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Abstract Background Acinetobacter baumannii (A. baumannii) is a life-threatening and challenging pathogen. In addition, it accounts for numerous serious infections, particularly among immunocompromised patients. Resistance to nearly all clinically used antibiotics and their ability to spread this resistance is one of the most important concerns related to this bacterium. Objectives This study describes different molecular mechanisms of two multidrug-resistant A. baumannii isolates obtained from endotracheal aspirates collected from the neonatal intensive care unit (NICU), Ain Shams University Hospital, Egypt. Methods Following the identification of two isolates, they were examined for susceptibility to antimicrobial agents. This was followed by multilocus sequence typing as well as whole-genome sequence (WGS). Additionally, a Pathosystems Resources Integration Center (PATRIC) analysis was performed. Results Two isolates, Ab119 and Ab123, exhibited resistance to all tested antibiotics except for tigecycline and colistin. The WGS analysis of antimicrobial resistance genes (AMR) indicated that both isolates shared beta-lactam, aminoglycoside, macrolides, and sulfonamide resistance genes. Furthermore, each strain revealed different resistance genes such as blaNDM-1, blaNDM-10, OXA-64, aph (3')-VI, Tet-B in Ab119 strain and blaOXA-68, blaPER-1, blaPER-7, Tet-39 in Ab123 strain. Multiple efflux pump genes were detected. Multilocus sequence typing indicated that both isolates belong to the same sequence type (ST931), which belongs to international clone (IC3). Both isolates exhibited the presence of multiple mobile genetic elements (MGEs), but no plasmid was detected in either of them. Conclusions A low prevalence of the IC3 sequence type was identified among two A. baumannii isolates obtained from the NICU in Egypt, exhibiting a high resistance level. Healthcare workers must have knowledge regarding the prevalence of A. baumannii among different populations in order to administer suitable treatment, improve patient outcomes, and apply effective infection control practices.

Background: Acinetobacter baumannii (A. baumannii) is a life-threatening and challenging pathogen. In addition, it accounts for numerous serious infections, particularly among immunocompromised patients. Resistance to nearly all clinically used antibiotics and their ability to spread this resistance is one of the most important concerns related to this bacterium. Objectives: This study describes different molecular mechanisms of two multidrug-resistant A. baumannii isolates obtained from endotracheal aspirates collected from the neonatal intensive care unit (NICU), Ain Shams University Hospital, Egypt. Methods: Following the identification of two isolates, they were examined for susceptibility to antimicrobial agents. This was followed by multilocus sequence typing as well as whole-genome sequence (WGS). Additionally, a Pathosystems Resources Integration Center (PATRIC) analysis was performed. Results: Two isolates, Ab119 and Ab123, exhibited resistance to all tested antibiotics except for tigecycline and colistin. The WGS analysis of antimicrobial resistance genes (AMR) indicated that both isolates shared beta-lactam, aminoglycoside, macrolides, and sulfonamide resistance genes. Furthermore, each strain revealed different resistance genes such as blaNDM-1, blaNDM-10, OXA-64, aph (3')-VI, Tet-B in Ab119 strain and blaOXA-68, blaPER-1, blaPER-7, Tet-39 in Ab123 strain. Multiple efflux pump genes were detected. Multilocus sequence typing indicated that both isolates belong to the same sequence type (ST931), which belongs to international clone (IC3). Both isolates exhibited the presence of multiple mobile genetic elements (MGEs), but no plasmid was detected in either of them. Conclusions: A low prevalence of the IC3 sequence type was identified among two A. baumannii isolates obtained from the NICU in Egypt, exhibiting a high resistance level. Healthcare workers must have knowledge regarding the prevalence of A. baumannii among different populations in order to administer suitable treatment, improve patient outcomes, and apply effective infection control practices. [ABSTRACT FROM AUTHOR]

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin. [ABSTRACT FROM AUTHOR]

