Clinical isolates of Streptococcus mitis/oralis-related species with reduced carbapenem susceptibility, harboring amino acid substitutions in penicillin-binding proteins in Japan.

Streptococcus mitis/oralis group isolates with reduced carbapenem susceptibility have been reported, but its isolation rate in Japan is unknown. We collected 356 clinical α-hemolytic streptococcal isolates and identified 142 of them as S. mitis/oralis using partial sodA sequencing. The rate of meropenem non-susceptibility was 17.6% (25/142). All 25 carbapenem-non-susceptible isolates harbored amino acid substitutions in/near the conserved motifs in PBP1A, PBP2B, and PBP2X. Carbapenem non-susceptibility is common among S. mitis/oralis group isolates in Japan.

Catheter-related bloodstream infection caused by Lacticaseibacillus paracasei: A case report and literature review.

Catheter-related bloodstream infections (CRBSIs) caused by Lactobacillus spp. and Lacticaseibacillus spp. are rare, and their clinical course and optimal treatment remain uncertain. In this report, we present a 46-year-old male patient who experienced clinically diagnosed Lacticaseibacillus paracasei CRBSI on four separate occasions, despite receiving systemic administration of antibiotics and antimicrobial lock therapy. The patient did not develop L. paracasei bacteremia after catheter removal. This case report furthers our knowledge of CRBSI caused by Lactobacillus and related genera and highlights the need for further research.

Difficulties in diagnosing Malassezia furfur bloodstream infection and possibility of spontaneous resolution in a patient undergoing chemotherapy for neuroblastoma: A case report.

Malassezia furfur is a lipophilic, yeast-like fungus that forms part of the normal human skin microflora and is associated with a wide range of infections, such as pityriasis versicolor, folliculitis, and systemic infections in immunocompromised patients. Although matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has enabled rapid identification of Malassezia species, it is still a challenge to diagnose systemic infections because Malassezia fungemia can often be missed by automated blood culture systems. We report a case in which M. furfur in blood was detected by the presence of yeast-like fungi in blood smears. Yeast-like organisms were observed in the blood smears of a 3-year-old boy, taken over 2 weeks without any symptoms. He had undergone several courses of chemotherapy for neuroblastoma via an indwelling central venous catheter (CVC) that was placed in his right anterior chest for 11 months. Although the blood cultures obtained from an automated blood culture system were negative, M. furfur growth was detected in the subcultured blood taken from the CVC. The CVC was removed, and the scheduled chemotherapy was postponed. No systemic M. furfur bloodstream infection occurred; the infection resolved spontaneously without any specific treatment; only prophylactic fluconazole was administered. M. furfur fungemia may not be diagnosable by an automated blood culture system. Further, M. furfur may not cause infections in humans even when administered intravenously. This report may lead to the discovery of factors related to human infectivity of this disease in the future.

Lysinibacillus fusiformis bacteremia: Case report and literature review.

A 93-year-old woman was diagnosed with Lysinibacillus fusiformis bacteremia complicated with coma blisters. Initial gram staining for L. fusiformis indicated the presence of gram-negative rods; however, subsequent staining of colonies from Mueller-Hinton agar revealed the presence of gram-positive and gram-negative rods with spherical endospores, and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (VITEK ® MS and microflex® LT/SH) definitively identified the organism as L. fusiformis. The two-week administration of piperacillin/tazobactam and ampicillin resulted in an improvement of the patient's general condition, and the skin lesions gradually improved.

Genetic and epidemiological analysis of ESBL-producing Klebsiella pneumoniae in three Japanese university hospitals.

