Rethinking residency recruitment, application, and interview processes to benefit applicants and programs long-term.

Pharmacy residency recruitment and interviews have been significantly impacted by the COVID-19 pandemic. Many traditional recruitment events and interviews were transitioned from in-person to virtual, and new approaches to recruitment, such as virtual open houses, were developed. There are limited data on how these changes impacted pharmacy residency applicants and programs, and the future of virtual events is currently unknown. We highlight recommendations for virtual recruitment and interviews and provide suggestions for residency programs and national organizations to improve virtual processes in the future.

Effect of Obesity on Clinical Outcomes of Patients Treated With Cefepime.

Background: As the prevalence of obesity climbs, dosing of antimicrobials, particularly cephalosporins, is becoming a greater challenge for clinicians. Data are lacking for appropriate dosing of cefepime, an anti-pseudomonal cephalosporin that is widely used as an empiric anti-pseudomonal agent. Objective: The purpose of this study was to determine the rate of clinical treatment failure in obese patients compared with nonobese patients receiving cefepime as definitive monotherapy. Methods: Adult inpatients treated with cefepime monotherapy for ≥72 hours were included. Patients were excluded if they (1) were not able to achieve culture clearance within 72 hours and (2) had polymicrobial infections requiring more than one antibiotic for definitive therapy. Results: Fifty-eight obese patients and 56 nonobese patients were included. Pseudomonas aeruginosa, Escherichia coli, and Enterobacter spp were the most prevalent organisms isolated. Most organisms had a minimum inhibitory concentration of ≤1 µg/mL to cefepime with no differences in minimum inhibitory concentration distributions between groups. Definitively, 60% of patients received cefepime 1 g, while almost 40% received cefepime 2 g. Clinical failure occurred in 52% of patients (67% obese vs 36% nonobese; P = .001), with study group (odds ratio = 1.057, 95% confidence interval = 1.008-1.109) and respiratory source (odds ratio = 3.251, 95% confidence interval = 1.378-7.667) being independent predictors of failure. There were no differences in hospital length of stay, all-cause mortality, or 30-day readmissions. Conclusions: Obese patients treated with cefepime are more likely to experience treatment failure than nonobese patients. Larger trials examining the reasons for clinical failure in obese patients treated with cefepime are needed to confirm the findings from this preliminary work.

An Evaluation of Pharmacist-Led Interventions for Inpatient HIV-Related Medication Errors.

Background: Inpatient HIV-related medication errors occur in up to 86% of patients. Objective: To evaluate the number of antiretroviral therapy (ART)- and opportunistic infection (OI)-related medication errors following the implementation of pharmacist-directed interventions. Methods: This quasi-experiment assessed adult patients with HIV who received ART, OI prophylaxis, or both from December 1, 2014, to February 28, 2017 (pre-intervention) or December 1, 2017, to February 28, 2018 (post-intervention). Pre-intervention patients were assessed retrospectively; verbal and written education were provided (intervention); prospective audit and feedback was conducted for post-intervention patients. The primary outcome was rate of ART errors between groups. Secondary outcomes included rate of OI errors, time to resolution of ART and OI errors, types of errors, and rate of recommendation acceptance. Results: Sixty-seven patients were included in each group. ART errors occurred in 44.8% and 32.8% (P = .156), respectively. OI prophylaxis errors occurred in 11.9% versus 9% (P = .572), respectively. Medication omission decreased significantly in the post-intervention group (31.3% vs 11.9%; P = .006). Pharmacist-based interventions increased in the post-intervention group (6.3% vs 52.9%; P = .001). No statistical difference was found in time to error resolution (72 vs 48 hours; P = .123), but errors resolved during admission significantly increased (50% vs 86.8%; P < .001). No difference was found in rate of intervention acceptance (100% vs 97%). Conclusion and Relevance: ART and OI prophylaxis errors resolved a day faster in the pharmacist-led, post-intervention period, and there was a trend toward error reduction. Future interventions should target prescribing errors on admission using follow-up education and evaluation of medication reconciliation practices in HIV-infected patients.

Ceftazidime/avibactam versus standard-of-care agents against carbapenem-resistant Enterobacteriaceae harbouring blaKPC in a one-compartment pharmacokinetic/pharmacodynamic model.

