BACKGROUND: Acinetobacter baumannii (A. baumannii) is an opportunistic pathogenic bacterium mainly associated with hospital acquired infections and in immunocompromised individuals who stay in hospitals for a long time. In recent years, it has become increasingly resistant to many different types of antibiotics. The production of the metallo-beta-lactamase (MBL) enzyme is one of the primary causes of this resistance. This study aimed to detect the presence of MBL genes that belong to the verona integrin metallo-β-lactamase (bla-VIM) and imipenemase (bla-IMP) groups in the isolates of Acinetobacter baumannii from burn patients.
METHODS: One hundred and seventeen (117) isolates of A. baumannii were obtained from patient specimens using traditional methods followed by using the VITEK 2 (BioMérieux, Les Pennes-Mirabeau, France) identification system. Metallo β-lactamases were detected in the imipenem-resistant strains by using imipenem disks on Muller-Hinton agar. The polymerase chain reaction (PCR) technique was utilized to examine 117 isolates for the detection of MBLs encoding genes such as bla-VIM, and bla-IMP.
RESULTS: Imipenem resistance was detected in 78.6% of the patients. The PCR assays of the isolates identified bla-VIM-1, bla-VIM-2, bla-IMP-1 and bla-IMP-2 genes at the rates of 17%, 40.1%, 29.9% and 4.2%, respectively.
CONCLUSIONS: The findings suggest that the majority of A. baumannii isolates harbour one or more of the detected genes, signifying that the production of MBLs plays a pivotal role in resistance mechanisms.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients\' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.

BACKGROUND: The objective of this study was to study the effect of Klebsiella-specific phage isolated from sewage with and without the combination of antibiotics (imipenem) on the growth of clinical isolates of multidrug-resistant Klebsiella pneumoniae by time-kill assay and also to study the effect of bacteriophage and bacteriophage-antibiotic (imipenem) combination on biofilm production.
METHODS: A total of 40 MDR K. pneumoniae isolates were used. Klebsiella-specific phage was isolated using K. pneumoniae subspp. pneumoniae ATCC 33495 as the host from sewage. In vitro time kill curve assays were performed to evaluate the effect of Klebsiella-specific phage with and without the combination of antibiotics on the viable cell counts of MDR K. pneumoniae isolates. Microtiter plate method of O\'Toole and Kolter was used to study the effect of Klebsiella-specific phage with and without the combination of antibiotics on biofilm production. For the Time kill assay, results were analyzed for significant differences using Friedman test. Tests for significant differences between the different groups were found using the Mann-Whitney U test. The correlation between the formation of biofilm was analyzed using Karl Pearson\'s coefficient of correlation. P value of <0.05 was considered to be statistically significant.
RESULTS: In vitro time-kill assay showed a 0.4 log decline and a 0.5 log decline in K. pneumoniae colony counts at 4 h, when phage was administered individually and in combination with imipenem, respectively (p < 0.001). Phage and phage-imipenem combinations reduced the ability of K. pneumoniae to produce biofilm by 38 % and 53 %, respectively.
CONCLUSIONS: In conclusion, this study suggests that phage therapy has inhibiting activity against MDR K. pneumoniae. It is found to reduce bacterial cell count and biofilm formation but does not have a total cidal effect. However, in order to get a notable result, a phage cocktail or combination of phage with other antibiotic(s) is suggested.

BACKGROUND: Prediction of antibiotic non-susceptibility based on patient characteristics and clinical status may support selection of empiric antibiotics for suspected hospital-acquired urinary tract infections (HA-UTIs).
METHODS: Prediction models were developed to predict non-susceptible results of eight antibiotic susceptibility tests ordered for suspected HA-UTI. Eligible patients were those with urine culture and susceptibility test results after 48 hours of admission between 2010-2021. Patient demographics, diagnosis, prescriptions, exposure to multidrug-resistant organisms, transfer history, and a daily calculated antibiogram were used as predictors. Lasso logistic regression (LLR), extreme gradient boosting (XGB), random forest, and stacked ensemble methods were used for development. Parsimonious models were also developed for clinical utility. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC).
RESULTS: In 10 474 suspected HA-UTI cases, the mean age was 62.1 ± 16.2 years and 48.1% were male. Non-susceptibility prediction for ampicillin/sulbactam, cefepime, ciprofloxacin, imipenem, piperacillin/tazobactam, and trimethoprim/sulfamethoxazole performed best using the stacked ensemble (AUROC 76.9, 76.1, 77.0, 80.6, 76.1, and 76.5, respectively). The model for ampicillin performed best with LLR (AUROC 73.4). Extreme gradient boosting only performed best for gentamicin (AUROC 66.9). In the parsimonious models, the LLR yielded the highest AUROC for ampicillin, ampicillin/sulbactam, cefepime, gentamicin, and trimethoprim/sulfamethoxazole (AUROC 70.6, 71.8, 73.0, 65.9, and 73.0, respectively). The model for ciprofloxacin performed best with XGB (AUROC 70.3), while the model for imipenem performed best in the stacked ensemble (AUROC 71.3). A personalised application using the parsimonious models was publicly released.
CONCLUSIONS: Prediction models for antibiotic non-susceptibility were developed to support empiric antibiotic selection for HA-UTI.