ABSTRACT Synergistic effects of phages in combination with antibiotics have received increasing attention. In this present study, we isolated a new phage pB3074 against clinically isolated multidrug-resistant Acinetobacter baumannii. Phage pB3074 combined with cell wall-targeting antibiotics could produce synergistic antibacterial effect in vitro bactericidal activities. Further research indicates that the bacteriophage dose is critical to synergistic antimicrobial effect of phage and antibiotic combination. Cefotaxime and meropenem were selected as the representative cell wall-targeting antibiotics for further synergistic antibacterial study. Results illustrated that phage pB3074 and cefotaxime or meropenem combination was very effective for the removal of mature biofilm and inhibition of biofilm formation. In a pig skin explant model, results also showed that phage pB3074 and cefotaxime or meropenem combination was very effective for the treatment of wound infection ex vivo. Subsequent studies showed that some extent recovery of drug sensitivity to cell wall-targeting antibiotics might be vital mechanism of synergistic antibacterial effect between bacteriophage pB3074 and these antibiotics. The existence of antibiotics could promote phage adsorption and proliferation, which might also be potential mechanism for synergistic antibacterial activities and have been observed in cefotaxime and meropenem application. In summary, results in the current study demonstrated that phage pB3074 has the potential to be developed as an antibacterial agent and combined application of phages and antibiotics might be a new choice for the treatment of current multidrug-resistant bacterial infections. IMPORTANCE Combined application of phages and antibiotics cannot only effectively inhibit the appearance of phage-resistant bacteria, but also reduce the effective use concentration of antibiotics, and even make some bacteria regain sensitivity to some resistant antibiotics. Therefore, phage-antibiotic combination (PAC) could improve the antibacterial activity of individual drug, providing a new choice for clinical treatment of multidrug-resistant bacterial infections.

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin.

ABSTRACT Phage-antibiotic combination (PAC) therapy is a potential new alternative to treat infections caused by pathogenic bacteria, particularly those caused by antibiotic-resistant bacteria. In the present study, phage YC#06 against highly multidrug-resistant Acinetobacter baumannii 4015 was isolated, identified, and characterized. Compared with antibiotics alone, the time-kill experiments in vitro showed that YC#06 and antibiotic mixtures that include the chloramphenicol, imipenem, and cefotaxime combination could produce phage-antibiotic synergy (PAS), which reduced the ultimate effective concentration of antibiotics. No phage-resistant bacteria have been isolated during the whole time-kill experiments in vitro. Of note, PAS was dose dependent, requiring a moderate phage dose to achieve maximum PAS effect. In addition, PAS could effectively inhibit biofilm formation and remove mature biofilms in vitro. Furthermore, PAS between the combination of YC#06 and antibiotic mixtures in vivo was validated using a zebrafish infection model. Overall, the results of this study demonstrate that PAC could be a viable strategy to treat infection caused by high-level multidrug-resistant Acinetobacter baumannii or other drug-resistant bacteria through switching to other types of phage and antibiotic mixtures. IMPORTANCE The treatment of multidrug-resistant bacterial infection is an urgent clinical problem. The combination of bacteriophages and antibiotics could produce synergistic bactericidal effects, which could reduce the emergence of antibiotic resistance and antibiotic consumption in antibiotic-sensitive bacteria, restore efficacy to antibiotics in antibiotic-resistant bacteria, and prevent the occurrence of phage-resistant bacteria. Phage-antibiotic combination (PAC) might be a potential new alternative for clinical treatment of multidrug-resistant bacterial infections.

Acinetobacter baumannii is an important pathogen in hospital acquired infections. Although tigecycline currently remains a potent antibiotic for treating infections caused by multidrug resistant A. baumannii (MDRAB) strains, reports of tigecycline resistant isolates have substantially increased. The resistance mechanisms to tigecycline in A. baumannii are far more complicated and diverse than what has been described in the literature so far. Here, we characterize in vitro-selected MDRAB strains obtained by increasing concentrations of tigecycline. We have identified mutations in adeS, rrf and rpoB that result in reduced susceptibility to tigecycline. Using in situ complementation experiments, we confirm that mutations in rrf, rpoB, and two types of mutations in adeS correlate with tigecycline resistance. By Western blot and polysome profile analysis, we demonstrate that the rrf mutation results in decreased expression of RRF, which affects the process of ribosome recycling ultimately leading to increased tigecycline tolerance. A transcriptional analysis shows that the mutated rpoB gene plays a role in regulating the expression of the SAM-dependent methyltransferase (trm) and transcriptional regulators, to confer moderate tigecycline resistance. This study provides direct in vitro evidence that mutations in the adeS, rpoB and rrf are associated with tigecycline resistance in A. baumannii.