Background: 'Last-line' antimicrobial usage has promoted the emergence of MDR bacteria. Production of Klebsiella pneumoniae carbapenemases (KPCs) is increasingly common and leads to resistance to most antimicrobials. However, ceftazidime/avibactam demonstrates activity against KPC-producing strains. Ceftazidime/avibactam in the empirical setting remains unknown. Methods: Strains underwent genetic analysis evaluating blaKPC presence/production and MICs were determined. Four strains were assessed in an in vitro, one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for 96 h. The following bolus dosing exposures were tested: 2.5 g of ceftazidime/avibactam every 8 h, 2 g of meropenem every 8 h, 1.25 mg/kg polymyxin B every 12 h, amikacin 'once-daily dosing' (peak of 70-80 mg/L), tigecycline at 200 mg ×1 dose followed by 100 mg every 12 h, and a drug-free growth control. Results: Thirty blaKPC-producing strains were evaluated; 97% of strains were ceftazidime/avibactam susceptible with MIC50/MIC90 values of 0.38/1.5 mg/L (range 0.032-16 mg/L). Two K. pneumoniae strains, one Klebsiella oxytoca strain and one Citrobacter freundii strain underwent further analysis in PK/PD models. Ceftazidime/avibactam displayed potent activity with a reduction of 4.23 ±âŸ0.42 cfu/mL from the initial inoculum at 96 h. Against susceptible isolates, amikacin displayed similar activity compared with ceftazidime/avibactam at 96 h, although this was not demonstrated against all strains. Polymyxin B produced comparable activity to ceftazidime/avibactam against two strains. Neither meropenem nor tigecycline produced effective killing and were comparable to the drug-free growth control at 96 h. Conclusions: blaKPC-producing organisms demonstrated susceptibility to ceftazidime/avibactam and bactericidal activity was observed in the PK/PD model. Based on these data, ceftazidime/avibactam is a valuable agent for treating KPC-producing organisms and should be considered for treatment of infections caused by these pathogens.

Risk Factors for Failure in Complicated Intraabdominal Infections.

OBJECTIVES: Approximately 20% of patients with complicated intraabdominal infections (cIAIs) fail therapy. The purpose of this study was to identify risk factors for clinical failure in patients with cIAIs. METHODS: International Classification of Diseases, Ninth Revision codes for cIAIs were obtained to identify patients. Adult patients who received at least 48 hours of intravenous antibiotics were included. Patients were chronologically matched for age, sex, and comorbidities. The primary outcome was clinical failure. Statistical analysis included bivariate tests and multivariable logistic regression. RESULTS: A total of 1405 patients were screened; 139 patients were included. The median (interquartile range) age and Charlson Comorbidity Index were 54 (37-62) years and 0 (0-1), respectively. Clinical failure was observed in 47 patients (34%), with 5 deaths (3.6%). Multivariate analysis of the unmatched population showed older age was protective (odds ratio [OR] 0.967, 95% confidence interval [CI] 0.944-0.991). In the matched population elevated serum creatinine (OR 2.2168, 95% CI 1.091-4.308) and increased time to source control (OR 1.015, 95% CI 1.000-1.030) were predictive of clinical failure. CONCLUSIONS: In a low comorbid cIAI population with and without surgical intervention, serum creatinine was an independent risk factor for clinical failure. In the matched case-control of patients, time to source-control procedure was an independent predictor of clinical failure.

Daptomycin in Combination with Ceftolozane-Tazobactam or Cefazolin against Daptomycin-Susceptible and -Nonsusceptible Staphylococcus aureus in an In Vitro, Hollow-Fiber Model.

Ceftolozane-tazobactam (TOL-TAZ) is a novel cephalosporin/beta-lactamase inhibitor with activity against several Gram-negative pathogens. Daptomycin (DAP) has demonstrated synergistic activity with beta-lactams against methicillin-resistant Staphylococcus aureus (MRSA) isolates with reduced lipopeptide and glycopeptide susceptibilities. Our objective was to determine if DAP and TOL-TAZ possess synergy in hollow-fiber pharmacokinetic/pharmacodynamic (PK/PD) models. One isogenic pair of daptomycin-susceptible and daptomycin-nonsusceptible MRSA strains was evaluated. DAP, TOL-TAZ, and cefazolin (CFZ) MIC determinations were performed. DAP MIC determinations were also performed in the presence of subinhibitory concentrations of TOL-TAZ and CFZ. Ninety-six-hour in vitro models were run, simulating DAP at 10 mg/kg of body weight/day; TOL-TAZ at 1,500 mg every 8 h; TOL at 1,000 mg every 8 h; and DAP combined with TOL-TAZ (DAP+TOL-TAZ), DAP+TOL, DAP+TAZ, and DAP+CFZ at 2,000 mg every 8 h. DAP MICs were 0.5 and 4 µg/ml for strains R8845 and R8846, respectively. In the presence of CFZ, R8845 and R8846 DAP MICs were reduced 8-fold and 16-fold, respectively. TOL and TAZ had no effect on DAP MICs. PK/PD models demonstrated bactericidal activity with DAP+CFZ against both strains. The combination of DAP+TOL-TAZ was bactericidal against R8845 but was not bactericidal against daptomycin-nonsusceptible strain R8846. DAP+TOL and DAP+TAZ were not bactericidal. No other regimens were bactericidal. DAP+TOL-TAZ did not demonstrate synergistic activity against daptomycin-nonsusceptible S. aureus but prevented daptomycin-nonsusceptible MRSA emergence. Because DAP+TOL or TAZ alone did not prevent daptomycin-nonsusceptible MRSA emergence, the combination TOL-TAZ may be necessary for synergy with DAP. DAP+CFZ demonstrated enhancement against both strains. The combination of DAP+CFZ warrants further clinical study.