UNASSIGNED: Machine learning is an important branch and supporting technology of artificial intelligence, we established four machine learning model for the drug sensitivity of Klebsiella pneumoniae to imipenem based on matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and compared their diagnostic effect.
UNASSIGNED: The data of MALDI-TOF-MS and imipenem sensitivity of 174 cases of K. pneumoniae isolated from clinical specimens in the laboratory of microbiology department of Tianjin Haihe Hospital from 2019 January to 2020 December were collected. The mass spectrometry and imipenem sensitivity of 70 cases of imipenem-sensitive and 70 resistant cases were randomly selected to establish the training set model, 17 cases of sensitive and 17 cases of resistant cases were randomly selected to establish the test set model. Mass spectral peak data were subjected to orthogonal partial least squares discriminant analysis (OPLS-DA), the training set data model was established by machine learning least absolute shrinkage and selection operator (LASSO) algorithm, logistic regression (LR) algorithm, support vector machines (SVM) algorithm, neural network (NN) algorithm, the area under the curve (AUC) and confusion matrix of training set and test set model were calculated and selected by Grid search and 3-fold Cross-validation respectively, the accuracy of the prediction model was verified by test set confusion matrix.
UNASSIGNED: The R²Y and Q² of OPLS-DA were 0.546 and 0.0178. The AUC of the best training set and test set models were 0.9726 and 0.9100, 1.0000 and 0.8581, 0.8462 and 0.6263, 1.0000 and 0.7180 evaluated by LASSO, LR, SVM and NN model respectively. The accuracy of the LASSO, LR, SVM and NN model were 87%, 79%, 62%, and 68% in test set, respectively.
UNASSIGNED: The LASSO prediction model of K. pneumoniae sensitivity to imipenem established in this study has a high accuracy rate and has potential clinical decision support ability.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

UNASSIGNED: In the RESTORE-IMI 2 trial, imipenem/cilastatin/relebactam (IMI/REL) was noninferior to piperacillin/tazobactam in treating hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. This post hoc analysis was conducted to determine independent predictors of efficacy outcomes in the RESTORE-IMI 2 trial, to assist in treatment decision making.
UNASSIGNED: A stepwise multivariable regression analysis was conducted to identify variables that were independently associated with day 28 all-cause mortality (ACM), favorable clinical response at early follow-up (EFU), and favorable microbiologic response at end of treatment (EOT). The analysis accounted for the number of baseline infecting pathogens and in vitro susceptibility to randomized treatment.
UNASSIGNED: Vasopressor use, renal impairment, bacteremia at baseline, and Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) II scores ≥15 were associated with a greater risk of day 28 ACM. A favorable clinical response at EFU was associated with normal renal function, an APACHE II score <15, no vasopressor use, and no bacteremia at baseline. At EOT, a favorable microbiologic response was associated with IMI/REL treatment, normal renal function, no vasopressor use, nonventilated pneumonia at baseline, intensive care unit admission at randomization, monomicrobial infections at baseline, and absence of Acinetobacter calcoaceticus-baumannii complex at baseline. These factors remained significant after accounting for polymicrobial infection and in vitro susceptibility to assigned treatment.
UNASSIGNED: This analysis, which accounted for baseline pathogen susceptibility, validated well-recognized patient- and disease-related factors as independent predictors of clinical outcomes. These results lend further support to the noninferiority of IMI/REL to piperacillin/tazobactam and suggests that pathogen eradication may be more likely with IMI/REL.
UNASSIGNED: NCT02493764.

Mycobacterium abscessus (MABS) is the most pathogenic and drug-resistant rapidly growing mycobacteria. However, studies on MABS epidemiology, especially those focusing on subspecies level, are scarce. We aimed to determine MABS subspecies distribution and its correlation with phenotypic and genotypic antibiotic profiles. A retrospective multicenter study of 96 clinical MABS isolates in Madrid between 2016 to 2021 was conducted. Identification at the subspecies level and resistance to macrolides and aminoglycosides were performed by the GenoType NTM-DR assay. The MICs of 11 antimicrobials tested against MABS isolates were determined using the broth microdilution method (RAPMYCOI Sensititer titration plates). Clinical isolates included 50 (52.1%) MABS subsp. abscessus; 33 (34.4%) MABS subsp. massiliense; and 13 (13.5%) MABS subsp. bolletii. The lowest resistance rates corresponded to amikacin (2.1%), linezolid (6.3%), cefoxitin (7.3%), and imipenem (14.6%), and the highest to doxycycline (100.0%), ciprofloxacin (89.6%), moxifloxacin (82.3%), cotrimoxazole (82.3%), tobramycin (81.3%), and clarithromycin (50.0% at day 14 of incubation). Regarding tigecycline, although there are no susceptibility breakpoints, all strains but one showed MICs ≤ 1 μg/mL. Four isolates harbored mutations at positions 2058/9 of the rrl gene, one strain harbored a mutation at position 1408 of the rrl gene, and 18/50 harbored the T28C substitution at erm(41) gene. Agreement of the GenoType results with clarithromycin and amikacin susceptibility testing was 99.0% (95/96). The rate of MABS isolates showed an upward trend during the study period, being M. abscessus subsp. abscessus the most frequently isolated subspecies. Amikacin, cefoxitin, linezolid, and imipenem showed great in vitro activity. The GenoType NTM-DR assay provides a reliable and complementary tool to broth microdilution for drug resistance detection. IMPORTANCE Infections caused by Mycobacterium abscessus (MABS) are increasingly being reported worldwide. Identifying MABS subspecies and assessing their phenotypic resistance profiles are crucial for optimal management and better patient outcomes. M. abscessus subspecies differ in erm(41) gene functionality, which is a critical determinant of macrolide resistance. Additionally, resistance profiles of MABS and the subspecies distribution can vary geographically, highlighting the importance of understanding local epidemiology and resistance patterns. This study provides valuable insights into the epidemiology and resistance patterns of MABS and its subspecies in Madrid. Elevated resistance rates were observed for several recommended antimicrobials, emphasizing the need for cautious drug use. Furthermore, we assessed the GenoType NTM-DR assay, which examines principal mutations in macrolides and aminoglycosides resistance-related genes. We observed a high level of agreement between the GenoType NTM-DR assay and the microdilution method, indicating its usefulness as an initial tool for early initiation of appropriate therapy.

