Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

In vitro synergistic activity of aztreonam (AZT) plus novel and old ß-lactamase inhibitor combinations against metallo-ß-lactamase-producing AZT-resistant Enterobacterales.

The emergence of metallo-ß-lactamase (MBL)-producing Enterobacterales, mainly New Delhi metallo-ß-lactamase (NDM), represents a clinical threat due to the limited therapeutic alternatives. Aztreonam (AZT) is stable to MBLs, but most MBL-producing Enterobacterales isolates usually co-harbour other ß-lactamases that confer resistance to AZT and, consequently, its use is restricted in these isolates. We compared the ability of sulbactam (SUL), tazobactam (TAZ), clavulanic acid (CLA) and avibactam (AVI) to restore the AZT activity in MBL-producing AZT-resistant Enterobacterales isolates. A collection of 64 NDM-producing AZT-resistant Enterobacterales from five hospitals in Buenos Aires city, Argentina, were studied during the period July-December 2020. MICs were determined using the agar dilution method with Mueller-Hinton agar according to Clinical and Laboratory Standards Institute (CLSI) recommendations. AVI, SUL and TAZ were used at a fixed concentration of 4 mg l-1, whereas CLA was used at a fixed concentration of 2 mg l-1. A screening method based on disc diffusion to evaluate this synergy was also conducted. Detection of bla KPC, bla OXA, bla NDM, bla VIM, bla CTXM-1, bla PER-2 and bla CIT was performed by PCR. The AZT-AVI combination restored the AZT activity in 98.4 % of AZT-resistant strains, whereas CLA, TAZ and SUL did so in 70.3, 15.6 and 12.5 %, respectively, in isolates co-harbouring extended-spectrum ß-lactamases, but were inactive in isolates harbouring AmpC-type enzymes and/or KPC. The synergy screening test showed an excellent negative predictive value to confirm the absence of synergy, but positive results should be confirmed by a quantitative method. The excellent in vitro performance of the AZT-CLA combination represents a much more economical alternative to AZT-AVI, which could be of use in the treatment of MBL-producing, AZT-resistant Enterobacterales.

Evaluation of Antibiotic Allergies in Surgical Patients.

Antibiotic administration in the perioperative period is the foundation of preventing surgical site infections. ß-Lactam antibiotics, notably the first-generation cephalosporin cefazolin, are the drugs of choice for this indication. However, reported antibiotic allergies often result in the use of suboptimal alternative agents that can lead to an increased risk of infection and adverse effects. A comprehensive allergy history and risk stratification should be completed preoperatively to determine whether or not a patient can be rechallenged with a ß-lactam antibiotic and what testing may be necessary prior to administration. Nursing staff can play a critical role in understanding the implications and management of reported antibiotic allergies in surgical patients in order to optimize patient care.

Successful treatment of infective endocarditis due to pandrug-resistant Klebsiella pneumoniae with ceftazidime-avibactam and aztreonam.

Pandrug-resistant (PDR) K. pneumoniae refractory to conventional treatment has been reported worldwide, causing a huge burden on the healthcare system, patient safety and the economy. K. pneumoniae is a prominent opportunistic pathogen causing hospital-acquired and community-acquired infections, but is rarely associated with infective endocarditis. Currently, there are sparse data guiding the optimal regimen when commonly used antibiotics fail, notably for the treatment of endocarditis infections. Here we report our experience in treating a 40-year-old female with PDR K. pneumoniae infection of cardiovascular implantable electronic device (CIED) and right-sided infective endocarditis. Initial susceptibility testing of the incriminated pathogen showed an apparent susceptibility to colistin but the prolonged course of colistin, gentamicin and meropenem did not resolve the infection. However, the synergistic combinations of aztreonam with ceftazidime-avibactam was able to overcome resistance and clear the infection rapidly. Genome sequencing showed that the PDR K. pneumoniae isolate belongs to the international high-risk clone ST14. The isolate harbored genes encoding NDM-1, OXA-48, CTX-M-14b, SHV-28 and OXA-1, explaining resistance to all ß-lactams, including carbapenems. It carried the armA gene conferring resistance to all clinically important aminoglycosides and had alterations in GyrA, ParC and MgrB, explaining resistance to ciprofloxacin and colistin.