Evaluation of tedizolid against Staphylococcus aureus and enterococci with reduced susceptibility to vancomycin, daptomycin or linezolid.

OBJECTIVES: Tedizolid displays potent activity against Gram-positive pathogens. In vitro studies against clinical isolates of Staphylococcus aureus and enterococci demonstrated improved tedizolid activity over linezolid. However, this is not well-characterized against a large collection of resistant isolates, including vancomycin-intermediate S. aureus (VISA), heterogeneous VISA (hVISA), daptomycin-non-susceptible (DNS) S. aureus, linezolid-resistant (LR) S. aureus and VRE. Therefore, our objective was to determine tedizolid activity versus other agents, against MRSA and VRE with various resistance phenotypes. METHODS: In total, 302 MRSA (75 DNS, 100 VISA, 120 hVISA and 7 LR) and 220 VRE [100 Enterococcus faecalis (all susceptible to daptomycin and linezolid) and 120 E. faecium (25 DNS and 10 LR)] were evaluated. LR isolates were analysed for the cfr gene. MICs of tedizolid, linezolid, ampicillin, clindamycin, daptomycin, gentamicin, levofloxacin, oxacillin, tigecycline, trimethoprim/sulfamethoxazole and vancomycin were determined in accordance with CLSI guidelines. RESULTS: Tedizolid MIC90 values for hVISA, VISA and DNS were 0.5 mg/L (versus 4, 4 and 2 mg/L, respectively, for linezolid). The tedizolid MIC range for LR MRSA was 0.063-1 mg/L. Two LR MRSA possessed the cfr gene with tedizolid MICs of 0.125 and 0.25 mg/L (linezolid MICs of 16 and 8 mg/L). The tedizolid MIC90 for vancomycin-resistant E. faecalis and E. faecium was 0.25 and 1 mg/L, respectively; three dilutions lower for E. faecalis and two dilutions lower for E. faecium compared with linezolid. CONCLUSIONS: Tedizolid MICs demonstrate activity against isolates with decreased susceptibility to alternative agents, including linezolid. Tedizolid may be a viable treatment option in clinical situations with MDR Gram-positive pathogens.

Ceftazidime/Avibactam: Who Says You Can't Teach an Old Drug New Tricks?

PURPOSE: Gram-negative resistance continues to rise with treatment options becoming more limited. Ceftazidime/avibactam was recently approved in the United States and Europe, which combines an established third-generation cephalosporin with a new, unique, non-ß-lactam ß-lactamase inhibitor. This review conducts a thorough examination of structure, pharmacology, spectrum of activity, pharmacokinetics/pharmacodynamics, in vitro and clinical efficacy and safety/tolerability of ceftazidime/avibactam, as well as detailed future directions for the agent. METHODS: Pubmed and clinicaltrials.gov searches, as well as abstracts from the 2015 Interscience Conference on Antimicrobial Agents and Chemotherapy/International Society of Chemotherapy (ICAAC/ICC) and ID Week meetings and the 2016 American Society of Microbiology Microbe meeting, were conducted from January 2004 - September 2016. Relevant search terms included ceftazidime, ceftazidime/avibactam, avibactam, NXL104 and AVE1330A. The US package insert for ceftazidime/avibactam (02/2015) and European public assessment report (06/2016) were also reviewed. RESULTS: In vitro susceptibility for ceftazidime/avibactam displayed potent activity against many Enterobacteriaceae including extended-spectrum-ß-lactamase (ESBL) and carbapenemase-producing strains, as well as Pseudomonas aeruginosa. Phase II clinical trials utilized for approval demonstrated comparable safety and efficacy to imipenem/cilistatin for treatment of complicated urinary tract infections (70.4% vs. 71.4%) and combined with metronidazole compared to meropenem in complicated intra-abdominal infections (91.2% vs 93.4%). Phase III data displayed non-inferior efficacy of ceftazidime/avibactam compared to doripenem for complicated urinary tract infections (70.2% vs 66.2%) and combined with metronidazole compared to meropenem in complicated intra-abdominal infections (82.5% vs 84.9%), as well as comparable safety. Ceftazidime/avibactam was well-tolerated but does require renal adjustments. Additionally, 3 case series and a single case report have demonstrated the potential for ceftazidime/avibactam against multidrug resistant organisms for compassionate use or failure after previous therapy. CONCLUSION: By adding avibactam to ceftazidime, clinicians' antimicrobial armamentarium is expanded, potentially increasing the ability to combat multi-drug resistant gram-negative pathogens, particularly ESBL and carbapenemase-producing organisms, as well as Pseudomonas aeruginosa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Telavancin demonstrates activity against methicillin-resistant Staphylococcus aureus isolates with reduced susceptibility to vancomycin, daptomycin, and linezolid in broth microdilution MIC and one-compartment pharmacokinetic/pharmacodynamic models.

