbapenem resistant KPC-2-producing Klebsiella pneumoniae occurred in a tertiary care hospital in Crete (Greece). The outbreak involved 22 patients, none of whom had travelled in a country with known high prevalence of such isolates. KPC-producing K. pneumoniae strains were mainly isolated from patients admitted in the Intensive Care Unit, on mechanical ventilation, with prolonged hospitalization, prolonged administration of antibiotics, and prolonged administration of carbapenems. Clinical diagnoses were: pneumonia (62% of cases), surgical site infection (19%), bacteremia (9.5%), urinary tract infection (4.7%), and peritonitis (4.7%). Overall, 61 KPC-producing K. pneumoniae isolates were recovered, mainly from the respiratory tract (59.1%), catheter tip (22.7%), surgical site (18.2%), and blood (18.2%). Among 16 patients for whom therapeutic data were available, 14 (87.5%) were treated with a combination of colistin and/or tigecycline and/or garamycin. Clinical failure was noted in 22.2% of 18 patients available for assessment of clinical outcome, and microbiologic failure in 87.5% of 8 patients available for assessment of microbiologic outcome. In conclusion, an outbreak of KPC-producing K. pneumoniae infections has occurred in a tertiary care hospital in Greece, with significant associated morbidity and mortality. Prospective studies are required to evaluate the available therapeutic options for these infections. Our efforts should focus on rational use of available antibiotics, enhancement of infection control measures, and implementation of active antibiotic resistance surveillance. [Copyright &y& Elsevier]

• Cefepime/zidebactam MIC 50/90 are 0.5/2 mg/L against Enterobacterales including MBLs. • Cefepime/zidebactam MIC 50/90 are 8/16 mg/L against Pseudomonas including MBLs. • Cefepime/zidebactam inhibits isolates resistant to new therapies and colistin. • β-lactam enhancer action provides MDR/XDR coverage to cefepime/zidebactam. Cefepime/zidebactam is in clinical development for the treatment of carbapenem-resistant Gram-negative infections. MICs of cefepime/zidebactam (1:1) and comparators against Enterobacterales (n = 563), Pseudomonas (n = 172) and Acinetobacter baumannii (n =181) collected from 15 Greek hospitals (2014-2018) were determined by reference broth microdilution method. The isolates exhibited high carbapenem resistance rates [(Enterobacterales (75%), Pseudomonas (75%) and A. baumannii (98.3%)]. Cefepime/zidebactam showed MIC 50/90 of 0.5/2 mg/L, against Enterobacterales including metallo-β-lactamases (MBL)-producers. Reduced susceptibility rates to tigecycline (16.8%), colistin (47.4%), ceftazidime/avibactam (59.8%), and imipenem/relebactam (61%) indicated high prevalence of multi-drug resistance among Greek Enterobacterales. Cefepime/zidebactam exhibited MIC 50/90 of 8/16 mg/L against Pseudomonas including MBL-producers. The MIC 50/90 of ceftazidime/avibactam and imipenem/relebactam were high (≥32 mg/L). Cefepime/zidebactam showed MIC 90 of 64 mg/L against A. baumannii which is within its therapeutic scope. Other antibiotics including colistin showed limited activity against A. baumannii. The activity of cefepime/zidebactam against multi-drug-resistant isolates is attributable to zidebactam mediated novel β-lactam-enhancer mechanism. [ABSTRACT FROM AUTHOR]