In vitro synergy of ticarcillin/clavulanate in combination with aztreonam and ceftolozane/tazobactam against SPM-1-producing Pseudomonas aeruginosa strains.

Minimal inhibitory concentrations (MICs) of ticarcillin/clavulanic acid (TLc), ceftolozane/tazobactam (C/T), and aztreonam (AT) were determined for 6 SPM-1-producing Pseudomonas aeruginosa (PSA) using Etest® strips and the synergistic effect of such antimicrobials against was evaluated by gradient diffusion strip crossing (GDSC) test. The fraction inhibitory concentration indexes (FICI) were calculated and showed a synergistic (n = 3) and additive (n = 2) effects of TLc + AT against SPM-1 producers, while TLc + C/T combination caused no effect. Average MIC reduction of TLc and AT by GDSC was 3-fold and 2-fold dilutions, respectively. Thus, TLc + AT might be a candidate as a combination therapy to treat SPM-1-producing PSA infections.

The clinical and microbiological utility of inhaled aztreonam lysine for the treatment of acute pulmonary exacerbations of cystic fibrosis: An open-label randomised crossover study (AZTEC-CF).

BACKGROUND: The objective of this study was to explore the clinical and microbiological outcomes associated with substituting inhaled aztreonam lysine for an intravenous antibiotic in the treatment of acute pulmonary exacerbations of CF. METHODS: An open-label randomised crossover pilot trial was conducted at a UK CF centre among 16 adults with CF and P. aeruginosa infection. Median [IQR] age was 29.5 [24.5-32.5], mean ± SD forced expiratory volume in 1 second (FEV1) was 52.4 ± 14.7 % predicted. Over the course of two exacerbations, participants were randomised to sequentially receive 14 days of inhaled aztreonam lysine plus IV colistimethate (AZLI+IV), or dual IV antibiotics (IV+IV). Primary outcome was absolute change in % predicted FEV1. Other outcomes evaluated changes in quality of life, bacterial load and the lung microbiota. RESULTS: The difference between mean change in lung function at day 14 between AZLI+IV and IV+IV was +4.6% (95% CI 2.1-7.2, p=0.002). The minimum clinically important difference of the Cystic Fibrosis Revised Questionnaire (CFQ-R) was achieved more frequently with AZLI+IV (10/12, 83.3%) than IV+IV (7/16, 43.8%), p=0.05. No differences were observed for modulation of serum white cell count, C-reactive protein or sputum bacterial load. Microbiome compositional changes were observed with IV+IV (Bray-Curtis r2=0.14, p=0.02), but not AZLI+IV (r2=0.03, p=0.64). CONCLUSION: In adults with CF and P. aeruginosa infection experiencing an acute pulmonary exacerbation, AZLI+IV improved lung function and quality of life compared to the current standard treatment. These findings support the need for larger definitive trials of inhaled antibiotics in the acute setting. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002832-34 ClinicalTrials.org NCT02894684.

Surgical infection prophylaxis prior to left ventricular assist device implantation: A survey of clinical practice.

BACKGROUND: Short duration, antimicrobial prophylaxis that includes antistaphylococcal activity is recommended at the time of left ventricular assist device (LVAD) implantation to reduce infection-related complications. There continues to be wide variability in surgical infection prophylaxis (SIP) regimens among implantation centers. The aim of this study is to characterize current SIP regimens at different LVAD centers. METHODS: A survey study was conducted from 26 September 2017 to 25 October 2017. Surveys were distributed electronically to LVAD coordinators and infectious diseases specialists at 75 US medical centers identified as having an LVAD program. Data collection included information about antimicrobial selection, duration, Staphylococcus aureus screening, and decolonization procedures. RESULTS: We received 29 survey responses. The majority of surveys were completed by infectious diseases physicians (72.4% [21 out of 29]). Most responding centers reported LVAD programs established for greater than 10 years (20 out of 29 [69%]). Cardiac transplantation was performed in 28 out of 29 (96%) centers. Of centers reporting a defined SIP regimen for non-penicillin allergic patients (96% [28 out of 29]), 17.9% (5 out of 28) reported a four-drug regimen, 35.7% (10 out of 28) reported a three-drug regimen, and 46.4% (13 out of 28) reported a two-drug regimen, while no centers reported a single-drug regimen. Empiric fluconazole was common (50% [14 out of 28]) and 96.4% (27 out of 28) of regimens included vancomycin. Duration of antimicrobial prophylaxis (24 hours to 5 days), S. aureus screening, decolonization procedures, and alterations due to drug allergies varied across participating centers. CONCLUSIONS: Our survey results indicate wide variation in SIP regimens among participating LVAD centers. These results highlight the need for studies evaluating the implications of SIP regimens, and whether clinical factors that prolong antimicrobial duration impact postoperative infection rates.