Methicillin-resistant Staphylococcus aureus (MRSA) isolates have arisen with reduced susceptibility to several anti-MRSA agents. Telavancin (TLV), a novel anti-MRSA agent, retains low MICs against these organisms. Our objective was to determine the MICs for TLV, daptomycin (DAP), vancomycin (VAN), and linezolid (LZD) against daptomycin-nonsusceptible (DNS) S. aureus, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), and linezolid-resistant (LZD(r)) S. aureus. We also evaluated these agents against each phenotype in pharmacokinetic/pharmacodynamic (PK/PD) models. Seventy DNS, 100 VISA, 180 hVISA, and 25 LZD(r) MRSA isolates were randomly selected from our library and tested to determine their MICs against TLV, DAP, VAN, and LZD via broth microdilution and a Trek panel. Four isolates were randomly selected for 168-h in vitro models to evaluate treatment with TLV at 10 mg/kg of body weight/day, DAP at 10 mg/kg/day, VAN at 1 g every 12 h (q12h), and LZD at 600 mg q12h. The MIC50/90 for TLV, DAP, VAN, and LZD against 70 DNS S. aureus isolates were 0.06/0.125 µg/ml, 2/4 µg/ml, 1/2 µg/ml, and 2/2 µg/ml, respectively. Against 100 VISA isolates, the MIC50/90 were 0.06/0.125 µg/ml, 1/1 µg/ml, 4/8 µg/ml, and 1/2 µg/ml, respectively. Against 170 hVISA isolates, the MIC50/90 were 0.06/0.125 µg/ml, 0.5/1 µg/ml, 1/2 µg/ml, and 1/2 µg/ml, respectively. Against 25 LZD(r) isolates, the MIC50/90 were 0.03/0.06 µg/ml, 1/1 µg/ml, 2/2 µg/ml, and 8/8 µg/ml, respectively. The TLV MIC was >0.125 µg/ml for 10/365 (2.7%) isolates. In PK/PD models, TLV was universally bactericidal at 168 h and statistically superior to all antibiotics against DNS S. aureus strain R2334. These data further establish the potency of TLV against resistant MRSA. The model data demonstrate in vitro bactericidal activity of TLV against hVISA, VISA, DNS S. aureus, and LZD(r) S. aureus strains. Further clinical research is warranted.

ß-Lactams enhance daptomycin activity against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium in in vitro pharmacokinetic/pharmacodynamic models.

Enterococcus faecalis and Enterococcus faecium are frequently resistant to vancomycin and ß-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate ß-lactam synergy with daptomycin (DAP) against resistant enterococci. One E. faecalis strain (R6981) and two E. faecium strains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h, in vitro models were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 µg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P < 0.001 and log10 CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P < 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P < 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.

Evaluation of Ceftaroline Alone and in Combination against Biofilm-Producing Methicillin-Resistant Staphylococcus aureus with Reduced Susceptibility to Daptomycin and Vancomycin in an In Vitro Pharmacokinetic/Pharmacodynamic Model.