TP-6076 is a synthetic fluorocycline antibiotic that inhibits bacterial protein synthesis. In this study, carbapenem-resistant Acinetobacter baumannii clinical isolates from 13 Greek hospitals were tested for susceptibility to TP-6076 and comparator antibiotics. Broth microdilution plates were used to determine minimum inhibitory concentrations (MICs). A total of 121 non-duplicate A. baumannii isolates were tested. The MIC 50 and MIC 90 values of TP-6076 were 0.03 mg/L and 0.06 mg/L, respectively. Tigecycline was the second most active antibiotic (MIC 90 , 2 mg/L), followed by minocycline (MIC 90 , 8 mg/L). TP-6076 exhibited MIC 90 values that were one dilution lower against tigecycline- and minocycline-susceptible isolates than against resistant isolates. There was no difference in the MIC 90 value for colistin-susceptible or -resistant isolates. In conclusion, TP-6076 exhibited greater antimicrobial activity in vitro against carbapenem-resistant A. baumannii than comparator antibiotics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A rapid increase was observed in the incidence of extensively drug-resistant Acinetobacter baumannii (XDR Aba) isolates in a Greek hospital during 2014. To investigate the causes of this rise, the antimicrobial resistance profiles of all carbapenem-resistant (CARB-R) Aba isolates recovered during 2014-2015 were determined. Selected XDR Aba isolates (n = 13) were characterized by molecular methods. XDR Aba (48 isolates) represented 21.4% of the 224 CARB-R Aba recovered during the study period. The 13 selected XDR Aba isolates were positive for the blaOXA-23, the intrinsic blaOXA-51, and the adeB gene of the AdeABC efflux pump, and all belonged to the 3LST ST101, corresponding to the international clone II. Three bloodstream isolates possessed two amino acid substitutions (A138T+A226V) in the deduced amino acid sequences of the pmrB gene, which may be implicated in colistin resistance. This study demonstrates that this clone still evolves by obtaining an ever-increasing arsenal of antibiotic resistance mechanisms. The clinical characteristics of the intensive care unit (ICU) patients with XDR Aba were reviewed retrospectively. Infected ICU patients with XDR Aba displayed higher death rates compared with infected ICU patients susceptible to colistin and tigecycline CARB-R Aba, although there were no statistically significant differences. Conclusively, continuous surveillance and molecular characterization of XDR Aba, combined with strict infection control measures are mandatory for combating nosocomial infections caused by this organism.

Background: Cefiderocol (S-649266), a siderophore cephalosporin, utilizes a novel mechanism of entry into the periplasmic space of Gram-negative bacteria and is broadly stable to ESBLs and carbapenemases., Methods: A collection of carbapenem-resistant Gram-negative bacteria isolated from clinical specimens in 18 Greek hospitals was tested for susceptibility to cefiderocol, meropenem, ceftazidime, cefepime, ceftazidime/avibactam, ceftolozane/tazobactam, aztreonam, amikacin, ciprofloxacin, colistin and tigecycline. Broth microdilution plates were used to determine MICs., Results: In total 189 non-fermentative Gram-negative bacteria (107 Acinetobacter baumannii and 82 Pseudomonas aeruginosa ) and 282 Enterobacteriaceae (including 244 Klebsiella pneumoniae , 14 Enterobacter cloacae and 11 Providencia stuartii ) were studied. For both A. baumannii and P. aeruginosa the MIC 90 of cefiderocol was 0.5 mg/L. For K. pneumoniae , E. cloacae and P. stuartii the MIC 90 of cefiderocol was 1, 1 and 0.5 mg/L, respectively. Tigecycline was the second most active antibiotic, followed by colistin., Conclusions: Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria than comparator antibiotics., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

An alarming increase in the resistance rates of tigecycline and colistin among carbapenemase-producing Acinetobacter baumannii recovered from a Greek hospital over a 3-year period (2011-2013) was investigated. The antimicrobial resistance profiles and carbapenemase gene content were determined for a collection of colistin- and/or tigecycline-resistant carbapenemase-producing A. baumannii isolates (n = 42), which were recovered consecutively during the study period. A gradual increase in the incidence of blaOXA-23 producers was observed from 2011 to 2013. A cluster of 21 isolates comprised tigecycline-resistant blaOXA-23 producers displayed a single antimicrobial resistance pattern. The emergence of two blaOXA-23 producers resistant to both tigecycline and colistin was documented. Furthermore, determination of the mechanisms of colistin and tigecycline resistance and molecular typing by the tri-locus sequence typing (3LST) scheme for nine isolates recovered from bloodstream infections were performed. Out of nine isolates, five tigecycline- and two colistin-resistant isolates were blaOXA-23 producers of 3LST ST101 corresponding to the international clone II recovered during 2012-2013. All nine isolates were positive for the presence of the adeB gene of the AdeABC efflux pump. Three colistin-resistant isolates possessed novel substitutions in PmrB, which may be implicated in colistin resistance. To the best of our knowledge, this is the first report of the acquisition of tigecycline and colistin resistance among blaOXA-23-producing A. baumannii of 3LST ST101 in Greece; thus, continuous surveillance and molecular characterization, prudent use of antibiotics and implementation of infection control measures for A. baumannii are urgent.