Intravenous Compatibility of Ceftazidime-Avibactam and Aztreonam Using Simulated and Actual Y-site Administration.

PURPOSE: The objective of this communication was to determine the intravenous compatibility of ceftazidime/avibactam and aztreonam using simulated and actual Y-site administration. METHODS: Ceftazidime-avibactam was reconstituted and diluted to concentrations of 8, 25, and 50 mg/mL in 0.9% sodium chloride. Aztreonam was reconstituted and diluted to concentrations of 10 and 20 mg/mL. Each combination of concentrations was tested for compatibility using visual, Tyndall beam, microscopy, turbidity, and pH assessments. Microscopy results were compared to those from sodium chloride 0.9% in water, pH was compared to that at time 0, and turbidity of combinations was compared to that of individual agents. Actual Y-site mixing was conducted over 2-h infusions with samples collected at 0, 1, and 2 h. Test results were evaluated at 0, 1, 2, 4, 8, and 12 h after mixing. All experiments were completed in triplicate. FINDINGS: Across simulated and actual Y-site experiments, no evidence of incompatibility between combinations of ceftazidime-avibactam + aztreonam was observed. Visual and microscopic tests revealed no particulate matter, color changes, or turbidity. Tyndall beam tests were negative with all combinations. No evidence of incompatibility was observed in turbidity testing. The pH values were consistent across each of the 6 combinations, from immediately after mixing until 12 h after mixing. When the addition of agents was reversed in simulated Y-site experiments, no differences in compatibility were observed. No differences in compatibility between actual and simulated Y-site administration were observed, and there was minimal variability across all replicate experiments. IMPLICATIONS: Ceftazidime-avibactam, at concentrations of 8, 25, and 50 mg/mL, appeared compatible with aztreonam at concentrations of 10 and 20 mg/mL.

Development of mechanism-based antibacterial synergy between Fmoc-phenylalanine hydrogel and aztreonam.

Recently, fluorenylmethyloxycarbonyl (Fmoc) conjugated amino acids (Fmoc-AA), especially Fmoc-phenylalanine (Fmoc-F), have been discovered to have antimicrobial properties specific to Gram-positive bacteria including MRSA. Their weak antibacterial activity against Gram-negative bacteria is due to their inability to cross the bacterial membrane. Here in order to increase the antibacterial spectrum of Fmoc-F, we prepared a formulation of Fmoc-F with the Gram-negative specific antibiotic aztreonam (AZT). This formulation displayed antibacterial activity against both Gram-positive and Gram-negative bacteria and significantly reduced the bacterial load in a mouse wound infection model. The combination produced a synergistic effect and higher efficacy against P. aeruginosa due to the increased Fmoc-F permeability by AZT through the bacterial membrane. This combinatorial approach could be an effective strategy for other Fmoc-AA having a Gram-positive specific antibacterial effect for the better management of bacterial wound infections.

Compatibility of aztreonam in four commercial peritoneal dialysis fluids.

The preferable route for treatment of peritoneal dialysis related peritonitis remains the intraperitoneal administration of antibiotics admixed to peritoneal dialysis fluids. It is important to know whether the administered drug is compatible with the PD fluids and its container. In the present study the compatibility of aztreonam with four commercial PDFs at storing temperatures and duration representative for storing conditions in the clinical settings was investigated. Aztreonam concentrations were determined using high-performance liquid chromatography. The antimicrobial activity of aztreonam was evaluated using an E. coli diffusion disk inhibition assay and P. aeruginosa time-kill curves. In Extraneal evaluated at 6 °C, 25 °C and 37 °C aztreonam was stable over the whole study period of 14 days and 24 hours, respectively. In Physioneal and Nutrineal aztreonam was stable at 6 °C for up to 14 days. Antimicrobial activity was retained in all PD fluids over the whole study period. Aztreonam remained stable and was compatible with the PD fluids, particularly with Extraneal or Nutrineal, and no compensatory dose adjustment is needed when stored for up to 14 days at refrigeration temperature before use.