Annually, medical device infections are associated with >250,000 catheter-associated bloodstream infections (CLABSI), with up to 25% mortality. Staphylococcus aureus, a primary pathogen in these infections, is capable of biofilm production, allowing organism persistence in harsh environments, offering antimicrobial protection. With increases in S. aureus isolates with reduced susceptibility to current agents, ceftaroline (CPT) offers a therapeutic alternative. Therefore, we evaluated whether CPT would have a role against biofilm-producing methicillin-resistant S. aureus (MRSA), including those with decreased susceptibilities to alternative agents. In this study, we investigated CPT activity alone or combined with daptomycin (DAP) or rifampin (RIF) against 3 clinical biofilm-producing MRSA strains in an in vitro biofilm pharmacokinetic/pharmacodynamic (PK/PD) model. Simulated antimicrobial regimens were as follows: 600 mg of CPT every 8 h (q8h) (free maximum concentration of drug [fCmax], 17.04 mg/liter; elimination half-life [t1/2], 2.66 h), 12 mg/kg of body weight/day of DAP (fCmax, 14.7 mg/liter; t1/2, 8 h), and 450 mg of RIF q12h (fCmax, 3.5 mg/liter; t1/2, 3.4 h), CPT plus DAP, and CPT plus RIF. Samples were obtained and plated to determine colony counts. Differences in log10 CFU/cm(2) were evaluated by analysis of variance with Tukey's post hoc test. The strains were CPT and vancomycin susceptible and DAP nonsusceptible (DNS). CPT displayed activity throughout the experiment. DAP demonstrated initial activity with regrowth at 24 h in all strains. RIF was comparable to the drug-free control, and little benefit was observed when combined with CPT. CPT plus DAP displayed potent activity, with an average log10 CFU/cm(2) reduction of 3.33 ± 1.01 from baseline. CPT demonstrated activity against biofilm-producing DNS MRSA. CPT plus DAP displayed therapeutic enhancement over monotherapy, providing a potential option for difficult-to-treat medical device infections.

The combination of ceftaroline plus daptomycin allows for therapeutic de-escalation and daptomycin sparing against MRSA.

OBJECTIVES: We previously demonstrated that ceftaroline enhances daptomycin against MRSA in vitro. However, prolonged combination therapy is clinically undesirable and possibly unnecessary. The purpose of this study was to determine if this combination could be de-escalated to a single agent without compromising efficacy. METHODS: We investigated the following simulated regimens against two clinical, daptomycin-non-susceptible MRSA isolates in an in vitro pharmacokinetic/pharmacodynamic hollow-fibre model over 192 h: 600 mg of ceftaroline every 12 h (fCmax 17.0 mg/L, t½ 2.66 h); 10 mg/kg/day daptomycin (fCmax 11.3 mg/L, t½ 8 h); 6 mg/kg/day daptomycin (fCmax 7.5 mg/L, t½ 8 h); ceftaroline+daptomycin; and ceftaroline+daptomycin de-escalated to ceftaroline, daptomycin or drug-free simulations. RESULTS: Daptomycin and ceftaroline MICs were 2 and 2 and 0.5 and 1 mg/L for strains R6063 and R5563, respectively. Ceftaroline+daptomycin (6 or 10 mg/kg/day) achieved a >5 log10 cfu/mL reduction within 96 h against both strains. Bacterial counts remained <1.5 log10 cfu/mL from 96 to 192 h regardless of de-escalation to either agent. There were no significant differences between combination or de-escalation regimens for either organism at either daptomycin dose. All combination/de-escalation to monotherapy regimens resulted in significantly improved activity compared with drug-free control, ceftaroline or daptomycin monotherapy (P<0.01). CONCLUSIONS: These findings confirm that ceftaroline+daptomycin is a potent combination against MRSA. The high degree of bactericidal activity observed with this combination appears sufficiently robust to allow for de-escalation to a single agent without bacterial regrowth. The equivalent activity observed with ceftaroline+daptomycin (6 and 10 mg/kg/day) suggests this combination could also be daptomycin sparing. Further research is warranted to optimize dose and de-escalation timing.

ß-Lactam combinations with daptomycin provide synergy against vancomycin-resistant Enterococcus faecalis and Enterococcus faecium.

