Small RNA-regulated expression of efflux pump affects tigecycline resistance and heteroresistance in clinical isolates of Klebsiella pneumoniae.

Tigecycline and the newly Food and Drug Administration-approved tetracyclines, including eravacycline and omadacycline, are regarded as last-resort treatments for multidrug-resistant Enterobacterales. However, tigecycline resistance in Klebsiella pneumoniae has increased, especially the underlying mechanism of heteroresistance is unclear. This study aimed to elucidate the mechanisms underlying tigecycline resistance and heteroresistance in clinical K. pneumoniae isolates. A total of 153 clinical K. pneumoniae isolates were collected, and identified 15 tigecycline-resistant and three tigecycline-heteroresistant isolates using broth microdilution and population analysis profile methods, respectively. Total RNAs from K. pneumoniae ATCC13883 and the laboratory-induced tigecycline-resistant strain were extracted and sequenced on an Illumina platform. Differentially expressed genes and regulatory small RNAs (sRNAs) were analyzed and validated in clinical isolates of K. pneumoniae using quantitative real-time PCR. RNA sequencing results showed that mdtABC efflux pump genes were significantly upregulated in the tigecycline-resistant strains. Overexpression of mdtABC was observed in a clinical K. pneumoniae isolate, which increased tigecycline minimum inhibitory concentrations (MICs) and was involved in tigecycline heteroresistance. Sequencing analysis of sRNA demonstrated that candidate sRNA-120 directly interacted with the mdtABC operon and was downregulated in tigecycline-resistant strains. We generated an sRNA-120 deletion mutation strain and a complemented strain of K. pneumoniae. The sRNA-120 deletion strain displayed increased mRNA levels of mdtA, mdtB, and mdtC and an increase in MICs of tigecycline. The complemented strain of sRNA-120 restored the mRNA levels of these genes and the susceptibility to tigecycline. RNA antisense purification and parallel reaction monitoring mass spectrometry were performed to verify the interactions between sRNA-120 and mdtABC. Collectively, our study highlights that the post-transcriptional repression of mdtABC through sRNA-120 may provide an additional layer of efflux pump gene expression control, which is important for resistance and heteroresistance in clinical K. pneumoniae isolates.

Severe hypoglycemia induced by Tigecycline in a diabetic and hemodialysis patient.

INTRODUCTION: Tigecycline has a broad spectrum of activity, including activity against drug-resistant Gram-positive and -negative microorganisms. Its side effects are significant, but hypoglycemia is a rare finding during treatment. We aim to present an event of severe hypoglycemia in a patient with type 2 diabetes mellitus with replacement renal therapy, and hemodialysis after initiating tigecycline. CASE PRESENTATION: A 54-year-old female diagnosed with type 2 diabetes mellitus was under treatment with basal-bolus insulin therapy and oral antihypertensive drugs. She started hemodialysis 24 months ago. She complained of recurrent fever for the last seven months and was treated with several antibiotics. In two separate blood cultures, she tested positive for methicillin-resistant Staphylococcus epidermidis (MRSE). Based on the antibiogram, we started treatment with tigecycline 100 mg/day. After 6-8 hours from the first dose, the patient is complicated with events of hypoglycemia and then continues with severe hypoglycemia (40-47 mg/dL). The patient continued to have hypoglycemia for about 16-18 hours after the last dose. We didn't find any reasons to explain the cause of episodes of hypoglycemia. She did not have high blood insulin levels (insulin 4.11 mIU/L [range 2.6-24.9]). We followed her for six months and the patient did not experience episodes of hypoglycemia. CONCLUSIONS: The association of severe hypoglycemia with tigecycline treatment is a very rare event and published papers on this topic are limited. Clinicians should be aware of this rare event when administering tigecycline and should routinely check blood glucose level during the treatment.

In vitro antimicrobial activity of doxycycline, minocycline, and tigecycline against Mycobacterium abscessus complex: A meta-analysis study.

