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Background. Extensively drug-resistant (XDR) Acinetobacter baumannii may cause serious infections in critically ill patients. Colistin often remains the only therapeutic option. Addition of rifampicin to colistin may be synergistic in vitro. In this study, we assessed whether the combination of colistin and rifampicin reduced the mortality of XDR A. baumannii infections compared to colistin alone. Methods. This multicenter, parallel, randomized, open-label clinical trial enrolled 210 patients with life-threatening infections due to XDR A. baumannii from intensive care units of 5 tertiary care hospitals. Patients were randomly allocated (1:1) to either colistin alone, 2 MU every 8 hours intravenously, or colistin (as above), plus rifampicin 600 mg every 12 hours intravenously. The primary end point was overall 30-day mortality. Secondary end points were infection-related death, microbiologic eradication, and hospitalization length. Results. Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46–1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization. Conclusions. In serious XDR A. baumannii infections, 30-day mortality is not reduced by addition of rifampicin to colistin. These results indicate that, at present, rifampicin should not be routinely combined with colistin in clinical practice. The increased rate of A. baumannii eradication with combination treatment could still imply a clinical benefit. Clinical Trials Registration. NCT01577862.

Abstract Background We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P = .174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI}, .118–.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021–9.202]). Conclusions Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration NCT01732250 In a retrospective analysis of a randomized controlled trial, infection with carbapenem-resistant, colistin-resistant Acinetobacter baumannii was associated with lower mortality than carbapenem-resistant, colistin-susceptible Acinetobacter. Colistin-carbapenem combination therapy was associated with higher mortality than colistin monotherapy in patients with colistin-resistant isolates.

Acinetobacter baumannii is a nosocomial pathogen of increasing importance due to its multiple resistance to antibiotics and ability to survive in the hospital environment linked to its capacity to form biofilms. To fully characterize the contribution of AdeABC, AdeFGH, and AdeIJK resistance-nodulation-cell division (RND)-type efflux systems to acquired and intrinsic resistance, we constructed, from an entirely sequenced susceptible A. baumannii strain, a set of isogenic mutants overexpressing each system following introduction of a point mutation in their cognate regulator or a deletion for the pump by allelic replacement. Pairwise comparison of every derivative with the parental strain indicated that AdeABC and AdeFGH are tightly regulated and contribute to acquisition of antibiotic resistance when overproduced. AdeABC had a broad substrate range, including β-lactams, fluoroquinolones, tetracyclines-tigecycline, macrolides-lincosamides, and chloramphenicol, and conferred clinical resistance to aminoglycosides. Importantly, when combined with enzymatic resistance to carbapenems and aminoglycosides, this pump contributed in a synergistic fashion to the level of resistance of the host. In contrast, AdeIJK was expressed constitutively and was responsible for intrinsic resistance to the same major drug classes as AdeABC as well as antifolates and fusidic acid. Surprisingly, overproduction of AdeABC and AdeIJK altered bacterial membrane composition, resulting in decreased biofilm formation but not motility. Natural transformation and plasmid transfer were diminished in recipients overproducing AdeABC. It thus appears that alteration in the expression of efflux systems leads to multiple changes in the relationship between the host and its environment, in addition to antibiotic resistance. IMPORTANCE Increased expression of chromosomal genes for RND-type efflux systems plays a major role in bacterial multidrug resistance. Acinetobacter baumannii has recently emerged as an important human pathogen responsible for epidemics of hospital-acquired infections. Besides its remarkable ability to horizontally acquire resistance determinants, it has a broad intrinsic resistance due to low membrane permeability, endogenous resistance genes, and antibiotic efflux. The study of isogenic mutants from a susceptible A. baumannii clinical isolate overproducing or deleted for each of the three major RND-type pumps demonstrated their major contribution to intrinsic resistance and to the synergism between overproduction of an efflux system and acquisition of a resistance gene. We have also shown that modulation of expression of the structural genes for the efflux systems results in numerous alterations in membrane-associated cellular functions, in particular, in a decrease in biofilm formation and resistance gene acquisition. Increased expression of chromosomal genes for RND-type efflux systems plays a major role in bacterial multidrug resistance. Acinetobacter baumannii has recently emerged as an important human pathogen responsible for epidemics of hospital-acquired infections. Besides its remarkable ability to horizontally acquire resistance determinants, it has a broad intrinsic resistance due to low membrane permeability, endogenous resistance genes, and antibiotic efflux. The study of isogenic mutants from a susceptible A. baumannii clinical isolate overproducing or deleted for each of the three major RND-type pumps demonstrated their major contribution to intrinsic resistance and to the synergism between overproduction of an efflux system and acquisition of a resistance gene. We have also shown that modulation of expression of the structural genes for the efflux systems results in numerous alterations in membrane-associated cellular functions, in particular, in a decrease in biofilm formation and resistance gene acquisition.

