PBPK Modeling of Azithromycin Systemic Exposure in a Roux-en-Y Gastric Bypass Surgery Patient Population.

In this investigation, PBPK modeling using the Simcyp® Simulator was performed to evaluate whether Roux-en-Y gastric bypass (RYGB) surgery impacts the oral absorption and bioavailability of azithromycin. An RYGB surgery patient population was adapted from the published literature and verified using the same probe medications, atorvastatin and midazolam. Next, a PBPK model of azithromycin was constructed to simulate changes in systemic drug exposure after the administration of different oral formulations (tablet, suspension) to patients pre- and post-RYGB surgery using the developed and verified population model. Clinically observed changes in azithromycin systemic exposure post-surgery following oral administration (single-dose tablet formulation) were captured using PBPK modeling based on the comparison of model-predicted exposure metrics (Cmax, AUC) to published clinical data. Model simulations predicted a 30% reduction in steady-state AUC after surgery for three- and five-day multiple dose regimens of an azithromycin tablet formulation. The relative bioavailability of a suspension formulation was 1.5-fold higher than the tablet formulation after multiple dosing. The changes in systemic exposure observed after surgery were used to evaluate the clinical efficacy of azithromycin against two of the most common pathogens causing community acquired pneumonia based on the corresponding AUC24/MIC pharmacodynamic endpoint. The results suggest lower bioavailability of the tablet formulation post-surgery may impact clinical efficacy. Overall, the research demonstrates the potential of a PBPK modeling approach as a framework to optimize oral drug therapy in patients post-RYGB surgery.

Penicillin-Binding Proteins and Alternative Dual-Beta-Lactam Combinations for Serious Enterococcus faecalis Infections with Elevated Penicillin MICs.

Ampicillin-ceftriaxone has become a first-line therapy for Enterococcus faecalis endocarditis. We characterized the penicillin-binding protein (PBP) profiles of various E. faecalis strains and tested for synergy to better inform beta-lactam options for the treatment of E. faecalis infections. We assessed the affinity of PBP2B from elevated-MIC strain E. faecalis LS4828 compared to type strain JH2-2 using the fluorescent beta-lactam Bocillin FL. We also characterized pbp4 and pbpA structures and PBP4 and PBP2B expression and used deletion and complementation studies to assess the impact of PBP2B on the levels of resistance. We tested penicillin-susceptible and -resistant E. faecalis isolates against ceftriaxone or ceftaroline combinations with other beta-lactams in 24-h time-kill studies. Two penicillin-susceptible strains (JH2-2 and L2052) had identical pbp sequences and similar PBP expression levels. One reduced-penicillin-susceptibility strain (L2068) had pbp sequences identical to those of the susceptible strains but expressed more PBP4. The second decreased-penicillin-susceptibility strain (LS4828) had amino acid substitutions in both PBP4 and PBP2B and expressed increased quantities of both proteins. PBP2B did not appear to contribute significantly to the elevated beta-lactam MICs. No synergy was demonstrable against the strains with both mutated PBPs and increased expression (L2068 and LS4828). Meropenem plus ceftriaxone or ertapenem plus ceftriaxone demonstrated the most consistent synergistic activity. PBP2B of strain LS4828 does not contribute significantly to reduced penicillin susceptibility. Neither the MIC nor the level of PBP expression correlated directly with the identified synergistic combinations when tested at static subinhibitory concentrations.

Coronavirus disease 2019 (COVID-19): Secondary bacterial infections and the impact on antimicrobial resistance during the COVID-19 pandemic.

Secondary bacterial infections and bacterial coinfections are an important complication of coronavirus disease 2019 (COVID-19), leading to antibiotic overuse and increased rates of antimicrobial resistance (AMR) during the COVID-19 pandemic. In this literature review, we summarize the reported rates of secondary bacterial infections and bacterial coinfections in patients with COVID-19, the impact on patient outcomes, the antibiotic treatment approaches employed, and the resistance patterns observed. The reported data suggest that although the incidence of secondary bacterial infections or bacterial coinfections is relatively low, they are associated with worse outcomes such as prolonged hospitalization, intensive care unit admission, mechanical ventilator use, and increased mortality. Interestingly, antibiotic prescription rates are typically higher than secondary bacterial and bacterial coinfection rates, and reports of AMR are common. These findings highlight the need for an improved understanding of secondary bacterial and bacterial coinfection in patients with COVID-19, as well as improved treatment options, to mitigate inappropriate antibiotic prescribing and AMR.

The Role of an Infectious Diseases Faculty Pharmacist and Pharmacy Students on an Antimicrobial Stewardship Team at a Community Non-teaching Hospital.