Antimicrobial resistance is increasing around the world and the search for effective treatment options, such as new antibiotics and combination therapy is urgently needed. The present study evaluates oregano essential oil (OEO) antibacterial activities against reference and multidrug-resistant clinical isolates of Acinetobacter baumannii (Ab-MDR). Additionally, the combination of the OEO and polymyxin B was evaluated against Ab-MDR. Ten clinical isolates were characterized at the species level through multiplex polymerase chain reaction (PCR) for the gyrB and blaOXA-51-like genes. The isolates were resistant to at least four different classes of antimicrobial agents, namely, aminoglycosides, cephems, carbapenems, and fluoroquinolones. All isolates were metallo-β-lactamase (MβL) and carbapenemase producers. The major component of OEO was found to be carvacrol (71.0%) followed by β-caryophyllene (4.0%), γ-terpinene (4.5%), p-cymene (3,5%), and thymol (3.0%). OEO showed antibacterial effect against all Ab-MDR tested, with minimum inhibitory concentrations (MIC) ranging from 1.75 to 3.50 mg mL−1. Flow cytometry demonstrated that the OEO causes destabilization and rupture of the bacterial cell membrane resulting in apoptosis of A. baumannii cells (p < 0.05). Synergic interaction between OEO and polymyxin B (FICI: 0.18 to 0.37) was observed, using a checkerboard assay. When combined, OEO presented until 16-fold reduction of the polymyxin B MIC. The results presented here indicate that the OEO used alone or in combination with polymyxin B in the treatment of Ab-MDR infections is promising. To the best of our knowledge, this is the first report of OEO and polymyxin B association against Ab-MDR clinical isolates. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is one of nosocomial pathogen which emerges as multidrug-resistance worldwide. Multidrugresistant A. baumannii (MDRAB) and carbapenem-resistant A. baumannii (CRAB) are highly concerned due to limitation of therapeutic options. Antibacterial activity of biapenem was explored in order to overcome bacterial resistance. A total of 412 A. baumannii clinical isolates from 13 tertiary care hospitals in Thailand were collected. MIC values of biapenem and comparators; imipenem, meropenem, colistin, sulbactam, ciprofloxacin ceftazidime and fosfomycin sodium, were determined by broth microdilution method in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines (2016). In total, 320 isolates (77.67%) were MDRAB and 328 isolates (79.61%) were CRAB while 58 isolates (14.07%) were colistin-resistant AB. A. baumannii showed widespread resistance to ceftazidime, ciprofloxacin and carbapenems in more than 90% of the strains; resistance to sulbactam, fosfomycin, and colistin were 85%, 60%, and 15% respectively. By comparison among carbapenems, biapenem showed MIC50/90 of 16/32 which were at least 2 folds lower than imipenem and meropenem (MIC50/90; 32/128, 32/64, respectively). In addition, 15% of imipenem and meropenemresistant A. baumannii were susceptible to biapenem. Also, 19% of colistin-resistant A. baumannii were susceptible to biapenem. Although more than 90% of MDRAB and CRAB were resistant to carbapenems, biapenem showed a good activity over other carbapenems. This drug might be a therapeutic option mono or combination therapy besides other antimicrobial agents. [ABSTRACT FROM AUTHOR]

The emergent issue of carbapenem-resistant Acinetobacter baumannii (A. baumannii) and Pseudomonas aeruginosa (P. aeruginosa) is a major problem in Thailand. The wide use of carbapenems can increase selective pressure of bacterial resistance. The objective of this study was to determine the relationship between carbapenem consumption and the susceptibility rates of A. baumannii and P. aeruginosa, including multi-drug resistance (MDR) strains. This was a retrospective study. Carbapenem consumption and susceptibility profiles were collected from 2007 to 2013 at the Her Royal Highness Princess Maha Chakri Sirindhorn Medical Center, Thailand. We found that the susceptibility rate of A. baumannii to imipenem and meropenem from the sputum and the bronchoalveolar lavage (BAL) specimens was significantly decreased during the study period, but no significant change was found in the P. aeruginosa data. The relationship between carbapenem consumption and the susceptibility rate of A. baumannii had a clear association with the use of ertapenem. We found a statistically significant negative correlation between ertapenem consumption and the susceptibility rate of A. baumannii to imipenem (r = −0.91; p = 0.004) and meropenem (r = −0.97; p = 0.000) in the data from the non-ICU wards. In addition, imipenem use had a moderate negative correlation with the MDR P. aeruginosa data but no statistical significance (r = −0.714; p > 0.05). In conclusion, our study suggested there is an association between carbapenem use and the susceptibility of A. baumannii and P. aeruginosa. Notwithstanding this, information on ecological factors should be considered for further study. These findings showed the need to optimize the carbapenem prescription policy. Avoiding carbapenem overuse and rethinking the appropriate initial therapy might decrease the rate of resistant organisms.