The aim of this study was to compare the responses of colistin treatment alone vs. a combination of colistin and rifampicin in the treatment of ventilator-associated pneumonia (VAP) caused by a carbapenem-resistant A. baumannii strain. Forty-three patients were randomly assigned to one of two treatment groups. Although clinical (P = 0·654), laboratory (P = 0·645), radiological (P = 0·290) and microbiological (P = 0·597) response rates were better in the combination group, these differences were not significant. However, time to microbiological clearance (3·1 ± 0·5 days, P = 0·029) was significantly shorter in the combination group. The VAP-related mortality rates were 63·6% (14/22) and 38·1% (8/21) for the colistin and the combination groups (P = 0·171), respectively. Our results suggest that the combination of colistin with rifampicin may improve clinical and microbiological outcomes of VAP patients infected with A. baumannii.

Carbapenem-resistant Acinetobacter baumannii (CRAB) is associated with nosocomial infections worldwide. Here, we used phage as a potential agent to evaluate the efficacy of daily cleaning practices combined with a bacteriophage-containing aerosol against CRAB. A two-phase prospective intervention study was performed at a 945-bed public teaching hospital. From March to December 2013, we performed terminal cleaning using standard procedures plus an aerosol with active bacteriophage in the intensive care units to evaluate the impact on nosocomial incidence density, carbapenem-resistance rates and antimicrobial drug consumption amounts. Patients with culture proven CRAB infection were transferred to the isolation room when the phage aerosol cleaning had been completed. A total of 264 new acquisitions of CRAB were identified in the intensive care units (191 in the pre-intervention period and 73 in the intervention period). The rates of new acquisitions of CRAB in the intensive care units decreased from 8.57 per 1000 patient-days in the pre-intervention period to 5.11 per 1000 patient-days in the intervention period (p = 0.0029). The mean percentage of resistant isolates CRAB decreased from 87.76% to 46.07% in the intensive care units (p = 0.001). All of the antimicrobials showed a significant reduction in consumption except imipenem. The bacteriophage was successful in decreasing the rates of infection caused by CRAB across intensive care units in a large teaching hospital.

The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin–meropenem combination therapy in carbapenem‐resistant Gram‐negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic–pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting Acinetobacter baumannii isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24 h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in vivo fitness was the most important factor for change in bacterial count. A model‐predicted growth at 24 h of ≥2‐log10 (164/207) correlated positively with clinical failure (adjusted odds ratio, aOR = 2.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti‐infective PKPD data can be integrated through pharmacodynamic modeling and identify patient‐ and pathogen‐specific factors related to clinical outcomes – an approach that may improve understanding of study outcomes.

Purpose Cefoperazone/sulbactam (CFP/SUL) is a β-lactam/β-lactamase inhibitor combination with little data available for the development of effective dosing guidelines during continuous renal replacement therapy. This study aimed to investigate the pharmacokinetics (PK) of cefoperazone/sulbactam in critically ill patients on continuous venovenous hemofiltration (CVVH). Methods A prospective, single-center, and open-label study was conducted. Critically ill patients receiving CVVH with 3 g cefoperazone/sulbactam (2.0/1.0 g) intravenously every 8 h were recruited. Serial blood and ultrafiltrate samples were paired collected for initial dose (occasion 1) and steady state (occasion 2). PK was assessed by non-compartmental analysis, and pharmacodynamics (PD) was evaluated by the percent of time for which drug concentrations exceed the minimum inhibitory concentration (% T >MIC ). Results Total fourteen patients were enrolled. Volume of distribution at steady state ( V ss ) of cefoperazone and sulbactam for initial doses (20.8 ± and 28.4 L, respectively) increased significantly compared with those in healthy volunteers ( P  = 0.009 for CFP, P  = 0.030 for SUL). Both cefoperazone and sulbactam showed significantly lower total clearance (CL t ) (46.2 and 117.6 mL/min, respectively) compared with healthy volunteers ( P  = 0.000 for CFP, P  = 0.017 for SUL). There is no significant difference in PK between occasion 1 and occasion 2 ( P  > 0.05). For occasion 1, mean CVVH clearance accounted for 34.3 and 33.9 % for CL t of cefoperazone and sulbactam, respectively. The minimum PD target of 60% T >MIC was achieved in seven of eight patients. For occasion 2, eight of nine patients achieved cefoperazone concentrations that were above the MIC for the entire dosing interval. Conclusions PK of cefoperazone/sulbactam was altered in critically ill patients undergoing CVVH. Therapeutic drug monitoring would be recommended to individualize the dose regimen.