Background: Antimicrobial stewardship program implementation at non-teaching community hospitals differs due to staffing and resource disparities. Objective: Demonstrate that an infectious disease (ID) pharmacist faculty with advanced pharmacy practice experience (APPE) students can expand antimicrobial stewardship services at non-teaching community hospitals. Methods: A single-center, retrospective chart review was conducted comparing prospective audit and feedback antimicrobial stewardship interventions by an ID pharmacist faculty with and without APPE students between January 16, 2020 to January 16, 2021. The primary endpoints were intervention rate and the intervention acceptance rate. Secondary endpoints included: the difference in the time from antimicrobial order to intervention and length of stay, as well as comparison of acceptance rates stratified by intervention type or the antimicrobial intervened upon. Results: A total of 739 antimicrobial stewardship interventions were made with an overall acceptance rate of 55.2%. The ID pharmacist faculty with APPE students had a higher number of interventions and intervention rate per working day compared to without students (428 vs 311 and 4.46 vs 2.99, respectively). Conversely, the intervention acceptance rate was lower for the ID pharmacist faculty with APPE students vs without (48.8% vs 64%, P < .001). Both the median time from antimicrobial order to the intervention and length of stay was lower for the ID pharmacist faculty with students vs without (2.50 days [interquartile range (IQR) 1.24 - 4.01] vs 2.99 days [IQR 1.64 - 4.95], P = .003, and 9.20 days [IQR 5.57 - 14.93] vs 11.69 days [IQR 6.89 - 22.31], P < .001, respectively). The acceptance rates by intervention type and the antimicrobial intervened upon were similar between groups. Conclusion: An ID pharmacist faculty with APPE students at a non-teaching community hospital increased the number of stewardship interventions, and was associated with decreased time from antimicrobial order to intervention and length of stay.

Meropenem plus Ceftaroline Is Active against Enterococcus faecalis in an In Vitro Pharmacodynamic Model Using Humanized Dosing Simulations.

The standard of care for serious Enterococcus faecalis infections is ampicillin plus ceftriaxone. Ampicillin's inconvenient dosing schedule, drug instability, allergy potential, along with ceftriaxone's high risk for Clostridioides difficile infection and its promotion of vancomycin-resistant enterococci (VRE), led our team to explore alternative options. This work aimed to understand the role of carbapenems in combination with cephalosporins in these infections. We selected two ampicillin and penicillin susceptible E. faecalis strains (AMP-MIC 0.5-2 µg/mL; PCN-MIC 2 µg/mL) and simulated human therapeutic dosing regimens in a 48-h in vitro pharmacodynamic model (IVPD) with ampicillin (2g q4h), ertapenem (1g q24h), meropenem (2g q8h), ceftriaxone (2g q12h), and ceftaroline (600 mg q8h). As expected, ampicillin plus ceftriaxone demonstrated enhanced activity compared with ampicillin monotherapy with no MIC increases in either isolate. Meropenem and ceftaroline demonstrated significant kill against both isolates, with no regrowth or MIC increases occurring. Meropenem plus ceftriaxone also demonstrated significant kill, and while no MIC increases were identified for meropenem, there was minor regrowth and larger standard deviations. Ertapenem combined with either ceftriaxone or ceftaroline enhanced activity at 24 h, but at 48 h, regrowth occurred, and ertapenem MIC increases were noted. Meropenem-based combination therapy against E. faecalis may provide clinicians with another regimen to treat severe E. faecalis infections. Meropenem plus ceftaroline was as active as the standard of care treatment (ampicillin plus ceftriaxone) and may serve as an alternative for serious E. faecalis infections. Further studies are warranted to determine the clinical efficacy.

Penicillin plus Ceftriaxone versus Ampicillin plus Ceftriaxone Synergistic Potential against Clinical Enterococcus faecalis Blood Isolates.

