Douglas N. Fish

Background: Daptomycin and linezolid may have more favorable safety and efficacy profiles compared to vancomycin and require less therapeutic monitoring. To capitalize on these advantages, the University of Colorado Hospital relaxed prescribing restrictions and updated local guidance for the treatment of Gram-positive infections, resulting in increased daptomycin and linezolid utilization. The objective of this study was to assess the impact of liberalized daptomycin and linezolid use on minimum inhibitory concentrations (MICs) in Gram-positive organisms. Methods: This retrospective, single-center study included all Staphylococcus and Enterococcus isolates across an 8-year period, including a 3-year follow-up period after implementing practice changes. Organisms were categorized as hospital-acquired (HA) if the culture was collected 48 hours after admission. Interrupted time series analyses were performed to measure changes in geometric mean (GM) of MICs before and after implementation. Results: Minimum inhibitory concentrations from 19 160 isolates were evaluated, of which 7224 were HA. Linezolid use increased to 43.7 days of therapy per 1000 patient days (DOT/1000PD), and daptomycin use increased to 15.7 DOT/1000PD post-implementation. Linezolid GM MICs trended downward pre-implementation, and the trajectory was unaffected by implementation except in coagulase-negative Staphylococcus (CoNS). Daptomycin GM MICs declined pre-implementation among Enterococcus, but not Staphylococcus. Implementation was associated with a significant slope change in vancomycin-resistant Enterococcus (VRE) and HA CoNS. Resistance rates and MIC distributions were not impacted by implementation. Conclusions: The liberalization of daptomycin and linezolid did not result in clinically relevant increases in resistance. Further studies are needed to confirm the durability of these results, specifically among CoNS and VRE.

Urinary tract infections (UTIs) are one of the most common infections and are frequently caused by Gram-negative organisms. The rise of resistant isolates has prompted evaluation of alternative therapies, including amoxicillin-clavulanate which has potent activity against Ambler class A enzymes. This study sought to evaluate clinical outcomes of patients with ceftriaxone non-susceptible UTIs receiving amoxicillin-clavulanate or standard of care (SOC). This was a single-center, retrospective, cohort study of adult patients with urinary tract infections caused by a ceftriaxone non-susceptible pathogen who received amoxicillin-clavulanate or SOC. The primary outcome was clinical failure at 90 days. Secondary outcomes included time to failure, isolation of a resistant organism, and hospital length of stay. Fifty-nine patients met study inclusion: 26 received amoxicillin/clavulanate and 33 received SOC. Amoxicillin-clavulanate recipients did not have higher failure rates compared to SOC recipients. For patients requiring hospital admission, hospital length of stay was numerically shorter with amoxicillin-clavulanate. The frequency of amoxicillin-clavulanate and carbapenem-resistant organisms did not differ significantly between groups. Amoxicillin-clavulanate may be a useful alternative therapy for the treatment of ceftriaxone non-susceptible Enterobacterales UTIs.

Tedizolid has activity against Gram-positive pathogens as well as Mycobacterium spp and Nocardia spp. Real-world evidence supporting long-term tolerability and clinical success of tedizolid is lacking. Prolonged tedizolid therapy (median, 188 days; interquartile range, 62–493 days) appeared to be well tolerated in 37 patients (8.1% experienced adverse effect leading to discontinuation). Clinical success was 81.3% in those evaluated.

Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with substantial morbidity and mortality. Monotherapy with first-line antimicrobials such as vancomycin (VAN; glycopeptide) and daptomycin (DAP; lipopeptide) are inadequate in some cases due to reduced antibiotic susceptibilities or therapeutic failure. In recent years, β-lactam antibiotics have emerged as a potential option for combination therapy with VAN/DAP that may meet an unmet therapeutic need for MRSA BSI. Ceftaroline (CPT), the only commercially available β-lactam in the United States with intrinsic in vitro activity against MRSA, has been increasingly studied in the setting of VAN and DAP failures. Novel combinations of first-line agents (VAN and DAP) with β-lactams have been the subject of many recent investigations due to in vitro findings such as the “see-saw effect”, where β-lactam susceptibility may be improved in the presence of decreased glycopeptide and lipopeptide susceptibility. The combination of CPT and DAP, in particular, has become the focus of many scientific evaluations, due to intrinsic anti-MRSA activities and potent in vitro synergistic activity against various MRSA strains. This article reviews the available literature describing these innovative therapeutic approaches for MRSA BSI, focusing on preclinical and clinical studies, and evaluates the potential benefits and limitations of each strategy.