Background. With an increase in the use of colistin methansulfonate (CMS) to treat carbapenem-resistant Acinetobacter baumannii infections, colistin resistance is emerging. Methods. Patients with infection or colonization due to colistin-resistant A. baumannii were identified at a hospital system in Pennsylvania. Clinical data were collected from electronic medical records. Susceptibility testing, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST) were performed. To investigate the mechanism of colistin resistance, lipid A was subjected to matrix-assisted laser desorption/ionization mass spectrometry. Results. Twenty patients with colistin-resistant A. baumannii were identified. Ventilator-associated pneumonia was the most common type of infection. Nineteen patients had received intravenous and/or inhaled CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection prior to identification of colistin-resistant isolates. The 30-day all-cause mortality rate was 30%. The treatment regimen for colistin-resistant A. baumannii infection associated with the lowest mortality rate was a combination of CMS, a carbapenem, and ampicillin-sulbactam. The colistin-susceptible and -resistant isolates from the same patients were highly related by PFGE, but isolates from different patients were not, suggesting evolution of resistance during CMS therapy. By MLST, all isolates belonged to the international clone II, the lineage that is epidemic worldwide. Phosphoethanolamine modification of lipid A was present in all colistin-resistant A. baumannii isolates. Conclusions. Colistin-resistant A. baumannii occurred almost exclusively among patients who had received CMS for treatment of carbapenem-resistant, colistin-susceptible A. baumannii infection. Lipid A modification by the addition of phosphoethanolamine accounted for colistin resistance. Susceptibility testing for colistin should be considered for A. baumannii identified from CMS-experienced patients.

To give an update on the molecular epidemiology and global distribution of carbapenemase encoding genes, we subjected 313 carbapenem-resistant Acinetobacter baumannii isolated from 114 study centers in 47 countries in five world regions, Africa, Asia, Europe, Latin America, and North America, to whole genome sequencing. Numbers of isolates investigated were proportional to the population size of the contributing countries. Molecular epidemiology was investigated using seven-loci and core genome multilocus sequence typing, whole-genome single nucleotide polymorphism phylogenies, and the intrinsic bla OXA-51-like variant. Carbapenemase encoding genes were identified by multiplex PCR and ResFinder. Among the total of 313 isolates, 289 (92.3%) were assigned to A. baumannii international clones (IC) IC1–IC8. IC2 predominated with 196 isolates (62.6%) and was spread worldwide, followed by IC5 with 44 isolates (14.1%) mainly confined to Latin America. Six isolates (1.9%) originating from Belgium, Egypt, Italy, and Pakistan represent the novel IC9. Acquired OXA-type carbapenemase genes were found in 300 (96%) isolates with bla OXA-23-like and bla OXA-40-like predominating, which constitutes a significant increase compared to our findings from 2010. Metallo-beta-lactamases were rare with seven isolates (2.2%). The distribution of ICs and carbapenemase determinants can vary widely among different geographical regions. Carbapenem-resistant Acinetobacter baumannii are of increasing public health importance, as they are resistant to last-line antibiotics. International clones with well-characterized resistance genes dominate globally; however, locally, other lineages with different properties may be of importance to consider. This study investigated isolates from a broad geographic origin from 114 hospitals in 47 countries and from five world regions ensuring the greatest possible diversity in an organism known for its propensity for clonal epidemic spread and reflecting the current global epidemiology of carbapenem-resistant A. baumannii . In Latin America, a lineage different from other geographic regions circulates, with a different resistance gene profile. This knowledge is important to adjust local infection prevention measures. In a global world with migration and increasing use of antimicrobials, multidrug-resistant bacteria will continue to adapt and challenge our healthcare systems worldwide.

Background COVID-19 is known as a new viral infection. Viral-bacterial co-infections are one of the biggest medical concerns, resulting in increased mortality rates. To date, few studies have investigated bacterial superinfections in COVID-19 patients. Hence, we designed the current study on COVID-19 patients admitted to ICUs. Methods Nineteen patients admitted to our ICUs were enrolled in this study. To detect COVID-19, reverse transcription real-time polymerase chain reaction was performed. Endotracheal aspirate samples were also collected and cultured on different media to support the growth of the bacteria. After incubation, formed colonies on the media were identified using Gram staining and other biochemical tests. Antimicrobial susceptibility testing was carried out based on the CLSI recommendations. Results Of nineteen COVID-19 patients, 11 (58%) patients were male and 8 (42%) were female, with a mean age of ~ 67 years old. The average ICU length of stay was ~ 15 days and at the end of the study, 18 cases (95%) expired and only was 1 case (5%) discharged. In total, all patients were found positive for bacterial infections, including seventeen Acinetobacter baumannii (90%) and two Staphylococcus aureus (10%) strains. There was no difference in the bacteria species detected in any of the sampling points. Seventeen of 17 strains of Acinetobacter baumannii were resistant to the evaluated antibiotics. No metallo-beta-lactamases -producing Acinetobacter baumannii strain was found. One of the Staphylococcus aureus isolates was detected as methicillin-resistant Staphylococcus aureus and isolated from the patient who died, while another Staphylococcus aureus strain was susceptible to tested drugs and identified as methicillin-sensitive Staphylococcus aureus . Conclusions Our findings emphasize the concern of superinfection in COVID-19 patients due to Acinetobacter baumannii and Staphylococcus aureus . Consequently, it is important to pay attention to bacterial co-infections in critical patients positive for COVID-19.