Lung clearance index to detect the efficacy of Aztreonam lysine inhalation in patients with cystic fibrosis and near normal spirometry - A single-centre feasibility study.

Comparing the efficacy of inhaled antibiotics can be difficult in small groups of patients with cystic fibrosis and mild lung disease. In a feasibility study we compared Aztreonam lysine for inhalation solution (AZLI; Cayston®) to standard inhaled antibiotic therapy in patients with cystic fibrosis and near normal spirometry. To detect treatment responses we used both lung clearance index (LCI) and forced expiratory volume in one second (FEV1). At baseline, median FEV1 was 87% pred. and median LCI was 8.6 (upper limit of normal: 7.0). After 4 weeks, LCI improved by -0.36 after AZLI and deteriorated by +0.12 after tobramycin treatment (p = 0.039). No significant differences between treatments (p = 0.195) were observed using FEV1. These results suggest that lung clearance index can be used to detect treatment induced changes in subjects with mild lung disease.

Antibiotic therapy for chronic infection with Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) a life-limiting inherited disease affecting a number of organs, but classically associated with chronic lung infection and progressive loss of lung function. Chronic infection by Burkholderia cepacia complex (BCC) is associated with increased morbidity and mortality and therefore represents a significant challenge to clinicians treating people with CF. This review examines the current evidence for long-term antibiotic therapy in people with CF and chronic BCC infection. OBJECTIVES: The objective of this review is to assess the effects of long-term oral and inhaled antibiotic therapy targeted against chronic BCC lung infections in people with CF. The primary objective is to assess the efficacy of treatments in terms of improvements in lung function and reductions in exacerbation rate. Secondary objectives include quantifying adverse events, mortality and changes in quality of life associated with treatment. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched online trial registries and the reference lists of relevant articles and reviews.Date of last search: 29 May 2019. SELECTION CRITERIA: Randomised controlled trials (RCTs) of long-term antibiotic therapy in people with CF and chronic BCC infection. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias and assessed the quality of the evidence using GRADE. MAIN RESULTS: We included one RCT (100 participants) which lasted 52 weeks comparing continuous inhaled aztreonam lysine (AZLI) and placebo in a double-blind RCT for 24 weeks, followed by a 24-week open-label extension and a four-week follow-up period. The average participant age was 26.3 years, 61% were male and average lung function was 56.5% predicted.Treatment with AZLI for 24 weeks was not associated with improvement in forced expiratory volume in one second (FEV1), mean difference 0.91% (95% confidence interval (CI) -3.15 to 4.97) (moderate-quality evidence). The median time to the next exacerbation was 75 days in the AZLI group compared to 51 days in the placebo group, but the difference was not significant (P = 0.27) (moderate-quality evidence). Similarly, the number of participants hospitalised for respiratory exacerbations showed no difference between groups, risk ratio (RR) 0.88 (95% CI 0.53 to 1.45) (moderate-quality evidence). Overall adverse events were similar between groups, RR 1.08 (95% CI 0.98 to 1.19) (moderate-quality evidence). There were no significant differences between treatment groups in relation to mortality (moderate-quality evidence), quality of life or sputum density.In relation to methodological quality, the overall risk of bias in the study was assessed to be unclear to low risk. AUTHORS' CONCLUSIONS: We found insufficient evidence from the literature to determine an effective strategy for antibiotic therapy for treating chronic BCC infection.

Airway Bacterial Load and Inhaled Antibiotic Response in Bronchiectasis.