Penicillin plus ceftriaxone is a promising alternative to ampicillin plus ceftriaxone for the treatment of Enterococcus faecalis infective endocarditis. Limited data is available supporting the utilization of penicillin plus ceftriaxone. A total of 20 E. faecalis isolates; one wild-type strain (JH2-2) and 19 clinical blood strains were assessed for penicillin plus ceftriaxone and ampicillin plus ceftriaxone synergy using a 24-h time-kill experiment. Susceptibility was determined by broth microdilution. Differences in bactericidal, bacteriostatic, or inactivity, as well as synergy between treatments were assessed by chi-square or Fisher exact test. All E. faecalis isolates were considered susceptible to ampicillin and penicillin. Ampicillin plus ceftriaxone versus penicillin plus ceftriaxone similarly demonstrated synergy. Bactericidal activity was more commonly observed for ampicillin plus ceftriaxone versus penicillin plus ceftriaxone. Among isolates with a penicillin MIC of 4 µg/mL (n = 7), synergistic activity for both combinations was less common compared to isolates with a penicillin MIC ≤ 2 µg/mL (n = 13). Ampicillin plus ceftriaxone and penicillin plus ceftriaxone demonstrate similar synergistic potential against E. faecalis clinical blood isolates, but strains with higher penicillin and ceftriaxone MICs less frequently demonstrated synergy. Further research is warranted to determine the role of the penicillin plus ceftriaxone therapy and the penicillin MIC in clinical practice. IMPORTANCE Penicillin plus ceftriaxone demonstrates similar synergistic activity against Enterococcus faecalis to ampicillin plus ceftriaxone. Isolates with a penicillin MIC of 4 mg/L and a ceftriaxone MIC of 512 or higher, lack penicillin plus ceftriaxone synergy despite the penicillin susceptibility MIC breakpoint of 8 mg/L.

Staphylococcus aureus Bacteremia in Patients Infected With COVID-19: A Case Series.

BACKGROUND: Previous viral pandemics have shown that secondary bacterial infections result in higher morbidity and mortality, with Staphylococcus aureus being the primary causative pathogen. The impact of secondary S. aureus bacteremia on mortality in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains unknown. METHODS: This was a retrospective observational case series of patients with coronavirus disease 2019 (COVID-19) who developed secondary S. aureus bacteremia across 2 New York City hospitals. The primary end point was to describe 14-day and 30-day hospital mortality rates of patients with COVID-19 and S. aureus bacteremia. Secondary end points included predictors of 14-day and 30-day hospital mortality in patients with COVID-19 and S. aureus bacteremia. RESULTS: A total of 42 patients hospitalized for COVID-19 with secondary S. aureus bacteremia were identified. Of these patients, 23 (54.8%) and 28 (66.7%) died at 14 days and 30 days, respectively, from their first positive blood culture. Multivariate analysis identified hospital-onset bacteremia (≥4 days from date of admission) and age as significant predictors of 14-day hospital mortality and Pitt bacteremia score as a significant predictor of 30-day hospital mortality (odds ratio [OR], 11.9; 95% CI, 2.03-114.7; P = .01; OR, 1.10; 95% CI, 1.03-1.20; P = .02; and OR, 1.56; 95% CI, 1.19-2.18; P = .003, respectively). CONCLUSIONS: Bacteremia with S. aureus is associated with high mortality rates in patients hospitalized with COVID-19. Further investigation is warranted to understand the impact of COVID-19 and secondary S. aureus bacteremia.

Evaluation of post-flexible cystoscopy urinary tract infection rates.

PURPOSE: The risk of urinary tract infection (UTI) development after flexible cystoscopy (FC) is not well described. It remains difficult to assess the role of pre-FC antimicrobial prophylaxis to reduce UTI risk. METHODS: In fall 2017, the urology service at the Providence Veterans Affairs Medical Center implemented routine oral antimicrobial prophylaxis in its outpatient FC clinic. Outpatients were randomly selected for a retrospective chart review to compare patients who received pre-FC antimicrobials (cefuroxime 500 mg tablet or sulfamethoxazole/trimethoprim [800 mg/160 mg] tablet) and those who underwent FC prior to fall 2017 and did not receive prophylaxis. The primary outcome was presence of symptomatic UTI within 30 days post FC. Secondary outcomes included symptomatic UTI that met colony-forming unit (CFU)/mL guideline requirements, and UTI treatment received. Potential risk factors for UTI were also assessed. RESULTS: A total of 296 patients were included in the final analysis: 139 who did not receive and 157 who received a prophylactic antimicrobial before FC. Rates of symptomatic UTI, symptomatic UTI meeting CFU/mL guideline requirements, and postprocedure treatment for UTI were similar with and without antimicrobial prophylaxis (2.5% vs 2.2% [P > 0.99], 1.9% vs 1.4% [P > 0.99], and 2.5% vs 4.3% [P = 0.53], respectively). The mean number of days from FC to the start of UTI treatment was 7.9 (range, 1-18 days). Age over 65 years was the only risk factor present in all patients with a post-FC UTI, irrespective of antimicrobial prophylaxis. CONCLUSION: The rate of post-FC symptomatic UTI was lower than rates previously described in the literature. The role of antimicrobial prophylaxis prior to FC warrants further exploration.

Towards precision medicine: Therapeutic drug monitoring-guided dosing of vancomycin and ß-lactam antibiotics to maximize effectiveness and minimize toxicity.