INTRODUCTION: We aimed to clarify the genetic background and molecular epidemiology of extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae (K. pneumoniae) at three geographically separated university hospitals in Japan. METHODS: From January 2014 to December 2016, 118 ESBL-producing K. pneumoniae (EPKP) strains that were detected and stored at three university hospitals were collected. Molecular epidemiological analysis was performed using enterobacterial repetitive intergenic consensus (ERIC)-polymerase chain reaction (PCR) and multi-locus sequence typing (MLST). The ESBL type was determined using the PCR-sequence method. The presence of plasmid-mediated fluoroquinolone resistance (PMQR) genes was analyzed by PCR. We compared the relationships between PMQR gene possession/quinolone resistance-determining region (QRDR) mutation and levofloxacin (LVFX)/ciprofloxacin (CPFX) susceptibility. RESULTS: The detection rate of EPKP was 4.8% (144/2987 patients). MLST analysis revealed 62 distinct sequence types (STs). The distribution of STs was diverse, and only some EPKP strains had the same STs. ERIC-PCR showed discriminatory power similar to that of MLST. The major ESBL genotypes were CTX-M-15-, CTX-M-14-, and SHV-types, which were detected in 47, 30, and 27 strains, respectively. Ninety-one out of 118 strains had PMQR genes and 14 out of 65 strains which were not susceptible to CPFX had QRDR mutations, and the accumulation of PMQR genes and QRDR mutations tended to lead to higher minimum inhibitory concentrations (MICs) of LVFX. CONCLUSIONS: At three geographically separated university hospitals in Japan, the epidemiology of EPKP was quite diverse, and no epidemic strains were found, whereas CTX-M-14 and CTX-M-15 were predominant.

Risk factors for antibiotic resistance in hospital-acquired and ventilator-associated pneumonia.

INTRODUCTION: Understanding risk factors for antibiotic resistance (AR) in patients with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) is important to select appropriate initial antibiotics and reduce broad-spectrum antibiotic overuse. However, available evidence is limited. We aimed to identify risk factors for AR in those patients. METHODS: This prospective observational study was conducted at a tertiary-care hospital. Pathogens with AR were defined as those resistant to ampicillin-sulbactam or ceftriaxone. Risk factors for AR in patients with HAP and VAP were assessed using penalized logistic regression analysis. RESULTS: In total, 557 patients with HAP and VAP were enrolled. Pathogens were isolated from 315 patients, with AR identified in 68.3% (215/315). Among antibiotic-resistant pathogens (ARPs), Pseudomonas aeruginosa was isolated most frequently, followed by methicillin-resistant Staphylococcus aureus (MRSA). Significant risk factors for AR were chronic renal diseases (adjusted odds ratio: 2.82, 95% confidence interval: 1.79-7.83), history of ARP infection/colonization within the past 1 year (2.80, 1.90-7.02), bedridden state (1.84, 1.28-3.91), tube feeding (1.58, 1.09-2.98), and peripheral or central venous catheterization (1.57, 1.06-2.96). Additionally, a risk factor for ARPs that should be treated with anti-MRSA antibiotics was prior MRSA infection/colonization history. Those for ARPs requiring dual antipseudomonal antibiotics included prior non-MRSA ARP or MRSA infection/colonization history and bedridden state. CONCLUSIONS: The five factors we highlighted can be important criteria for identifying patients at risk of AR. Physicians should consider these potential risk factors when selecting antibiotics for initial empirical therapy in patients with HAP and VAP.

Epidemiology and molecular characterization of fecal carriage of third-generation cephalosporin-resistant Enterobacterales among elderly residents in Japan.

INTRODUCTION: The spread of third-generation cephalosporin-resistant Gram-negative bacteria is a serious concern in acute and post-acute care settings. This study aimed to understand the epidemiology and molecular background of fecal colonization of resistant Enterobacterales in elderly people. METHODS: In December 2015-December 2017, stool or rectal swab samples were collected from 101 elderly patients receiving home care, using long-term care facilities (LTCF), and living in nursing homes repeatedly at 3-9-month intervals. Patient clinical background data were collected from medical records. After phenotypic screening for extended-spectrum ß-lactamase (ESBL), AmpC-type ß-lactamase or carbapenemase production, drug resistance genes of isolates were analyzed using polymerase chain reaction (PCR). ESBL-producing Escherichia coli isolates obtained from the same patients in repetitive screenings were analyzed using PCR-based ORF typing. Risk factors for persistent carriage of resistant Enterobacterales were analyzed using multivariate analysis. RESULTS: Resistant Enterobacterales isolates were detected in 37 of 101 (36.6%) and 29 of 80 (36.3%) residents in first and second screenings, respectively. ESBL-producing E. coli accounted for 80% isolates, the most common being CTX-M-9-group ß-lactamase producers. Molecular epidemiological analysis revealed probable transmissions of ESBL-producing E. coli; 58% of ESBL-producing E. coli colonizers were persistent colonizers at least after 3 -month intervals. Age > 87 years and LTCF residence were independent risk factors for persistent carriage of ESBL-producing E. coli. CONCLUSIONS: We showed, for the first time, high persistent colonization rate of ESBL-producing E. coli among elderly people in post-acute care settings with probable horizontal transmission. We also identified significant risk factors for persistent colonization.