Rationale: The principal underlying inhaled antibiotic treatment in bronchiectasis is that airway bacterial load drives inflammation, and therefore antibiotic treatment will reduce symptoms. Objectives: To determine the relationship between bacterial load and clinical outcomes, assess the stability of bacterial load over time, and test the hypothesis that response to inhaled antibiotics would be predicted by baseline bacterial load. Methods: We performed three studies. Studies 1 and 2 were prospective studies including adults with bronchiectasis. Study 3 was a post hoc analysis of a randomized trial of inhaled aztreonam. A priori patients were divided into low (<105 cfu/g), moderate (105-106 cfu/g), and high bacterial load (≥107 cfu/g) using quantitative sputum culture. Measurements and Main Results: Bacterial load was a stable trait associated with worse quality of life and more airway inflammation in studies 1, 2, and 3. In study 3, patients with high bacterial load showed an improvement in the primary endpoint (Quality of Life-Bronchiectasis-Respiratory Symptoms Score at Week 4) in favor of aztreonam (mean difference of 9.7 points; 95% confidence interval, 3.4-16.0; P = 0.003). The proportion of patients who achieved an increase above the minimum clinically important difference was higher in the aztreonam group at Week 4 (63% vs. 37%; P = 0.01) and at Week 12 (62% vs. 38%; P = 0.01) only in high bacterial load patients. Conclusions: Improvement of quality of life with inhaled aztreonam was only evident in patients with high bacterial load. Bacterial load may be a useful biomarker of severity of disease and treatment response.

The effects of cycled inhaled aztreonam on the cystic fibrosis (CF) lung microbiome.

BACKGROUND: To improve clinical outcomes, cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infections are prescribed inhaled anti-pseudomonal antibiotics. Although, a diverse microbial community exists within CF airways, little is known about how the CF microbiota influences patient outcomes. We hypothesized that organisms within the CF microbiota are affected by inhaled-antibiotics and baseline microbiome may be used to predict therapeutic response. METHODS: Adults with chronic P. aeruginosa infection from four clinics were observed during a single 28-day on/off inhaled-aztreonam cycle. Patients performed serial sputum collection, CF-respiratory infection symptom scores (CRISS), and spirometry. Patients achieving a decrease of ≥2 CRISS by day 28 were categorized as subjective responders (SR). The airway microbiome was defined by Illumina MiSeq analysis of the 16S rRNA gene. RESULTS: Thirty-seven patients (median 37.4 years and FEV1 44% predicted) were enrolled. No significant cohort-wide changes in the microbiome were observed between on/off AZLI cycles in either alpha- or beta-diversity metrics. However, at an individual level shifts were apparent. Twenty-one patients (57%) were SR and fourteen patients did not subjectively respond. While alpha-diversity metrics did not associate with response, patients who did not subjectively respond had a higher abundance of Staphylococcus and Streptococcus, and lower abundance of Haemophilus. CONCLUSIONS: The CF microbiome is relatively resilient to AZLI perturbations. However, associated changes were observed at the individual patient level. The relative abundance of key "off-target" organisms associated with subjective improvements suggesting that the microbiome may be used as a tool to predict patient response - potentially improving outcomes.

Impact of a Standardized Beta-Lactam Allergy Questionnaire on Aztreonam Use.

METHODS: This quasi-experimental study compared the aztreonam utilization in patients with self-reported beta-lactam allergies admitted to an inpatient service between two study periods (pre- and post-implementation). Post-implementation followed the initiation of a standardized beta-lactam allergy questionnaire, a student pharmacist-driven performance improvement project for beta-lactam allergy documentation. Interviews clarified the allergy, reaction history, and any previous tolerance of beta-lactams. If receiving aztreonam at the time of the questionnaire, recommendations were made for changes in therapy if deemed appropriate by the pharmacist. RESULTS: A total of 95 patients were included in the pre-implementation group versus 65 patients in the post-implementation group. Baseline characteristics were similar. The average number of aztreonam doses per 1000 patient-days in the post-implementation group was decreased (21.23 vs 9.05, P = .003). The average number of days of therapy per 1000 patient-days in the post-implementation group was decreased (8.79-4.24, P = .016). An increase in the number of aztreonam de-escalations was observed post-implementation (P = .003). A total of 122 questionnaires were completed with 114 allergy documentation updates. There were no reported instances of adverse events. CONCLUSION: Utilization of a standardized beta-lactam allergy questionnaire as a pharmacy education tool resulted in a statistically significant decrease in aztreonam utilization, based on doses, days of therapy, and de-escalations.

In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae.