PURPOSE: The goal of this review is to explore the role of antimicrobial therapeutic drug monitoring (TDM), especially in critically ill, obese, and older adults, with a specific focus on ß-lactams and vancomycin. SUMMARY: The continued rise of antimicrobial resistance prompts the need to optimize antimicrobial dosing. The aim of TDM is to individualize antimicrobial dosing to achieve antibiotic exposures associated with improved patient outcomes. Initially, TDM was developed to minimize adverse effects during use of narrow therapeutic index agents. Today, patient and organism complexity are expanding the need for precision dosing through TDM services. Alterations of pharmacokinetics and pharmacodynamics (PK/PD) in the critically ill, obese, and older adult populations, in conjunction with declining organism susceptibility, complicate attainment of therapeutic targets. Over the last decade, antimicrobial TDM has expanded with the emergence of literature supporting ß-lactam TDM and a shift from monitoring vancomycin trough concentrations to monitoring of the ratio of area under the concentration (AUC) curve to minimum inhibitory concentration (MIC). PK/PD experts should be at the forefront of implementing precision dosing practices. CONCLUSION: Precision dosing through TDM is expanding and is especially important in populations with altered PK/PD, including critically ill, obese, and older adults. Due to wide PK/PD variability in these populations, TDM is vital to maximize antimicrobial effectiveness and decrease adverse event rates. However, there is still a need for studies connecting TDM to patient outcomes. Providing patient-specific care through ß-lactam TDM and transitioning to vancomycin AUC/MIC monitoring may be challenging, but with experts at the forefront of this initiative, PK-based optimization of antimicrobial therapy can be achieved.

Weak biofilm formation among carbapenem-resistant Klebsiella pneumoniae.

Biofilm formation of multidrug and extensively drug resistant Klebsiella pneumoniae isolates is poorly understood. We investigated 139 diverse clinical K. pneumoniae isolates that possess various resistance patterns to evaluate the relationship between biofilm formation and resistance. Antimicrobial resistance was compared among a diverse collection of weak versus strong biofilm-forming K. pneumoniae, and predictors of strong biofilm formation were identified. Multi-drug resistant isolates were more common among weak (97.9%) versus strong biofilm formers (76%; P = 0.002). Carbapenem-resistant K. pneumoniae were 91% less likely to form strong biofilm (odds ratio 0.09; 95% confidence interval 0.02-0.33). The statistically significant inverse relationship between biofilm formation and antibiotic resistance suggests that virulence may be a trade-off for survival.

Comparative Effectiveness of Exclusive Exposure to Nafcillin or Oxacillin, Cefazolin, Piperacillin/Tazobactam, and Fluoroquinolones Among a National Cohort of Veterans With Methicillin-Susceptible Staphylococcus aureus Bloodstream Infection.

OBJECTIVE: Beta-lactam antibiotics are recommended as first-line for treatment of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. The objective of this study was to compare effectiveness of anti-MSSA therapies among bacteremia patients exclusively exposed to 1 antimicrobial. METHOD: This was a national retrospective cohort study of patients hospitalized in Veterans Affairs medical centers with MSSA bacteremia from January 1, 2002, to October 1, 2015. Patients were included if they were treated exclusively with nafcillin, oxacillin, cefazolin, piperacillin/tazobactam, or fluoroquinolones (moxifloxacin and levofloxacin). We assessed 30-day mortality, time to discharge, inpatient mortality, 30-day readmission, and 30-day S. aureus reinfection. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using propensity-score (PS) matched Cox proportional hazards regression model. RESULTS: When comparing nafcillin/oxacillin (n = 105) with cefazolin (n = 107), 30-day mortality was similar between groups (PS matched n = 44; HR, 0.67; 95% CI, 0.11-4.00), as were rates of the other outcomes assessed. As clinical outcomes did not vary between nafcillin/oxacillin and cefazolin, they were combined for comparison with piperacillin/tazobactam (n = 113) and fluoroquinolones (n = 103). Mortality in the 30 days after culture was significantly lower in the nafcillin/oxacillin/cefazolin group compared with piperacillin/tazobactam (PS matched n = 48; HR, 0.10; 95% CI, 0.01-0.78), and similar when compared with fluoroquinolones (PS matched n = 32; HR, 1.33; 95% CI, 0.30-5.96). CONCLUSIONS: In hospitalized patients with MSSA bacteremia, no difference in mortality was observed between nafcillin/oxacillin and cefazolin or fluoroquinolones. However, higher mortality was observed with piperacillin/tazobactam as compared with nafcillin/oxacillin/cefazolin, suggesting it may not be as effective as a monotherapy in MSSA bacteremia.