OBJECTIVES: Enterococcus faecalis (Efc) and Enterococcus faecium (Efm) are frequently resistant to vancomycin and ß-lactams (BLs). In vitro data suggest synergy between several BLs and glycopeptides or lipopeptides against resistant pathogens. Our objective was to conduct combination MIC and time-kill experiments to evaluate BL synergy with daptomycin against enterococci. METHODS: Fifteen Efc and 20 Efm strains were evaluated for daptomycin enhancement via combination MICs. Daptomycin MICs were obtained by microdilution in the absence and presence of ceftaroline, ertapenem, cefepime, ceftriaxone, cefotaxime, cefazolin and ampicillin. Two Efc strains (R6981 and R7808) and one isogenic daptomycin-susceptible/daptomycin-non-susceptible Efm pair (8019/5938) were evaluated in time-kill experiments. Daptomycin at 0.5 × MIC was used in combination with BL at biological free concentration. Strain 5938 was evaluated for enhancement of daptomycin binding in fluorescently labelled daptomycin (BoDipy) experiments. RESULTS: Ceftaroline reduced daptomycin MIC values the most against all strains. In time-kill experiments, ceftaroline, ertapenem, cefepime, ceftriaxone and ampicillin demonstrated synergy with daptomycin against all strains, cefazolin demonstrated none and cefotaxime demonstrated synergy against only R7808. Bacterial reduction at 24 h was greater for daptomycin + ceftaroline, ertapenem, cefepime, ceftriaxone or ampicillin for all strains compared with any single agent or daptomycin + cefazolin or cefotaxime (P < 0.001). In BoDipy daptomycin experiments, ceftaroline enhanced daptomycin binding most compared with all other agents (P < 0.001). CONCLUSIONS: The data support the potential use of daptomycin/BL combination therapy in infections caused by VRE. Combination regimens, other than those involving cefazolin and cefotaxime, provide better kill compared with daptomycin alone. Further clinical research involving daptomycin combinations is warranted.

Ceftobiprole and ampicillin increase daptomycin susceptibility of daptomycin-susceptible and -resistant VRE.

OBJECTIVES: The synergistic combination of daptomycin plus ampicillin has proven to be effective against VRE including daptomycin-non-susceptible strains. Ceftobiprole is a cephalosporin with broad binding affinity for enterococcal PBP subtypes including PBP5. Given the synergy between ß-lactams and daptomycin against VRE, it was of interest to determine whether ceftobiprole offered any synergistic advantage with daptomycin compared with ampicillin. METHODS: MICs were determined by broth microdilution in the presence and absence of ampicillin or ceftobiprole for 20 ampicillin-resistant VRE. Six strains, including two isogenic pairs of vancomycin-resistant Enterococcus faecium and two vancomycin-resistant Enterococcus faecalis, were evaluated for synergy using time-kill methods. Synergy was defined as a ≥2 log10 cfu/mL reduction of the combination over the most active single agent. Binding of daptomycin-bodipy in the presence and absence of ceftobiprole was quantified. RESULTS: Daptomycin MICs ranged from 2 to 256 mg/L. The addition of ceftobiprole and ampicillin reduced daptomycin MICs by a median of 3 and 4 log2 dilutions, respectively. In time-kill studies, daptomycin plus either ceftobiprole or ampicillin was synergistic against four of six strains, but not the same strains. Both combinations were synergistic against the vancomycin-resistant E. faecalis strains. Ceftobiprole exposure increased daptomycin-bodipy binding by 2.8 times (P<0.0001). CONCLUSIONS: Ceftobiprole appears to offer a similar degree of synergistic activity to ampicillin when combined with daptomycin against VRE. Further research should explore the genetic and phenotypic qualities of strains that respond preferentially to ceftobiprole as opposed to ampicillin.

A novel approach utilizing biofilm time-kill curves to assess the bactericidal activity of ceftaroline combinations against biofilm-producing methicillin-resistant Staphylococcus aureus.

Medical device infections frequently require combination therapy. Beta-lactams combined with glycopeptides/lipopeptides are bactericidal against methicillin-resistant Staphylococcus aureus (MRSA). Novel macrowell kill-curve methods tested synergy between ceftaroline or cefazolin plus daptomycin, vancomycin, or rifampin against biofilm-producing MRSA. Ceftaroline combinations demonstrated the most pronounced bacterial reductions. Ceftaroline demonstrated greatest kill with daptomycin (4.02 ± 0.59 log10 CFU/cm(2)), compared to combination with vancomycin (3.36 ± 0.35 log10 CFU/cm(2)) or rifampin (2.68 ± 0.61 log10 CFU/cm(2)). These data suggest that beta-lactam combinations are useful against MRSA biofilms.

Evaluation of ceftaroline, vancomycin, daptomycin, or ceftaroline plus daptomycin against daptomycin-nonsusceptible methicillin-resistant Staphylococcus aureus in an in vitro pharmacokinetic/pharmacodynamic model of simulated endocardial vegetations.