PURPOSE: Mycobacterium abscessus complex (MABC) infections are increasing worldwide. Furthermore, these infections have a low treatment success rate due to their resistance to many current antibiotics. This study aimed to determine the overall in vitro activity of the tetracyclines doxycycline (DOX), minocycline (MIN), and tigecycline (TGC) against MABC clinical isolates. PATIENTS AND METHODS: A systematic review of PubMed/MEDLINE, Web of Science, and Embase was conducted up to August 28, 2023. Studies applying the drug susceptibility testing standards of the Clinical and Laboratory Standards Institute were considered. A random effects model was used to assess the total in vitro resistance rates of the MABC clinical isolates to DOX, MIN, and TGC. The I2 and Cochran's Q statistics were employed to evaluate the origins of heterogeneity. All analyses were conducted using CMA V.3 software. RESULTS: Twenty-six publications (22, 12, and 11 studies on DOX, MIN, and TGC, respectively) were included. The pooled in vitro resistance rates of the MABC clinical isolates to DOX and MIN at the breakpoint of 8 µg/mL were 93.0 % (95 % CI, 89.2 %-95.5 %) and 87.2 % (95 % CI, 76.5 %-93.4 %), respectively. In the case of TGC, the breakpoints of 2, 4, and 8 µg/mL were associated with pooled resistance rates of 2.5 % (95 % CI, 0.5 %-11.6 %), 7.2 % (95 % CI, 4.0 %-12.5 %), and 16.8 % (95 % CI, 4.7 %-45.0 %), respectively. CONCLUSION: Among the three examined tetracyclines, MABC exhibited extremely high resistance rates to DOX and MIN, thereby limiting their use in treating MABC infections. Conversely, MABC showed an increased susceptibility rate to TGC, highlighting TGC administration as a viable treatment option for patients with MABC infections.

Fitness cost of tet(A) type I variant-mediated tigecycline resistance in Klebsiella pneumoniae.

OBJECTIVE: The aim of the present study is to explore the impact of the tet(A) type I variant (tetA-v1) on its fitness effect in Klebsiella pneumoniae. METHODS: Clinical K. pneumoniae strains were utilized as parental strains to generate strains carrying only the plasmid vector (pBBR1MCS-5) or the tetA-v1 recombinant plasmid (ptetA-v1). Antimicrobial susceptibility testing was conducted to estimate the contribution of tetA-v1 to drug resistance. Plasmid stability was evaluated by serial passage over 10 consecutive days in the absence of tigecycline. Biological fitness was examined through growth curve analysis, in vitro competition assays and a neutropenic mouse thigh infection model. RESULTS: A 2-4-fold increase in tigecycline MIC was observed following the acquisition of tetA-v1. Without tigecycline treatment, the stability of ptetA-v1 plasmids has been decreasing since day 1. The ptetA-v1 plasmid in Kp89, Kp91, and Kp93 exhibited a decrease of about 20% compared to the pBBR1MCS-5 plasmid. The acquisition of the tetA-v1 gene could inhibit the growth ability of K. pneumoniae strains both in vitro and in vivo. tetA-v1 gene imposed a fitness cost in K. pneumoniae, particularly in the CRKP strain Kp51, with a W value of approximately 0.56. CONCLUSION: The presence of tetA-v1 is associated with a significant fitness cost in K. pneumoniae in the absence of tigecycline, both in vitro and in vivo.

Evaluation of role of Tigecycline among clinically significant multidrug resistant pathogens from a tertiary care hospital.

Background: Tigecycline, a glycylcycline antibiotic is a promising option for the treatment of single or multidrug resistant pathogens. The aim of the study was to evaluate the in-vitro Tigecycline susceptibility of various pathogens from clinical samples received at the tertiary care hospitals in South India. Methods: The analysis of specimens from patients admitted were carried out in this prospective cross sectional study. The identification and antimicrobial susceptibility testing was performed by semi-automated Vitek 2 systems and Kirby Bauer method. Pattern of data analysis was done by descriptive statistics. Results: Among 2574 isolates, 812 isolates were Gram positive pathogens and 1762 isolates were Gram negative pathogens. Resistance to Tigecycline was more common among Gram negative pathogens (18.62%) in comparison to the Gram positive pathogens (0.49%). Among 740 Extended Spectrum Beta Lactamases (ESBL) producers such as Klebsiella species & E coli, 629 isolates were susceptible, and 93 isolates were resistant to the tigecycline. All the methicillin resistant Staphylococcus aureus (MRSA) isolates were susceptible to tigecycline. Conclusion: Multidrug resistant (MDR) pathogens like Acinetobacter species, and Klebsiella species were found to be highly effective in vitro to tigecycline for elimination of infections caused by both Gram positive and Gram negative pathogens. The use of combination therapy becomes crucial to prevent the development of Pan Drug resistance.

