In Vitro Activity of Auranofin in Combination With Aztreonam-Avibactam Against Metallo-ß-lactamase (MBL)-Producing Enterobacterales.

Objectives: To assess the efficacy of aztreonam-avibactam-auranofin (ATM-AVI-AUR) against a collection of 88 carbapenemase-producing Enterobacterales (CPE) clinical isolates and 6 in vitro selected ATM-AVI-resistant CPE with CMY-16 Tyr150Ser and Asn346His mutants or transformants. Methods: MICs of imipenem, ceftazidime-avibact8am (CAZ-AVI), ATM-AVI, CAZ-AVI-AUR and ATM-AVI-AUR were determined via the broth microdilution method. Genetic background and carbapenemase genes were determined by PCR and Sanger sequencing. Results: AUR alone showed little antibacterial activity with AUR MICs were greater than 64 µg/mL for all the 88 clinical CPE isolates. The addition of AUR (16 µg/mL) resulted in an 3-folding dilutions MIC reduction of ATM-AVI MIC50 (0.5 to 0.0625 µg/mL) and a 2-folding dilutions MIC reduction of MIC90 (1 to 0.25 µg/mL) against all 88 clinical CPE isolates, respectively. Notably, the reduced ATM-AVI MIC values were mainly found in MBL-producers, and the MIC50 and MIC90 reduced by 2-folding dilutions (0.25 to 0.0625 µg/mL) and 3-folding dilutions (2 to 0.25 µg/mL) respectively by AUR among the 51 MBL-producers. By contrast, the addition of AUR did not showed significant effects on ATM-AVI MIC50 (0.0625 µg/mL) and MIC90 (0.125 µg/mL) among single KPC-producers. Interestingly, the addition of AUR restored the ATM-AVI susceptibility against the 6 in vitro selected ATM-AVI-resistant CMY-16 Tyr150Ser and Asn346His mutants or transfromants, with the MICs reduced from ≥32 µg/mL (32->256 µg/mL) to ≤8 µg/mL (0.0625-8 µg/mL). Conclusions: Our results demonstrated that AUR potentiated the activities of CAZ-AVI and ATM-AVI against MBL-producing isolates in vitro. Importantly, AUR restored the ATM-AVI activity against ATM-AVI resistant mutant strains. As a clinically approved drug, AUR might be repurposed in combination with ATM-AVI to treat infections caused by highly resistant MBL-producing Enterobacterales.

Resistance Trends of Klebsiella pneumoniae Causing Urinary Tract Infections in Chongqing, 2011-2019.

PURPOSE: To analyze the characteristics and trends of drug resistance for Klebsiella pneumoniae (K. pneumoniae), isolated from urinary tract infections (UTIs), to common antibiotics used in clinics. METHODS: This retrospective study was conducted in a teaching hospital in Chongqing from 2011 to 2019. Laboratory data of isolated bacteria were collected and analyzed. RESULTS: Among the 17,966 non-repetitive strains isolated from the urine sample, a total of 1543 K. pneumoniae isolates were identified, with an isolation frequency secondary only to Escherichia coli (E. coli) and there was a peak in the K. pneumoniae isolates in the year 2013. During the period, the rate of extended-spectrum ß-lactamase (ESBL)-producing K. pneumoniae fell from 48.4% in 2011 to 32.9% in 2019, and a marked jump of resistance was seen in carbapenems from 2.2% to 18.0%. The peak of carbapenem resistance rate (22.6%) to K. pneumoniae was observed in 2017 along with a low ESBL-producing rate (30.9%). Piperacillin/tazobactam and cefepime resistance levels went up from 4.4% to 25.7% and from 18.2% to 30.5%, respectively. Moreover, the K. pneumoniae isolates resistance rate to carbapenems and amikacin gradually grew up, showing their peaks in 2017, and then dropped year by year. However, ceftazidime and aztreonam resistance levels were relatively stable, fluctuating between 21.8% and 35.6%, 32.2% and 39.4%, respectively. CONCLUSION: There is a significant upward tendency in carbapenem resistance rate and a downward tendency in ESBL-production rate in K. pneumoniae isolates from UTIs, and continuous surveillance is necessary in the future.

Multidrug Resistance Mechanisms of Carbapenem Resistant Klebsiella pneumoniae Strains Isolated in Chongqing, China.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is considered a serious global threat. However, little is known regarding the multidrug resistance (MDR) mechanisms of CRKP. This study investigated the phenotypes and MDR mechanisms of CRKP and identified their clonal characteristics. METHODS: PCR and sequencing were utilized to identify antibiotic resistance determinants. Integron gene cassette arrays were determined by restriction fragment length polymorphism (RFLP) analysis. Multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were used for epidemiological analysis. Plasmids were typed by using a PCR-based replicon typing and analyzed by conjugation and transformation assays. RESULTS: Seventy-eight strains were identified as resistant to at least one carbapenem; these CRKP strains had a high prevalence rate (38.5%, 30/78) of carbapenemase producers. Additionally, most isolates harbored MDR genes, including Extended spectrum ß-lactamases (ESBLs), AmpC, and quinolone and aminoglycoside resistance genes. Loss of porin genes was observed, and Class 1 integron was detected in 66.7% of the investigated isolates. PFGE and MLST results excluded the occurrence of clonal dissemination among these isolates. CONCLUSIONS: A high prevalence of NDM-1 genes encoding carbapenem resistance determinants was demonstrated among the K. pneumoniae isolates. Importantly, this is the first report of bla(NDM-1) carriage in a K. pneumoniae ST1383 clone in China and of a MDR CRKP isolate co-harboring bla(NDM-1), bla(KPC-2), bla(CTX-M), bla(SHV), acc(6')-Ib, rmtB, qnrB, and acc(6')-Ib-cr.