Fungal endocarditis after transcatheter aortic valve replacement (TAVR): Case report and review of literature.

The reported number of transcatheter aortic valve replacement-associated infective endocarditis (TAVR-IE) cases has been increasing worldwide, but information about the incidence and clinical features of fungal TAVR-IE is quite limited. We present a patient who acquired TAVR-IE caused by Candida parapsilosis four month after TAVR, who was successfully treated redo-aortic valve replacement and prolonged antifungal therapy.

Active surveillance in response to the identification of a single carbapenemase-producing Escherichia coli at a Japanese university hospital.

This report described the experience of active surveillance culture implemented in response to the identification of a single carbapenemase-producing Escherichia coli in a Japanese university hospital. It revealed a horizontal transmission event and an additional asymptomatic carrier of carbapenemase-producing Escherichia coli with unique drug susceptibility and resistance gene profiles. Early implementation of active surveillance culture as a part of multifaceted infection control measures appeared to be useful to control further transmission of carbapenemase-producing Escherichia coli even in the low endemic facility. Further investigations on the timing and usefulness of active surveillance culture in the control of carbapenemase-producing Enterobacteriaceae would be warranted.

Pneumococcal biliary tract infections - How rare are they?

Pneumococcal biliary tract infections (PBTIs) were reported as rare due to the bacterium's bile solubility. The purpose of this study was to determine the occurrence and clinical characteristics of PBTIs. A retrospective case series review was conducted from January 2006 to August 2014 at a tertiary referral university hospital in Japan. Patients with a blood or bile culture positive for Streptococcus pneumoniae diagnosed with definite cholangitis or cholecystitis according to Tokyo Guideline 2013 were enrolled in this study. Data on clinical information, treatments, and outcomes were collected. During 104 months, 48 cases of positive blood cultures and 13 cases of positive bile cultures were recorded, and after excluding 43 and 5 of these, respectively, a total of 10 patients were diagnosed with PBTI. Most patients (9/10) had biliary tract problems and biliary devices in place. PBTIs were not rare; conversely, they were a relatively common cause of pneumococcal bacteremia in this center treating a high volume of biliary tract illnesses.

[Multicenter surveillance of Pseudomonas aeruginosa strains for antimicrobials in Aichi prefecture in 2009].

We investigated the susceptibility to antimicrobials of 204 Pseudomonas aeruginosa strains isolated from 21 hospitals in Aichi prefecture from September to November 2009. MIC distributions of various antimicrobials were analyzed in terms of geographic region of isolation, patient status (outpatient or inpatient), and type of specimens that the strain was isolated from. The results were as follows. 1. Although more than 90% of strains were susceptible to all aminoglycosides and colistin, 80-90% of them were susceptible to beta-lactams and fluoroquinolones. MIC distributions of all antimicrobials measured were not significantly different between regions. 2. Only 1 strain (0.5%) was multi-drug resistant Pseudomonas aeruginosa (MDRP). Thirteen strains (6.4%) showed imipenem MIC > or = 16 microg/mL, and 16 strains (7.8%) showed ciprofloxacin MIC > or = 4 microg/mL. These strains tended to be more isolated from urine, respiratory tract specimens, or surgical specimens. 3. The MICs of tazobactam/piperacillin, panipenem, meropenem, doripenem, biapenem, sulbactam/cefoperazone, cefepime, and aztreonam were significantly higher in strains isolated from inpatients than in those from outpatients. MIC distributions of antimicrobials other than beta-lactams were not significantly different between situations where strains were isolated. 4. MIC distributions of piperacillin, all carbapenems, cefepime, gentamicin, and all fluoroquinolones were significantly different among samples from which strains were isolated. The strains isolated from blood showed lower MICs against all antimicrobials than those from other samples. No difference was found in MIC distributions when categorized according to bacteremic origin. The MICs were apparently elevated against beta-lactams, fluoroquinolones, and gentamicin in strains isolated from respiratory tract specimens, and against beta-lactams, and fluoroquinolones in strains isolated from urine. It was suggested that in P. aeruginosa surveillance, the results should be reported by stratifying with patient status, and type of specimens that the strain was isolated from and that regional surveillance should be useful with such stratification to establish antibiograms for empirical antimicrobial choice.