Molecular mechanisms of tigecycline-resistance among Enterobacterales.

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.

Tandem amplification of a plasmid-borne tet(A) variant gene confers tigecycline resistance in Escherichia coli.

OBJECTIVES: To elucidate the mechanism of tigecycline resistance in Escherichia coli that is mediated by the tet(A) variant gene. METHODS: E. coli strain 573 carried a plasmid-borne tet(A) variant gene, tentatively designated tet(A)TIG, that conferred decreased tigecycline susceptibility (MIC 0.5 mg/L). When exposed to increasing concentrations of tigecycline (0.25-8 mg/L), mutants growing at 2, 4 and 8 mg/L were obtained and sequenced. Copies of plasmid and tet(A)TIG relative to the chromosomal DNA in the mutants were determined by WGS and quantitative PCR (qPCR). Expression of tet(A)TIG in the mutants was evaluated by RT-qPCR. The tet(A)TIG-carrying plasmids were visualized by S1-PFGE and Southern blot hybridization. PCR served for the detection of a tet(A)TIG-carrying unconventional circularizable structure (UCS). RESULTS: Tigecycline resistance with maximum MICs of 16 mg/L was seen in E. coli mutants selected in the presence of tigecycline. Compared with the parental strain, the relative copy number and transcription level of tet(A)TIG in the mutants increased significantly in the presence of 2, 4 and 8 mg/L tigecycline, respectively. With increasing tigecycline selection pressure, the tet(A)TIG-carrying plasmids in the mutants increased in size, correlating with the number of tandem amplificates of a ΔTnAs1-flanked UCS harbouring tet(A)TIG. These tandem amplificates were not stable in the absence of tigecycline. CONCLUSIONS: Tigecycline resistance is due to the tandem amplification of a ΔTnAs1-flanked tet(A)TIG-carrying plasmid-borne segment in E. coli. The gain/loss of the tandem amplificates in the presence/absence of tigecycline represents an economic way for the bacteria to survive in the presence of tigecycline.

Efficacy of Cefiderocol, a Novel Siderophore Cephalosporin, against Multidrug Resistant Acinetobacter baumannii Clinical Isolates in Japan.

Multidrug-resistant Acinetobacter baumannii (MDRAB) is an important pathogen that causes nosocomial infections and is resistant to almost all antibiotics, including carbapenems. Cefiderocol is a novel siderophore cephalosporin active against a broad spectrum of gram-negative bacteria. However, the susceptibility of MDRAB to cefiderocol has not yet been reported in Japan. In this study, we measured the minimum inhibitory concentrations (MICs) of antibiotics including cefiderocol against MDRAB clinical isolates collected during a nosocomial outbreak between 2009 and 2010 at the Teikyo University Hospital in Japan. We found that all 10 MDRAB clinical isolates tested were susceptible to cefiderocol, with an MIC range of 0.12 to 1 µg/mL. All the isolates also exhibited resistance to ampicillin-sulbactam and an intermediate resistance to colistin, whereas nine of them were susceptible to tigecycline. DNA sequencing revealed that all strains harbored an OXA-51-like carbapenemase, a major cause of carbapenem resistance in A. baumannii in Japan. In conclusion, this study showed that the cefiderocol susceptibility of MDRAB clinical isolates in Japan was equivalent to that to colistin or tigecycline, and thus cefiderocol is a potential treatment option for MDRAB infections.

Treatment outcomes of patients with non-bacteremic pneumonia caused by extensively drug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii complex isolates: Is there any benefit of adding tigecycline to aerosolized colistimethate sodium?