Histamine-2 receptor antagonists (H2RA) and proton pump inhibitors (PPI) are frequently used to prevent stress-related mucosal bleeding (SRMB). A paucity of data implicates these agents with pneumonia and Clostridium difficile infection (CDI). This review comparatively evaluates the effectiveness of H2RAs and PPIs and delineates their associations with these infectious complications. A literature review through 30 September 2014 was performed. The rate of SRMB is declining, likely due better resuscitation strategies and the early provision of enteral nutrition. Therefore, gastric acid-suppressing therapies arguably reduce SRMB. However, they may contribute to pneumonia and CDI. The risks of these infectious complications depend on the extent of acid suppression and may vary by patient population. PPIs are associated with the greatest hazard for these infections, likely because they provide stronger acid suppression. Intermittent administration of H2RAs has theoretical advantages over continuous H2RA or PPI therapies as this dosing strategy does not fully suppress gastric acid and may limit infection risk. Placebo-controlled studies are warranted because clinical equipoise exists as the detrimental outcomes of these infections may outweigh the benefit of preventing SRMB given the infrequent occurrence of SRMB.

Oral voriconazole is recommended over intravenous (IV) voriconazole in patients with CrCl < 50 ml/min to avoid accumulation of SBECD; however, poor enteral absorption in ICU patients may lead to inadequate plasma concentrations and treatment failure. The purpose of this study was to evaluate the pharmacokinetics of SBECD and IV voriconazole in ICU patients undergoing CRRT. CRRT is effective at removing SBECD and allows use of IV voriconazole without concern of SBECD accumulation. Patients > 18 years of age receiving IV voriconazole therapy for treatment or prophylaxis of systemic fungal infection while undergoing CRRT were eligible. Intensive pharmacokinetic sampling for determination of SBECD and voriconazole concentrations was completed on study days 1, 3, and 5; then sparse sampling every 3-5 days thereafter. Voriconazole and SBECD plasma and effluent concentrations were measured by LC MS/MS. Six patients were enrolled. Patients were (mean ± SD) 56 ± 11 years old, 67% male, 83 ± 12 kg, and had APACHE II scores of 30.5 ± 3.3. All patients received CVVH with a median predilution replacement fluid rate of 36 (IQR 32-39) ml/kg/hr and effluent rate of 38 (IQR 35-40) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 7.9 ± 2.6 mg/kg/day and 126 ± 42 mg/kg/day. Mean ± SD plasma voriconazole Cmax, Cmin, Vd, t1/2, AUC0-12, total systemic clearance, and CRRT clearance were 3.6 ± 1.6 mg/L, 1.6 ± 0.8 mg/L, 2.8 ± 0.6 L/kg, 15 ± 7 hrs, 29 ± 10 mg*hr/L, 0.15 ± 0.05 L/hr/kg, and 0.03 ± 0.03 L/hr/kg, respectively. Mean ± SD plasma SBECD Cmax, Cmin, Vd, t1/2, AUC0-12, total systemic clearance, and CRRT clearance were 276 ± 154 mg/L, 55 ± 47 mg/L, 0.5 ± 0.2 L/kg, 6.6 ± 2.4 hrs, 1600 ± 1000 mg*hr/L, 0.05 ± 0.02 L/hr/kg, and 0.03 ± 0.01 L/hr/kg, respectively. Minimal increases in SBECD Cmax (255 ± 143 to 331 ± 255 mg/L; p=0.54) and Cmin (64 ± 59 to 76 ± 64 mg/L; p=0.74) were observed after study day 1. CVVH effectively removed SBECD at a rate similar to the effluent rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.

Purpose. The stability of extemporaneously prepared phenylephrine hydrochloride injection stored in polypropylene syringes was studied.

Purpose. The physical and chemical stability of repackaged acetylcysteine 600 mg/3 mL solution in oral syringes stored under refrigeration or at room temperature was studied for six months; a cost analysis was also conducted.

Although aminoglycosides remain an essential part of therapy of severe gram-negative infections in critically ill patients, the use of extended-interval aminoglycoside dosing (EIAD) in this population is highly controversial. The rationale for EIAD is based on major pharmacodynamic characteristics of the aminoglycosides, which include concentration-dependent bactericidal effects, postantibiotic effect, and adaptive resistance. Alterations in the pharmacokinetics of aminoglycosides in the critically ill have been well documented, including changes in both drug distribution and elimination. These pharmacokinetic alterations may prevent critically ill patients from realizing the potential benefits of EIAD by reducing serum concentrations achieved by recommended EIAD regimens and may perhaps place patients at risk of therapeutic failure. Although numerous studies of EIAD have been conducted, there is a lack of data specifically concerning the efficacy and safety of EIAD in the critically ill. The most appropriate methods for monitoring EIAD in this population are also not clearly established. There are thus many questions regarding the suitability of EIAD in the critically ill. This article briefly reviews the rationale for EIAD and data related to the pharmacokinetics, efficacy, safety, and clinical monitoring of EIAD in critically ill patients. Considerations and recommendations for use of EIAD in the critically ill are provided.