Infective endocarditis (IE) caused by methicillin-resistant Staphylococcus aureus (MRSA) with reduced susceptibility to vancomycin and daptomycin has few adequate therapeutic options. Ceftaroline (CPT) is bactericidal against daptomycin (DAP)-nonsusceptible (DNS) and vancomycin-intermediate MRSA, but supporting data are limited for IE. This study evaluated the activities of ceftaroline, vancomycin, daptomycin, and the combination of ceftaroline plus daptomycin against DNS MRSA in a pharmacokinetic/pharmacodynamic (PK/PD) model of simulated endocardial vegetations (SEVs). Simulations of ceftaroline-fosamil (600 mg) every 8 h (q8h) (maximum concentration of drug in serum [Cmax], 21.3 mg/liter; half-life [t1/2], 2.66 h), daptomycin (10 mg/kg of body weight/day) (Cmax, 129.7 mg/liter; t1/2, 8 h), vancomycin (1 g) q8h (minimum concentration of drug in serum [Cmin], 20 mg/liter; t1/2, 5 h), and ceftaroline plus daptomycin were evaluated against 3 clinical DNS, vancomycin-intermediate MRSA in a two-compartment, in vitro, PK/PD SEV model over 96 h with a starting inoculum of ∼8 log10 CFU/g. Bactericidal activity was defined as a ≥ 3-log10 CFU/g reduction from the starting inoculum. Therapeutic enhancement of combinations was defined as ≥ 2-log10 CFU/g reduction over the most active agent alone. MIC values for daptomycin, vancomycin, and ceftaroline were 4 mg/liter, 4 to 8 mg/liter, and 0.5 to 1 mg/liter, respectively, for all strains. At simulated exposures, vancomycin was bacteriostatic, but daptomycin and ceftaroline were bactericidal. By 96 h, ceftaroline monotherapy offered significantly improved killing compared to other agents against one strain. The combination of DAP plus CPT demonstrated therapeutic enhancement, resulting in significantly improved killing versus either agent alone against 2/3 (67%) strains. CPT demonstrated bactericidal activity against DNS, vancomycin-intermediate MRSA at high bacterial densities. Ceftaroline plus daptomycin may offer more rapid and sustained activity against some MRSA in the setting of high-inoculum infections like IE and should also be considered.

Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy.

Ceftaroline has been approved for acute bacterial skin infections and community-acquired bacterial pneumonia. Limited clinical experience exists for use outside these indications. The objective of this study was to describe the outcomes of patients treated with ceftaroline for various infections. Retrospective analyses of patients receiving ceftaroline ≥72 h from 2011 to 2013 were included. Clinical and microbiological outcomes were analyzed. Clinical success was defined as resolution of all signs and symptoms of infection with no further need for escalation while on ceftaroline treatment during hospitalization. A total of 527 patients received ceftaroline, and 67% were treated for off-label indications. Twenty-eight percent (148/527) of patients had bacteremia. Most patients (80%) were initiated on ceftaroline after receipt of another antimicrobial, with 48% citing disease progression as a reason for switching. The median duration of ceftaroline treatment was 6 days, with an interquartile range of 4 to 9 days. A total of 327 (62%) patients were culture positive, and the most prevalent pathogen was Staphylococcus aureus, with a frequency of 83% (271/327). Of these patients, 88.9% (241/271) were infected with methicillin-resistant S. aureus (MRSA). Clinically, 88% (426/484) achieved clinical success and hospital mortality was seen in 8% (40/527). While on ceftaroline, adverse events were experienced in 8% (41/527) of the patients and 9% (28/307) were readmitted within 30 days after discharge for the same infection. Patients treated with ceftaroline for both FDA-approved and off-label infections had favorable outcomes. Further research is necessary to further describe the role of ceftaroline in a variety of infections and its impact on patient outcomes.

Evaluation of the novel combination of daptomycin plus ceftriaxone against vancomycin-resistant enterococci in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation model.