＜Editors' Choice＞ Multicenter survey for carbapenemase-producing Enterobacterales in central Japan.

Carbapenemase-producing Enterobacterales (CPE) raise concerns about the treatment options for infectious diseases and infection control. We conducted a multicenter study to clarify the molecular epidemiology of CPE in the Aichi Prefecture during the first 3-month period from 2015 to 2019. Carbapenemase production was screened using a modified carbapenem inactivation method, and the genotypes of the carbapenemase genes were determined by polymerase chain reaction sequencing. Genetic relatedness was analyzed using multilocus sequence typing (MLST). Twenty-four hospitals participated in this study. Of the 56,494 Enterobacterales strains detected during the study period, 341 (0.6%) that met the susceptibility criteria were analyzed. Sixty-five of the 341 strains were determined to be CPE, with an incidence rate of 0.12% (65/56,494). The bacterial species responsible for CPE were Klebsiella pneumoniae (n = 24), Enterobacter cloacae complex (n = 23), Klebsiella oxytoca (n = 10), and Escherichia coli (n = 8). Most of the carbapenemase genotypes were IMP-1 (58/65), and only three were IMP-6 types. Three E. coli strains that produced NDM-5 were detected. MLST analysis showed that Sequence type (ST) 78 was predominant in E. cloacae complex CPE (14/23, 60.9%). Meanwhile, various STs were detected in carbapenemase-producing (CP) K. pneumoniae, of which ST37 and ST517 were the most common. The incidence rate of CPE in this region was comparable to national data. This 3-month surveillance revealed the spread of ST78 of CP E. cloacae complex and ST517 and ST592 of CP K. pneumoniae across hospitals, indicating the need to strengthen regional infection control programs.

Effects of lymphocyte and neutrophil counts and their time courses on mortality in patients with postoperative pneumonia.

The prognostic significance of absolute lymphocyte count (ALC) and absolute neutrophil count (ANC) remains unclear in patients with postoperative pneumonia (POP). The study objectives were to investigate the prognostic effects of ALC and ANC in POP patients, and to evaluate the time courses of ALC and ANC during hospitalization. This post-hoc analysis of a single-center prospective observational study evaluated consecutive POP patients, and comparatively analyzed community-acquired pneumonia (CAP) patients to highlight features of POP. In total, 228 POP patients and 1027 CAP patients were assessed. Severe lymphopenia (ALC < 500 cells/µL) at diagnosis was associated with worse 90-day survival in both types of pneumonia. In POP patients, neutrophilia (ANC > 7500 cells/µL) was associated with better survival, whereas CAP patients with neutrophilia tended to have a lower survival rate. Prolonged lymphopenia and delayed increase in neutrophils were characteristic time-course changes of non-survivors in POP. The time courses of ALC and ANC between survivors and non-survivors in POP trended differently from those in CAP. Our study showed that ALC and ANC at pneumonia diagnosis can serve as prognostic factors in POP patients. Differences in time-course changes of ALC and ANC between survivors and non-survivors may provide important information for future immunological research in pneumonia.

Clinical characteristics and treatment outcomes of carbapenem-resistant Enterobacterales infections in Japan.