Few therapeutic options exist for various infections caused by extensively drug-resistant Acinetobacter calcoaceticus-Acinetobacter baumannii (XDR-Acb) complex isolates, including pneumonia. This study investigated the clinical efficacy between aerosolized colistimethate sodium (AS-CMS, 2 million units thrice a day) treatment alone or in combination with standard-dose tigecycline (TGC) in patients with non-bacteremic pneumonia due to XDR-Acb, and explored the factors influencing patients' 30-day mortality.A 1:1 case (n = 106; receiving TGC plus AS-CMS) control (receiving AS-CMS alone with matching scores) observational study was conducted among adult patients with non-bacteremic XDR-Acb complex pneumonia in a Taiwanese medical center from January 2014 through December 2016. The clinically relevant data were retrospectively recorded. The primary endpoint was 30-day case fatality. Secondary endpoints investigated that if the co-morbidities, XDR-A. baumannii as a pneumonic pathogen, therapy-related factors, or airway colonization with colistin-resistant Acb negatively influenced the 14-day clinical condition of enrolled patients.A higher 30-day mortality rate was noted among the group receiving combination therapy (34.0% vs 22.6%; P = .17). The ≥7-day AS-CMS therapy successfully eradicated > 90% of airway XDR-Acb isolates. Nevertheless, follow-up sputum specimens from 10 (6.4% [10/156]) patients were colonized with colistin-resistant Acb isolates. After the conditional factors were adjusted by multivariate logistic analysis, the only factor independently predicting the 30-day case-fatality was the failure of treating XDR-Acb pneumonia at 14 days (adjusted odds ratio [aOR] = 38.2; 95% confidence interval [CI] = 9.96-142.29; P < .001). Cox proportional regression analysis found that chronic obstructive pulmonary disease (COPD) (adjusted hazard ratio [aHR] = 2.08; 95% CI = 1.05-4.10; P = .035), chronic renal failure (aHR = 3.00; 95% CI = 1.52-5.90; P = .002), non-invasive ventilation use (aHR = 2.68; 95% CI = 1.37-5.25; P = .004), and lack of TGC therapy (aHR = 0.52; 95% CI = 0.27-1.00; P = .049) adversely influenced the 14-day clinical outcomes. Conversely, the emergence of colistin-resistant Acb isolates in the follow-up sputum samples was not statistically significantly associated with curing or improving XDR-Acb pneumonia.In conclusion, aggressive pulmonary hygiene care, the addition of TGC, and corticosteroid dose tapering were beneficial in improving the 14-day patients' outcomes.

Adverse events of high-dose tigecycline in the treatment of ventilator-associated pneumonia due to multidrug-resistant pathogens.

The off-label uses of tigecycline (TGC) to treat ventilator-associated pneumonia (VAP) have aroused worldwide concerns. The efficacy about TGC has been recently reported. However, the adverse events (AEs) remain controversial. Our study aims to analyze the safety of the high-dose (HD) regimens in the treatment of VAP due to multidrug-resistant (MDR) pathogens.The clinical data of 134 patients who were diagnosed with VAP from January 2013 to December 2015 in the NeuroScience Care Unit (NCU) were analyzed retrospectively. The incidence and the occurrence time of AEs, 28-day mortality, and the factors of clinical effectiveness were explored.A total of 54 patients received the standard dose group (SD), 69 in the HD, and 11 in the nonstandard HD group (NHD). Acinetobacter baumannii were the main pathogenic bacteria. There was no statistic difference in the incidence of AEs and the 28-day mortality among the 3 groups (P > .05). Total bilirubin (TBIL) increased significantly after SD of TGC treatment (P = .004). Liver dysfunction occurred the latest (10.83 ±â€Š7.08), not in the duration of HD group (9.63 ±â€Š3.92), whereas in the SD group (13.00 ±â€Š7.57) and NHD group (12.64 ±â€Š3.70). Patients with septic shock, MODS, and higher APACHE II score were of high risk in mortality. The HD group was associated with higher clinical effective rate and bacteria clearance rate.HD TGC was relatively safe and tolerable in ICU patients. The risk of side effects was related to the TGC duration, although not increased as the dosage rose. Full course of the HD regimen was associated with better outcomes for the treatment of VAP patients, especially for the MDR gram-negative bacilli infection. Inappropriate antimicrobial treatment might lead to clinical treatment failure.