In 2010 the Hellenic center for disease control and prevention launched the "Prokroustes" nationwide action plan to tackle the increasing rates of carbapenem resistance among gram-negative nosocomial pathogens. In the present report, data from a Greek tertiary-care hospital are presented three years after the adoption of the infection control measures. Carbapenem resistance rates have been contained for Klebsiella pneumoniae and Acinetobacter baumannii but not for Pseudomonas aeruginosa. More worryingly, in accordance with their overuse against carbapenem-resistant bacteria, resistance rates to colistin and tigecycline have risen significantly.

Background: This 3-year prospective, observational, single-center study was undertaken to describe prescription, microbiology findings, tolerance, and efficacy of tigecycline for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections after liver transplantation in the intensive care unit (ICU)., Methods: All patients after liver transplantation treated with tigecycline for ≥3 days for CRKP infections in our ICU from January 1, 2010, to December 31, 2012, were studied. Patient characteristics, indication of treatment, bacteriology, and ICU mortality were collected. The main end points were clinical and microbiologic efficacy and tolerance of tigecycline., Results: Over the study period, 8 men and 2 women (18 CRKP isolates), aged 54.3 ± 7.7 years, were included in the study. Acute Physiology and Chronic Health Evaluation and Sequential Organ Failure Assessment scores on ICU admission were 13.7 ± 2.7 and 10 ± 2.2, respectively. In 7 isolates, tigecycline was prescribed for CRKP blood stream infection (BSI), in 6 for complicated intra-abdominal infection (IAI), in 2 for ventilator-associated pneumonia (VAP), in 2 for surgical site infection, and in 1 for urinary tract infection. In 4 cases, tigecycline was prescribed for secondary BSI followed by VAP and/or IAI. All isolates were susceptible to tigecycline, 83.4% to colistin, 44.5% to gentamicin, and 27.8% to amikacin. In 2 patients, tigecycline was prescribed as monotherapy. Three patients had clinical failure. The microbiologic response rate was 70%. Superinfection was detected in 5 patients, and Pseudomonas aeruginosa was the most frequently isolated pathogen. Tigecycline was generally well tolerated. The ICU mortality rate was 60% with attributable mortality rate 30%., Conclusions: Our pilot study suggests that tigecycline shows a good safety and tolerance profile in patients with CRKP infections in the ICU after orthotopic liver transplantation. Limited therapeutic options for such infections leave physicians no choice but to use tigecycline for off-label indications such as urinary tract and blood stream infections.

Purpose: To identify the risk factors for incident enteric colonization by KPC-producing Klebsiella pneumoniae (KPC-Kp) resistant to colistin or tigecycline during Intensive Care Unit (ICU) stay., Method: A prospective observational study of patients admitted to the ICU was conducted during a 27-month period. Rectal samples taken upon admission and weekly afterwards were inoculated on selective chromogenic agar. K. pneumoniae isolates were characterized by standard methodology. Mean inhibitory concentration (MIC) to colistin and tigecycline were determined by E-test. The presence of bla KPC gene was confirmed by PCR., Results: Among 254 patients, 62 (24.4%) became colonized by colistin- resistant KPC-Kp during their stay. Multivariate analysis revealed that corticosteroid, colistin administration and number of colonized patients in nearby beds per day were significantly associated with colonization. Among 257 patients, 39 (17.9%) became colonized by tigecycline resistant KPC-Kp during their stay. Risk factors identified by multivariate analysis were: days at risk, obesity, number of colonized patients treated in nearby beds per day and administration of tigecycline., Conclusions: The high prevalence of colistin or tigecycline resistant KPC-Kp enteric carriage in ICU patients indicate that dissemination is due to their transfer from patient to patient via the personnel and indicates the importance of strict infection control protocols.