OBJECTIVES: The dissemination of difficult-to-treat carbapenem-resistant Enterobacterales (CRE) is of great concern. We clarified the risk factors underlying CRE infection mortality in Japan. METHODS: We conducted a retrospective, multicentre, observational cohort study of patients with CRE infections at 28 university hospitals from September 2014 to December 2016, using the Japanese National Surveillance criteria. Clinical information, including patient background, type of infection, antibiotic treatment, and treatment outcome, was collected. The carbapenemase genotype was determined using PCR sequencing. Multivariate analysis was performed to identify the risk factors for 28-day mortality. RESULTS: Among the 179 patients enrolled, 65 patients (36.3%) had bloodstream infections, with 37 (20.7%) infections occurring due to carbapenemase-producing Enterobacterales (CPE); all carbapenemases were of IMP-type (IMP-1: 32, IMP-6: 5). Two-thirds of CPE were identified as Enterobacter cloacae complex. Combination therapy was administered only in 46 patients (25.7%), and the 28-day mortality rate was 14.3%. Univariate analysis showed that solid metastatic cancer, Charlson Comorbidity Index ≥3, bloodstream infection, pneumonia, or empyema, central venous catheters, mechanical ventilation, and prior use of quinolones were significant risk factors for mortality. Multivariate analysis revealed that mechanical ventilation (OR: 6.71 [1.42-31.6], P = 0.016), solid metastatic cancers (OR: 5.63 [1.38-23.0], P = 0.016), and bloodstream infections (OR: 3.49 [1.02-12.0], P = 0.046) were independent risk factors for 28-day mortality. CONCLUSION: The significant risk factors for 28-day mortality in patients with CRE infections in Japan are mechanical ventilation, solid metastatic cancers, and bloodstream infections.

Bursitis, Bacteremia, and Disseminated Infection of Mycobacteroides (Mycobacterium) abscessus subsp. massiliense.

We herein report a 59-year-old woman with a 2-year history of chronic bursitis of the hand who took 50 mg/day prednisolone for several autoimmune diseases. Mycobacteroides abscessus subsp. massiliense was isolated from the abscess and blood culture. Combination therapy (imipenem/cilastatin, amikacin, and clarithromycin) was administered for a month. Two months later, M. massiliense was detected from a blood culture again, and disseminated lesions were found. Clarithromycin and sitafloxacin were administered following eight weeks of the same regimen. Six months after the diagnosis, M. massiliense was isolated from a blood culture, and she expired due to multiple organ failure.

Number of concomitant drugs with thrombocytopenic adverse effects and the extent inflammatory response resolution are risk factors for thrombocytopenia in patients treated with linezolid for more than 14 days.

Prolonged treatment with linezolid (LZD) is known to cause thrombocytopenia. However, some patients do not develop thrombocytopenia despite long-term administration of LZD. To determine the risk factors for LZD-associated thrombocytopenia in patients undergoing long-term LZD therapy, we conducted a retrospective cohort study among 212 patients receiving LZD treatment between December 2011 and June 2014 at a tertiary referral university hospital in Nagoya, Japan. Of the 217 patients who received LZD, 37 were treated with LZD for more than 14 days and were enrolled in the study. We compared data on demographic characteristics, underlying disease, microbiology, concomitant drugs, and laboratory tests between the thrombocytopenia group and the non-thrombocytopenia group. Thrombocytopenia was defined as having a platelet count < 100 × 103/µL or a ≥ 50% reduction in platelet count compared to baseline. Among the 37 patients who received LZD for more than 14 days, 17 (45.9%) developed thrombocytopenia. Multivariate logistic regression revealed that both the number of concomitant drugs with thrombocytopenic adverse effects (DTADE) (OR = 1.690; 95% CI = 1.037-2.754; P = 0.035) and a small decrease in the level of C-reactive protein (CRP) 14 days post-administration (OR = 0.965; 95% CI = 0.939-0.993; P = 0.013) were associated with thrombocytopenia during long-term LZD therapy. Therefore, the number of concomitant DTADE and a small decrease in CRP on the 14th day of treatment were key factors for the appearance of LZD-associated thrombocytopenia in patients with long-term LZD therapy. Our findings may be useful for preventing thrombocytopenia in patients treated with LZD for longer than 14 days.

Molecular epidemiological analysis and risk factors for acquisition of carbapenemase-producing Enterobacter cloacae complex in a Japanese university hospital.