Comparison of virulence between matt and mucoid colonies of Klebsiella pneumoniae coproducing NDM-1 and OXA-232 isolated from a single patient.

Nine Klebsiella pneumoniae isolates coproducing NDM-1 and OXA-232 carbapenemases were successively isolated from a single patient. Although they were isolated simultaneously and were isogenic, they presented different colony phenotypes (matt and mucoid). All nine isolates were resistant to most antibiotics except colistin and fosfomycin. In addition, matt-type isolates were resistant to tigecycline. No differences were detected in the cps cluster sequences, except for the insertion of IS5 in the wzb gene of two matt-type isolates. In vitro virulence assays based on production of capsular polysaccharide, biofilm formation, and resistance to human serum indicated that the mucoid-type isolates were significantly more virulent than the matt-type. In addition, mucoid-type isolates showed higher survival rates than the matt-type ones in infection experiments in the fruit fly, suggesting a higher virulence of K. pneumoniae isolates with a mucoid phenotype. To our knowledge, this is the first report of K. pneumoniae colonies with different phenotypes being isolated from the same sample. In addition, we show that virulence varies with colony phenotype. Dissemination of K. pneumoniae isolates expressing both antibiotic resistance and high virulence would constitute a great threat.

In vitro activity of eravacycline and comparator antimicrobials against 143 recent strains of Bacteroides and Parabacteroides species.

Eravacycline, a novel fluorocycline antibiotic, has been evaluated against complicated mixed aerobic/anaerobic intra-abdominal infections but scant supporting in vitro data against anaerobes has been published. We found that eravacycline had good anaerobic in vitro activity with MICs of 4 µg/ml or less against all Bacteroides and Parabacteroides strains tested, except for two B. ovatus strains that had MICs of 8 µg/ml and one strain that had an MIC of 16 µg/ml. Eravacycline was four-to-eight fold more active than tigecycline.

Evolution of tigecycline- and colistin-resistant CRKP (carbapenem-resistant Klebsiella pneumoniae) in vivo and its persistence in the GI tract.

Emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) strains that also exhibit resistance to tigecycline and colistin have become a major clinical concern, as these two agents are the last-resort antibiotics used for treatment of CRKP infections. A leukemia patient infected with CRKP was subjected to follow-up analysis of variation in phenotypic and genotypic characteristics of CRKP strains isolated from various specimens at different stages of treatment over a period of 3 years. Our data showed that (1) carbapenem treatment led to the emergence of CRKP in the gastrointestinal (GI) tract of the patient, which subsequently caused infections at other body sites as well as septicemia; (2) treatment with tigecycline led to the emergence of tigecycline-resistant CRKP, possibly through induction of the expression of a variant tet(A) gene located in a conjugative plasmid; (3) colistin treatment was effective in clearing CRKP from the bloodstream but led to the emergence of mcr-1-positive Enterobacteriaceae strains as well as colistin-resistant CRKP in the GI tract due to inactivation of the mgrB gene; and (4) tigecycline- and colistin-resistant CRKP could persist in the human GI tract for a prolonged period even without antibiotic selection pressure. In conclusion, clinical CRKP strains carrying a conjugative plasmid that harbors the blaKPC-2 and tet(A) variant genes readily evolve into tigecycline- and colistin-resistant CRKP upon treatment with these two antibiotics and persist in the human GI tract.

[Safety and Effectiveness of High Dose Tigecycline for Treating Patients with Acute Leukemia after Ineffctiveness of Carbapenems Chemotherapy Combinating with Febrile Neutropenia: Retrospective study].