Epidemiology, antifungal susceptibilities, and risk factors for invasive candidiasis from 2011 to 2013 in a teaching hospital in southwest China.

BACKGROUND: Invasive candidiasis (IC) is the most common cause of invasive fungal infections. Identification of risk factors for such infection may help in the empirical therapeutic decision-making process. We conducted this study to characterize the clinical epidemiology of such infection and to differentiate risk factors between Candida albicans and Candida non-albicans species. METHODS: We retrospectively evaluated patients with IC from 2011 to 2013. Clinical data, antibiotic therapy, underlying condition, and invasive procedures were analyzed and compared between C. albicans and C. non-albicans species. RESULTS: C. albicans was the most frequently isolated Candida species (48.6% of all IC patients), although C. non-albicans spp. were more commonly isolated overall. C. albicans, Candida tropicalis, and Candida parapsilosis have a high susceptibility rate to all antifungal agents (>90%), whereas Candida glabrata showed decreased susceptibility to fluconazole and itraconazole. Amphotericin B demonstrated excellent antifungal activity against all Candida species. Univariate analyses showed that IC patients with C. albicans had a higher ratio of older age (p = 0.008), solid tumor (p = 0.029), and hypoproteinemia (p = 0.019), whereas those with C. non-albicans spp. had a higher ratio of hospital length of stay (p = 0.005), usage of corticosteroids (p = 0.011), duration on corticosteroids (p = 0.005), chemotherapy (p = 0.022), hematologic malignancy (p = 0.039), neutropenia (p = 0.030), and usage of glycopeptides (p = 0.002). Multivariate analyses showed that a significant predictor of IC due to C. albicans was hypoproteinemia [odds ratio (95% confidence interval) = 2.133 (1.164-3.908), p = 0.014]. CONCLUSION: C. albicans was the most frequently isolated Candida species. The risk factors between C. albicans and C. non-albicans species are different.

Characterization of carbapenemases, extended spectrum ß-lactamases, quinolone resistance and aminoglycoside resistance determinants in carbapenem-non-susceptible Escherichia coli from a teaching hospital in Chongqing, Southwest China.

Carbapenem-resistant Escherichiacoli isolates harboring carbapenemases or combining an extended-spectrum ß-lactamase (ESBL) enzyme with loss of porins present an increasingly urgent clinical danger. Combined resistance to aminoglycosides and fluoroquinolones in carbapeneme non-susceptible (CNS) isolates will inevitably create problems. In the current study, we characterized the carbapenemases and ESBLs, and the prevalence of quinolone resistance determinants and aminoglycoside resistance determinants in carbapenem-non-susceptible (CNS) E.coli isolates from a teaching hospital in Chongqing, Southwest China in 2012. Thirty non-duplicated CNS E.coli isolates were screened via antimicrobial susceptibility testing, and the drug resistance profiles of the 30 strains were analyzed. Carbapenemase genes blaKPC-2, ESBL genes including blaCTX-M-3, blaCTX-M-14, blaCTX-M-55 and blaTEM, ARD genes including aac(6')-Ib, armA and rmtB, and QRD genes including qnrA, qnrB, qnrC, qnrD, qnrS and aac(6')-Ib-cr were identified and clonal relatedness was investigated by pulsed-field gel electrophoresis. Of the 30 isolates, 2 (6.7%) harbored carbapenemase gene blaKPC-2; 29 (96.7%) carried ESBLs; 20 (66.7%) were QRD positive; and 11 (36.7%) were ARD positive. Between the two blaKPC-2 positive strains, one contained ESBL, QRD and ARD genes, while the other expressed ESBL genes but was negative for both QRD and ARD genes. Of the 29 ESBLs positive isolates, 2 (6.9%) were carbapenemase positive, 19 (65.5%) were QRD positive, and 11 (37.9%) were ARD positive. PFGE revealed genetic diversity among the 30 isolates, indicating that the high prevalence of CNS E. coli isolates was not caused by clonal dissemination. Production of ESBLs was associated with the carbapenem resistance and QRD genes were highly prevalent among the CNS E. coli isolates. Multiple resistant genes were co-expressed in the same isolates. This is the first report of a multidrug resistant carbapenem-non-susceptible E.coli co-harboring resistant determinants blaKPC-2, blaCTX-M-14, blaCTX-M-55, blaTEM, aac(6')-Ib-cr, qnrB, aac(6')-Ib and rmtB from Chongqing, mainland China.