Pseudomonas aeruginosa can develop resistance. Therefore, it is necessary to design proper treatment for it. Pseudomonas aeruginosa can develop resistance against levofloxacin due to the development of efflux pumps. However, the development of these efflux pumps cannot develop resistance against imipenem. Additionally, the MexCDOprJ efflux system which is responsible for the resistance of Pseudomonas aeruginosa to levofloxacin is highly susceptible to imipenem. The objective of the study was to evaluate the emergence of resistance of Pseudomonas aeruginosa against 750 mg levofloxacin, 250 mg imipenem, and a combination of 750 mg levofloxacin and 250 mg imipenem. An in vitro pharmacodynamic model was selected for the evaluation of the emergence of resistance. Pseudomonas aeruginosa strain 236, Pseudomonas aeruginosa strain GB2, and Pseudomonas aeruginosa strain GB65 were selected. Susceptibility testing of both antibiotics was done by agar dilution methodology. A disk diffusion bioassay was performed for antibiotics. RT-PCR measurement was done for the evaluation of expressions of Pseudomonas aeruginosa genes. Samples were tested at 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, and 30 h. Levofloxacin and imipenem both individually reported a decrease in colony-forming unit per milliliter of strength in the initial stage but in the later stage both develop resistance individually. Levofloxacin with imipenem had no resistance to Pseudomonas aeruginosa during 30 h. Time after the start of development of resistance or decrease in clinical efficacy was higher for levofloxacin and imipenem combination in all strains. The concentration of Pseudomonas aeruginosa at the time after the start of development of resistance or decrease in clinical efficacy was fewer for levofloxacin and imipenem combination. Levofloxacin with imipenem is recommended for the treatment of infection due to Pseudomonas aeruginosa.

Background and Objectives: Acute cholangitis (AC) is still lethal if not treated promptly and effectively. Biliary drainage, also known as source control, has been acknowledged as the backbone treatment for patients with AC; nonetheless, antimicrobial therapy allows these patients to undergo non-emergent drainage procedures. This retrospective study aims to observe the bacterial species involved in AC and analyze the antimicrobial resistance patterns. Materials and Methods: Data were collected for four years, comparing patients with benign and malignant bile duct obstruction as an etiology for AC. A total of 262 patients were included in the study, with 124 cases of malignant obstruction and 138 cases of benign obstruction. Results: Positive bile culture was obtained in 192 (73.3%) patients with AC, with a higher rate among the benign group compared with malignant etiologies (55.7%.vs 44.3%). There was no significant difference between the Tokyo severity scores in the two study groups, identifying 34.7% cases of malignant obstruction with Tokyo Grade 1 (TG1) and 43.5% cases of TG1 among patients with benign obstruction. Similarly, there were no significant differences between the number of bacteria types identified in bile, most of them being monobacterial infections (19% in the TG1 group, 17% in the TG2 group, and 10% in the TG3 group). The most commonly identified microorganism in blood and bile cultures among both study groups was E. coli (46.7%), followed by Klebsiella spp. (36.0%) and Pseudomonas spp. (8.0%). Regarding antimicrobial resistance, it was observed that significantly more patients with malignant bile duct obstruction had a higher percentage of bacterial resistance for cefepime (33.3% vs. 11.7%, p-value = 0.0003), ceftazidime (36.5% vs. 14.5%, p-value = 0.0006), meropenem (15.4% vs. 3.6%, p-value = 0.0047), and imipenem (20.2% vs. 2.6%, p-value < 0.0001). Conclusions: The positive rate of biliary cultures is higher among patients with benign biliary obstruction, while the malignant etiology correlates with increased resistance to cefepime, ceftazidime, meropenem, and imipenem.