OBJECTIVE: To investigate the safety and efficacy of high dose tigecycline for treatment of fibric neutrope-nia in acute leukemia patients after ineffectiveness of carbapenems chemotherapy of acute leukemia. METHODS: The clinical data of 41 acute leukemia patients with febrile ncutropenia received high dose tigecycline (100 mg q12h), who showed ineffectiveness of treatment with carbapenems, from 20151.30-2017.1. 29 in our hospital were collected and analyzed retrospectively. The temperature, inflammatory indicators as well as hepatic and renal function before and after treatment with tigecycline were compared. RESULTS: Among 41 patients treated with tigecycline due to ineffectiveness of treatment with carbapenems, the infection had been controled in 34 cases, 7 patients died due to ineffectiveness of anti-infective treatment, these patients all were patients with relapse/refractory leukemia. 41 patients were examined etialogically, as a result, 22 patients showed possitive, among them the gram-negative bacill was found in 11(11/22) cases. The average deferves counce time of tigecycline was 28.2±12.0 hours. The temperature of patients treated with tigecycline for 48 hours decreased significantly (P<0.05). There were no significant differences in calcitonin and C-reactive protein levels after treatment with tigecycline (P>0.05), but cacitonin level displayed decrease tread. There was no hepatic and renal impairment after treatment with tigecycline, but levels of as partate aminotransferase, total bilirubin and blood area nitrogen in blood significantly increased as compared with levels before treatment with tigecycline (P<0.05). CONCLUSION: The application of high dose tigecycline for treatment of febrile neutropenia is safety and effective. The high dose tigecycline can decrease the temperature, calcitonin and C-reactive protein levels, and can control infection without the hepatic and renal impairment, but it needs to be confimed by more prospective studies.

In vitro analysis of the minimal inhibitory concentration values of different generations of anti-methicillin-resistant Staphylococcus aureus antibiotics.

Methicillin-resistant Staphylococcus aureus (MRSA) resistance to antimicrobials may result in the increased risk of treatment failure. The objective of the study was to analyse in vitro MRSA susceptibility to vancomycin, linezolid, daptomycin, tigecycline, ceftaroline, dalbavancin, clindamycin, ciprofloxacin and trimethoprim/sulfamethoxazole. All MRSA strains isolated from hospitalised patients were analysed according to the current microbiological recommendations. Finally, a total of 124 MRSA strains were analysed; all were susceptible to tested antibiotics. Dalbavancin had the lowest minimum inhibitory concentration (MIC), and vancomycin the highest MIC value. There were 28/124 strains of MRSA susceptible for clindamycin, 36/124 for ciprofloxacin and 121/124 for trimethoprim/sulfamethoxazole. Dalbavancin was the most effective antimicrobial in our study.

Tigecycline resistance among Klebsiella pneumoniae isolated from febrile neutropenic patients.

Febrile neutropenic patients are at a high risk of life-threatening bacterial infections. Tigecycline was developed to treat multidrug-resistant isolates, however resistance to tigecycline in Klebsiella pneumoniae has been reported. Here, we investigated tigecycline resistance among K. pneumoniae isolated from febrile neutropenic patients admitted to Hematology ICU, Egypt. Out of 75 enrolled febrile neutropenic patients, 48 cases showed bacteriologically confirmed infection. The majority of cases were infected with K. pneumoniae, of which nine were tigecycline non-susceptible. Expression levels of the efflux pump genes acrB and oqxB and their regulatory genes ramA and rarA were analysed. Six isolates had overexpression of the four efflux-related genes while one showed baseline expression. This study emphasizes the importance of growing tigecycline resistance in K. pneumoniae infecting febrile neutropenic patients. Concerning the mechanism of resistance, it was clear that the ramA gene plays the major role, although alternative resistance mechanisms may also exist.

Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program.

A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014-2016 were screened for the presence of the plasmid-borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations. Genes from the mcr-3 family were found in isolates from Thailand, including mcr-3.1 (n = 3) and mcr-3.2 (n = 1). An E. coli isolated from a patient with a urinary tract infection in Colombia contained the recently discovered mcr-5. The full colistin-resistant collection was tested against a panel of antimicrobial agents with ceftazidime-avibactam and tigecycline exhibiting the highest activity.

In vitro activity of tigecycline and comparators against a European collection of anaerobes collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) 2010-2016.