Background: To clarify the molecular epidemiology of carbapenem-resistant Enterobacter cloacae complex (CREC) and the risk factors for acquisition of carbapenemase-producing E. cloacae complex (CPEC). Methods: Using clinical CREC isolates detected in a Japanese university hospital over 4 years, carbapenemase production was screened with phenotypic methods. Carbapenemase genes were analysed by PCR and sequencing. Molecular epidemiological analyses were conducted with repetitive extragenic palindromic (REP)-PCR and multilocus sequence typing (MLST). CRECs were identified to the subspecies level by hsp60 sequencing. Whole-genome sequencing of plasmids was conducted. A case-control study was performed to identify risk factors for acquisition of CPEC among patients with CREC. Results: Thirty-nine CRECs including 20 CPECs carrying blaIMP-1 were identified. Patients with CPEC had longer hospital stay before detection (26.5 days vs. 12 days, p = 0.008), a urinary catheter (odds ratio [OR], 5.36; 95% confidence interval [CI], 1.14-30.9; p = 0.023), or intubation (OR, 7.53; 95% CI, 1.47-53.8; p = 0.008) compared to patients without CPEC. Four genetically closely related CPEC clusters were observed, which showed that three of four CPEC clusters corresponded to E. asburiae (ST 53), E. hormaechei subsp. steigerwaltii (ST 113 and ST 1047) and E. cloacae subsp. cloacae (ST 513) by MLST and hsp60 sequencing. Seven representative plasmids shared structures with class I integron containing blaIMP-1 and IncHI2A replicon type. Conclusions: A longer hospital stay, presence of a urinary catheter, and intubation are risk factors for CPEC acquisition. In addition to horizontal transmission of genetically indistinguishable CPECs, IncHI2A plasmid carrying blaIMP-1 appeared to be transferred among genetically different ECs.

Recurrent bacteremia and liver abscess caused by Clostridium difficile: A case report.

RATIONALE: Clostridium difficile bacteremia (CDB) and liver abscess is a quite rare presentation of C. difficile infection. PATIENTS CONCERNS: A 74-year-old male with primary biliary cirrhosis and hepatocellular carcinoma who underwent transarterial chemoembolization (TACE) developed a high fever on post-TACE day 14. Intravenous ceftriaxone and following meropenem were administered, however, his clinical response was poor. On post-TACE day 24, 2 sets of blood culture were taken due to elevation of C-reactive protein levels. DIAGNOSIS: CDB, caused by bacterial translocation. INTERVENTIONS: Intravenous vancomycin and oral metronidazole were administered for two weeks. OUTCOMES: One month after recurrent CDB, the patient was re-admitted due to a liver abscess at the same site of TACE. C. difficile was isolated from the liver abscess and the patient received 6 weeks of oral metronidazole treatment. CDB and liver abscess have not recurred since completion of antibiotic treatment. LESSONS: The spore-forming ability of C. difficile may contributed to the recurrent CDB episodes and liver abscess formation in necrotic liver tissue following TACE, and long-term metronidazole therapy was considered to be effective to C. difficile liver abscess.

Risk factors for and role of OprD protein in increasing minimal inhibitory concentrations of carbapenems in clinical isolates of Pseudomonas aeruginosa.

PURPOSE: This study examined the risk factors for, and molecular mechanisms underlying, the increase in carbapenem minimum inhibitory concentrations (MICs) in clinical isolates of Pseudomonas aeruginosa. METHODOLOGY: Consecutive clinical isolates of P. aeruginosa were collected. The MicroScan WalkAway system detected more than fourfold increases in the MICs of carbapenems in P. aeruginosa isolates serially recovered from some patients during their clinical course. The clinical risk factors associated with this increase were examined by multiple logistic regression analysis. Western blot analysis and nucleotide sequencing of the oprD gene of 19 clonally related and paired P. aeruginosa isolates from the same patients were undertaken to examine the mechanisms underlying the increase in MICs. RESULTS: The results showed that prior use of carbapenems (OR, 2.799; 95 % CI, 1.088-7.200; P=0.033) and the use of ventilators or tracheostomies (OR, 2.648; 95 % CI, 1.051-6.671; P=0.039) were risk factors for increased carbapenem MICs. Analysis of the underlying mechanisms revealed that loss of functional OprD protein due to mutation of the oprD gene tended to occur in P. aeruginosa isolates with imipenem MICs of more than 8 µg ml-1; a reduction in OprD expression was observed in P. aeruginosa isolates with imipenem MICs of 4 or 8 µg ml-1. This difference in the resistance mechanism was not correlated with the MICs of meropenem. CONCLUSION: This difference in the resistance mechanism of P. aeruginosa indicates a critical breakpoint at an imipenem MIC of 8 µg ml-1, in accordance with EUCAST criteria. Reducing carbapenem use will prevent P. aeruginosa clinical isolates from developing resistance to carbapenems.