The rapid emergence of multidrug-resistant Acinetobacter baumannii (MDRAB) is recognized as a significant health problem worldwide, including Thailand. Due to a limitation of treatment option, a new antimicrobial agent has been challenged. Sitafloxacin, a new fluoroquinolone antimicrobial agent, has shown a good in vitro activity against MDRAB and carbapenemresistant A. baumannii (CRAB). The aim of this study was to evaluate in vitro activity of sitafloxacin and compare that with other antimicrobial agents against A. baumannii clinical isolates, focusing on multidrug-resistant A. baumannii and carbapenemresistant A. baumannii (MDR-CRAB). All 350 A. baumannii clinical isolates were collected from thirteen tertiary care hospitals in all regions of Thailand. The minimum inhibitory concentrations (MICs) were determined by broth microdilution method. To determine rate of susceptibilities, a susceptible isolate with sitafloxacin was considered as MIC values of ≤ 2 µg/mL and ≤ 1 µg/mL. For other antimicrobial agents, MIC breakpoints were considered according to the Clinical and Laboratory Standards Institute (CLSI) 2018. Our study found that 278 clinical isolates were identified as MDR-CRAB. The MIC range, MIC50 and MIC90 of sitafloxacin against MDRCRAB isolates were ≤ 0.0625-8 µg/mL, 1 µg/mL and 2 µg/ mL, respectively. Additionally, almost of the colistin-resistant isolates were susceptible to sitafloxacin (92.86%). Sitafloxacin had a good activity against multidrug-resistant isolates in Thailand. Thus, sitafloxacin can be considered as an alternative choice for treatment of MDRAB and CRAB infections. Further studies are needed to evaluate treatment outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Ventilator-associated pneumonia (VAP) caused by multidrug-resistant Acinetobacter baumannii (MDR-AB) is common in hospitals and impacts patient survival. We determined the incidence of MDR-AB VAP in critical care units and examined the predictors of 14-day mortality in these patients. Methodology: A retrospective case series study was conducted at a tertiary referral teaching hospital in north Jordan. A list of patients with a positive culture of A. baumannii between January 2007 and June 2013 was retrieved using computerized hospital databases. Medical records of all these patients were reviewed, and cases of VAP infected with MDR-AB were identified. Predictors of 14-day mortality were determined using multivariable logistic regression adjusted for possible confounders. Results: Out of 121 A. baumannii-VAP cases, 119 (98.3%) were caused by MDR-AB. The incidence rate of MDR-AB VAP was 1.59 cases per 100 critical care unit admissions. The mortality of A. baumannii-VAP cases in critical care units was 42% (50/119). Being prescribed two or more definitive antibiotics (prescribed based on susceptibility data) (OR = 0.075, 95% CI = 0.017-0.340, p = 0.001) and ipratropium/salbutamol during mechanical ventilation (OR = 0.140, 95% CI = 0.028-0.705, p = 0.017) were independently associated with lower hospital mortality. Conclusions: Our results suggest incidence of MDR-AB VAP in critical care units is high and that prescription of antibiotics based on antibiotic susceptibility and use of bronchodilators is associated with lower mortality in this population. Larger prospective studies are needed to explore whether these findings can be replicated in different clinical settings. [ABSTRACT FROM AUTHOR]

The emergent issue of carbapenem-resistant Acinetobacter baumannii (A. baumannii) and Pseudomonas aeruginosa (P. aeruginosa) is a major problem in Thailand. The wide use of carbapenems can increase selective pressure of bacterial resistance. The objective of this study was to determine the relationship between carbapenem consumption and the susceptibility rates of A. baumannii and P. aeruginosa, including multi-drug resistance (MDR) strains. This was a retrospective study. Carbapenem consumption and susceptibility profiles were collected from 2007 to 2013 at the Her Royal Highness Princess Maha Chakri Sirindhorn Medical Center, Thailand. We found that the susceptibility rate of A. baumannii to imipenem and meropenem from the sputum and the bronchoalveolar lavage (BAL) specimens was significantly decreased during the study period, but no significant change was found in the P. aeruginosa data. The relationship between carbapenem consumption and the susceptibility rate of A. baumannii had a clear association with the use of ertapenem. We found a statistically significant negative correlation between ertapenem consumption and the susceptibility rate of A. baumannii to imipenem (r = −0.91; p = 0.004) and meropenem (r = −0.97; p = 0.000) in the data from the non-ICU wards. In addition, imipenem use had a moderate negative correlation with the MDR P. aeruginosa data but no statistical significance (r = −0.714; p > 0.05). In conclusion, our study suggested there is an association between carbapenem use and the susceptibility of A. baumannii and P. aeruginosa. Notwithstanding this, information on ecological factors should be considered for further study. These findings showed the need to optimize the carbapenem prescription policy. Avoiding carbapenem overuse and rethinking the appropriate initial therapy might decrease the rate of resistant organisms. [ABSTRACT FROM AUTHOR]