The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global program that aims to monitor the in vitro antimicrobial activities of current therapeutic agents against clinical isolates. This study presents surveillance data for Gram-positive and Gram-negative anaerobic isolates (N = 7008) collected from nine European countries between 2010 and 2016. Presented in this study are antimicrobial susceptibility data, according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST) breakpoints, and minimum inhibitory concentration (MIC) distributions. The antimicrobial agents tested were cefoxitin (Gram-negative isolates only), clindamycin, meropenem, metronidazole, penicillin (Gram-positive isolates only), piperacillin-tazobactam and tigecycline. Among all Gram-positive and Gram-negative anaerobes, the lowest rates of resistance were to meropenem and metronidazole (0.0%-1.7% and 0.0%-1.9%, respectively). High rates of resistance were reported to clindamycin, in particular among isolates of the Bacteroides fragilis group (22.1%-48.1%) and Prevotella spp. (10.9%-32.2%). The majority of MIC distributions were unimodal, with the exception of clindamycin, which were mostly bimodal. Fifty percent of Gram-negative isolates gave tigecycline MICs between 0.06 and 1 mg/L, and 50% of Gram-positive isolates exhibited tigecycline MICs between 0.06 and 0.25 mg/L. The findings of this study suggest that the majority of anaerobic isolates were susceptible to meropenem and metronidazole, and that tigecycline remained active, but clindamycin resistance is a cause for concern in Europe. Surveillance studies, such as T.E.S.T., provide information on changes in the susceptibility of clinically important pathogens to commonly prescribed antimicrobial agents, and can highlight problems of antimicrobial resistance that need to be addressed.

Contributions of ferric uptake regulator Fur to the sensitivity and oxidative response of Acinetobacter baumannii to antibiotics.

Ferric uptake regulator (Fur) is important in the regulation of bacterial iron metabolism and uptake of Fe from the environment. We evaluated the contribution of fur to the sensitivity and oxidative response of A. baumannii to antibiotics. Deletion of fur increased the sensitivity of A. baumannii AB5075 to colistin, gentamicin, rifampicin and tigecycline. Furthermore, activities of superoxide dismutase and catalase in Δfur mutant decreased significantly compared to the parental strain. Conversely, •O2- and H2O2 accumulate in colistin, gentamicin, rifampicin or tigecycline-treated Δfur mutant compared to the parental strain. Ferrous ion (Fe2+) content of Δfur mutant increased compared to the parental strain. Fe chelator 2,2'-bipyridyl lowered the sensitivity of A. baumannii to the antibiotics. The antibiotics, except tigecycline, raised the NAD+/NADH and ADP/ATP ratio of Δfur mutant compared to the WT. Glutathione content of Δfur mutant was significantly depleted compared to parental strain following exposure to the antibiotics. We conclude that decreased capability of Δfur mutant to detoxify reactive oxygen species raised its susceptibility to antibiotics through Fenton chemistry.

Analysis of global prevalence of antibiotic resistance in Acinetobacter baumannii infections disclosed a faster increase in OECD countries.

Acinetobacter baumannii is one of the most challenging nosocomial pathogens due to the emergence and widespread of antibiotic resistance. We aimed to provide the first analysis of global prevalence of antibiotic resistance in A. baumannii infections, by synthesizing data and knowledge through a systematic review. We searched studies reporting antibiotic resistance in A. baumannii infections using the Medline, Embase, Web of Science, and Cochrane databases from January 2000 to December 2016. Studies were eligible if they investigated and reported antibiotic resistance in A. baumannii infections with inpatients or outpatients in hospital. Our investigation showed a high prevalence of resistance to the common prescribed antibiotics in A. baumannii infections in both OECD (Organization for Economic Co-operation and Development) and non-OECD countries. Strikingly, though OECD countries have substantially lower pooled prevalence of resistance compared to non-OECD countries based on the data during 2006-2016, a further investigation in a time scale disclosed a faster increase in OECD countries during the past 11 years, and currently both of them have a comparable prevalence of resistance (2011-2016). Tigecycline and colistin are still active but their resistances are expected to become common if the preventative measures are not taken. Antibiotic resistance in A. baumannii infection developed fast and is a crisis for both OECD and non-OECD countries. A "post-antibiotic era" for A. baumannii infection is expected in the next 10-20 years without immediate actions from pharmaceutical companies and governments.