Background: In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains. Methods: The microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA-232 carbapenemase-producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase-producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase-producing K. pneumoniae strain Y8 Infection was performed in the mouse model. Results: The time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy. Conclusion: This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved.

Synergy of nebulized phage PEV20 and ciprofloxacin combination against Pseudomonas aeruginosa.

Nebulization is currently used for delivery of antibiotics for respiratory infections. Bacteriophages (or phages) are effective predators of pathogens including Pseudomonas aeruginosa commonly found in the lungs of patients with cystic fibrosis (CF). It is known that phages and antibiotics can potentially show synergistic antimicrobial effect on bacterial killing. In the present study, we investigated synergistic antimicrobial effect of phage PEV20 with five different antibiotics against three P. aeruginosa strains isolated from sputum of CF patients. The antibiotics included ciprofloxacin, tobramycin, colistin, aztreonam and amikacin, which are approved by U.S Food and Drug Administration (FDA) for inhaled administration. Phage and antibiotic synergy was determined by assessing bacterial killing performing time-kill studies. Among the different phage-antibiotic combinations, PEV20 and ciprofloxacin exhibited the most synergistic effect. Two phage-ciprofloxacin combinations, containing 1/4 and 1/2 of the minimum inhibitory concentration (MIC) of ciprofloxacin against P. aeruginosa strains FADD1-PA001 (A) and JIP865, respectively were aerosolized using both air-jet and vibrating mesh nebulizers and the synergistic antibacterial activity was maintained after nebulization. Air-jet nebulizer generated droplets with smaller volume median diameters (3.6-3.7 µm) and slightly larger span (2.3-2.4) than vibrating mesh nebulizers (5.1-5.3 µm; 2.1-2.2), achieving a higher fine particle fraction (FPF) of 70%. In conclusion, nebulized phage PEV20 and ciprofloxacin combination shows promising antimicrobial and aerosol characteristics for potential treatment of respiratory tract infections caused by drug-resistant P. aeruginosa.

Initiative to reduce aztreonam use in patients with self-reported penicillin allergy: Effects on clinical outcomes and antibiotic prescribing patterns.

PURPOSE: Evaluation of the clinical impact of a pharmacist led-penicillin allergy assessment initiative to enhance antibiotic selection is reported. METHODS: A retrospective analysis was conducted on patients with a self-reported penicillin allergy (SRPA) at a 529-bed community teaching hospital and compared clinical response rate before and after implementation of a penicillin allergy assessment initiative, consisting of pharmacy staff education and pocket card development. Patients admitted with SRPA who received antibiotics with gram-negative coverage for at least 48 hours were included. The primary outcome was the clinical response rate of penicillin-allergic patients determined preimplementation and postimplementation of the initiative and was based upon improvement in signs and symptoms of infection. Secondary outcomes included antibiotics used, antibiotic durations, length of stay, survival rate, antibiotic discontinuation rate, and Clostridium difficile infection rate. RESULTS: A total of 280 patients were reviewed. Clinical response rate improved after implementation of the initiative (p = 0.047). There were significant differences in the type of antibiotics prescribed between the preimplementation group and the postimplementation group: increased cephalosporin use (p < 0.001), decreased aztreonam use (p = 0.017), and lower fluoroquinolone use (p = 0.008). Median length of stay (p = 0.943), in-hospital mortality rate (p = 0.173), and C. difficile infection rate (p = 0.426) were similar before and after implementation of the initiative. CONCLUSION: After implementation of an initiative to encourage the use of cephalosporins rather than aztreonam in patients with SRPA, the rate of clinical response and cephalosporin use increased and rates of exposure to aztreonam and fluoroquinolones decreased.

Simplified Aztreonam Dosing in Patients with End-Stage Renal Disease: Results of a Monte Carlo Simulation.

The manufacturer-recommended aztreonam dosing for patients with creatinine clearance values of <10 ml/min/1.73 m2 is complex. It is not known whether simpler posthemodialysis dosing administered once daily or thrice weekly can reliably achieve pharmacodynamic goals. We found that 1 or 2 g administered once daily after hemodialysis had >90% probability of target attainment up to MICs of 4 or 8 mg/liter, respectively. Thrice-weekly dosing should generally be avoided, except in nonsevere infections with MICs of ≤0.5 mg/liter.