OBJECTIVES: Daptomycin has demonstrated synergy with ß-lactams against Enterococcus faecium and this combination has been used successfully to treat infections refractory to daptomycin. We investigated daptomycin alone and combined with ceftriaxone against vancomycin-resistant enterococci (VRE) in an in vitro pharmacokinetic/pharmacodynamic simulated endocardial vegetation (SEV) model. METHODS: Daptomycin (6 and 12 mg/kg/day) with and without 2 g of ceftriaxone every 24 h were evaluated against two clinical E. faecium strains (8019 and 5938) and one Enterococcus faecalis (6981) in a 96 h in vitro pharmacokinetic/pharmacodynamic SEV model. FITC-labelled poly-l-lysine was used to assess ß-lactam-induced changes in cell surface charge. RESULTS: For 8019 and 6981, daptomycin 6 mg/kg with ceftriaxone and daptomycin 12 mg/kg alone and in combination with ceftriaxone displayed significantly more activity than daptomycin 6 mg/kg alone from 48 to 96 h (P ≤ 0.005). The addition of ceftriaxone significantly enhanced activity of daptomycin 6 mg/kg against both strains at 96 h (8019, reductions -0.55 versus 3.64 log10 cfu/g; 6981, reductions 1.11 versus 5.67 log10 cfu/g; P < 0.001) and improved daptomycin 12 mg/kg against 8019 at 96 h. Daptomycin 12 mg/kg plus ceftriaxone displayed no appreciable activity against 5938 (daptomycin MIC 32 mg/L). Daptomycin non-susceptibility developed in 8019 and 6981 versus daptomycin 6 mg/kg by 96 h. Ampicillin or ceftriaxone exposure reduced daptomycin surface charge in 8019, resulting in significantly increased FITC-poly-l-lysine binding. CONCLUSIONS: The combination of daptomycin and ceftriaxone may be promising for eradicating high-inoculum, deep-seated enterococcal infections. Further research is warranted to examine the enhancement of daptomycin and innate immunity killing of VRE by ceftriaxone and other ß-lactams.

Potent synergy of ceftobiprole plus daptomycin against multiple strains of Staphylococcus aureus with various resistance phenotypes.

OBJECTIVES: Ceftobiprole is a broad-spectrum cephalosporin that demonstrates activity against Staphylococcus aureus resistant to methicillin, including strains with reduced susceptibility to glycopeptides and lipopeptides. The addition of this agent provides a potential therapeutic option for difficult-to-treat infections. Synergy has been demonstrated between ß-lactams combined with glycopeptides and lipopeptides against S. aureus. This study sought to determine whether ceftobiprole was synergistic with daptomycin, vancomycin or standard-of-care combination agents (gentamicin or rifampicin) against methicillin-resistant S. aureus (MRSA) strains with varying degrees of vancomycin susceptibility. METHODS: Broth microdilution MICs of ceftobiprole, daptomycin, vancomycin, rifampicin and gentamicin were evaluated for 20 MRSA isolates. Combination MICs were additionally evaluated in the presence of subinhibitory concentrations of ceftobiprole to assess synergism. Time-kill curves for five representative isolates were performed utilizing combinations of ceftobiprole plus daptomycin, vancomycin, rifampicin and gentamicin to further quantify the degree of synergy for each regimen. RESULTS: Ceftobiprole plus daptomycin represented the most potent combination with a 4-fold decrease in MIC and synergy against all strains evaluated in time-kill evaluations. Additionally, binding studies demonstrated enhanced daptomycin binding in the presence of subinhibitory concentrations of ceftobiprole. CONCLUSIONS: The use of combination therapy with ceftobiprole may provide a needed addition for the treatment of Gram-positive infections resistant to daptomycin or vancomycin. Consistent with what has been observed with other ß-lactams, ceftobiprole increased bodipy-tagged daptomycin binding on the surface of S. aureus, potentially explaining this potent synergy observed in time-kill evaluations. More detailed evaluation of ceftobiprole is warranted to better characterize observed synergy.

High-dose amphotericin: yay or nay? A case series and literature review.

Invasive fungal infections pose significant morbidity and mortality risks, particularly those caused by moulds. Available antifungal classes are limited by toxicities and are increasingly susceptible to resistance, particularly amongst challenging fungal pathogens. The purpose of this case series and literature review was to characterize the use of a high-dose lipid formulation of amphotericin B. A case series is presented including patients who received high-dose lipid formulation amphotericin B (≥7.5 mg/kg/day) between June 2012 and August 2021. Additionally, a systematic literature review was conducted by searching the PubMed database for English-language studies involving individuals who received high-dose amphotericin B therapy (≥7.5 mg/kg) using lipid formulations. Nine patients were included in the case series, receiving an average of 8.9 ± 1.3 mg/kg liposomal amphotericin B over a mean of 11.0 ± 10.8 days predominantly for mould infections including Mucorales, aspergillosis and Fusarium. The patients were primarily cared for in intensive care units, with varying treatment histories and outcomes. A total of 11 studies (n=260 patients) met inclusion criteria for the literature review. Responses to high-dose liposomal amphotericin B ranged from 8% to 100%, often showing favourable outcomes. High doses of liposomal amphotericin B were well tolerated both in the case series and in published literature, with serum creatinine changes being the most commonly reported adverse event. However, multi-patient studies continue to report less than favourable (range 8-62%) response rates. High-dose liposomal amphotericin B, either alone or in combination with other antifungal agents, might be a viable strategy for managing invasive fungal infections when few treatment choices exist. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.