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Dustin T Wilson,1,2 V Paul Dimondi,1,3 Steven W Johnson,1,4 Travis M Jones,1 Richard H Drew1,5 1Department of Pharmacy Practice, Campbell University College of Pharmacy & Health Sciences, Buies Creek, NC, USA; 2Department of Pharmacy, Duke University Hospital, Durham, NC, USA; 3Department of Pharmacy, Durham VA Medical Center, Durham, NC, USA; 4Department of Pharmacy, Forsyth Medical Center, Winston-Salem, NC, USA; 5Division of Infectious Diseases, Duke University Hospital, Durham, NC, USA Abstract: Despite recent advances in both diagnosis and prevention, the incidence of invasive fungal infections continues to rise. Available antifungal agents to treat invasive fungal infections include polyenes, triazoles, and echinocandins. Unfortunately, individual agents within each class may be limited by spectrum of activity, resistance, lack of oral formulations, significant adverse event profiles, substantial drug–drug interactions, and/or variable pharmacokinetic profiles. Isavuconazole, a second-generation triazole, was approved by the US Food and Drug Administration in March 2015 and the European Medicines Agency in July 2015 for the treatment of adults with invasive aspergillosis (IA) or mucormycosis. Similar to amphotericin B and posaconazole, isavuconazole exhibits a broad spectrum of in vitro activity against yeasts, dimorphic fungi, and molds. Isavuconazole is available in both oral and intravenous formulations, exhibits a favorable safety profile (notably the absence of QTc prolongation), and reduced drug–drug interactions (relative to voriconazole). Phase 3 studies have evaluated the efficacy of isavuconazole in the management of IA, mucormycosis, and invasive candidiasis. Based on the results of these studies, isavuconazole appears to be a viable treatment option for patients with IA as well as those patients with mucormycosis who are not able to tolerate or fail amphotericin B or posaconazole therapy. In contrast, evidence of isavuconazole for invasive candidiasis (relative to comparator agents such as echinocandins) is not as robust. Therefore, isavuconazole use for invasive candidiasis may initially be reserved as a step-down oral option in those patients who cannot receive other azoles due to tolerability or spectrum of activity limitations. Post-marketing surveillance of isavuconazole will be important to better understand the safety and efficacy of this agent, as well as to better define the need for isavuconazole serum concentration monitoring. Keywords: isavuconazole, azole, antifungal, aspergillosis, Mucormycetes, mucormycosis

Travis M Jones,1,2 Steven W Johnson,1,3 V Paul DiMondi,1,4 Dustin T Wilson,1,2 1Department of Pharmacy Practice, College of Pharmacy and Health Sciences, Campbell University, Buies Creek, 2Department of Pharmacy, Duke University Hospital, Durham, 3Department of Pharmacy, Forsyth Medical Center, Novant Health, Winston-Salem, 4Department of Pharmacy, Durham VA Medical Center, Durham, NC, USA Abstract: JNJ-Q2 is a novel, fifth-generation fluoroquinolone that has excellent in vitro and in vivo activity against a variety of Gram-positive and Gram-negative organisms. In vitro studies indicate that JNJ-Q2 has potent activity against pathogens responsible for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), such as Staphylococcus aureus and Streptococcus pneumoniae. JNJ-Q2 also has been shown to have a higher barrier to resistance compared to other agents in the class and it remains highly active against drug-resistant organisms, including methicillin-resistant S. aureus, ciprofloxacin-resistant methicillin-resistant S. aureus, and drug-resistant S. pneumoniae. In two Phase II studies, the efficacy of JNJ-Q2 was comparable to linezolid for ABSSSI and moxifloxacin for CABP. Furthermore, JNJ-Q2 was well tolerated, with adverse event rates similar to or less than other fluoroquinolones. With an expanded spectrum of activity and low potential for resistance, JNJ-Q2 shows promise as an effective treatment option for ABSSSI and CABP. Considering its early stage of development, the definitive role of JNJ-Q2 against these infections and its safety profile will be determined in future Phase III studies. Keywords: JNJ-Q2, fluoroquinolone, ABSSSI, CABP, MRSA

Objectives: People living with HIV face several challenges as they age, including the potential for polypharmacy and increased susceptibility to drug-related adverse effects. Thus, effective and well-tolerated regimens with minimal or no drug interactions would be useful in this population. We present real-world effectiveness and safety data for individuals aged >50 years who achieved virological suppression (HIV-1 RNA <50 copies/mL) and switched to dolutegravir/lamivudine (DTG/3TC)., Methods: This retrospective, observational, single-centre study conducted in Portugal included individuals aged >50 years who switched to DTG/3TC while virologically suppressed and had ≥12 months of follow-up. Proportions of individuals maintaining virological suppression were described at 12 months; CD4+ cell counts were described at baseline and 12 months. Descriptive subgroup analyses were performed based on age, sex assigned at birth, and availability of historical genotypic resistance results., Results: Overall, 538 individuals aged >50 years were included (74% male; mean age, 62 years; mean time on previous therapy, 160 months). High proportions (intention-to-treat population, 97%; on-treatment population, 98%) of individuals who switched to DTG/3TC maintained virological suppression through 12 months of follow-up. CD4+ cell counts remained stable (mean baseline: 727 cells/mm 3 [range 94-2371]; mean month 12: 742 cells/mm 3 [range 99-2659]). No individuals experienced virological failure. Nine (2%) individuals discontinued DTG/3TC for non-treatment-related reasons. Proportions with virological suppression at month 12 were similar between on-treatment subgroups by age, sex assigned at birth, and historical genotypic resistance results availability., Conclusions: DTG/3TC demonstrated robust effectiveness and a good safety profile in individuals aged >50 years with virological suppression in Portugal., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Objectives: There is debate on whether the use of third-generation cephalosporins (3GC) increases the risk of clinical failure in bloodstream infections (BSIs) caused by chromosomally-mediated AmpC-producing Enterobacterales (CAE). This study evaluates the impact of definitive 3GC therapy versus other antibiotics on clinical outcomes in BSIs due to Enterobacter, Serratia, or Citrobacter species., Methods: This multicenter, retrospective cohort study evaluated adult hospitalized patients with BSIs secondary to Enterobacter, Serratia, or Citrobacter species from 1 January 2006 to 1 September 2014. Definitive 3GC therapy was compared to definitive therapy with other non-3GC antibiotics. Multivariable Cox proportional hazards regression evaluated the impact of definitive 3GC on overall treatment failure (OTF) as a composite of in-hospital mortality, 30-day hospital readmission, or 90-day reinfection., Results: A total of 381 patients from 18 institutions in the southeastern United States were enrolled. Common sources of BSIs were the urinary tract and central venous catheters (78 (20.5%) patients each). Definitive 3GC therapy was utilized in 65 (17.1%) patients. OTF occurred in 22/65 patients (33.9%) in the definitive 3GC group vs. 94/316 (29.8%) in the non-3GC group (p = 0.51). Individual components of OTF were comparable between groups. Risk of OTF was comparable with definitive 3GC therapy vs. definitive non-3GC therapy (aHR 0.93, 95% CI 0.51-1.72) in multivariable Cox proportional hazards regression analysis., Conclusions: These outcomes suggest definitive 3GC therapy does not significantly alter the risk of poor clinical outcomes in the treatment of BSIs secondary to Enterobacter, Serratia, or Citrobacter species compared to other antimicrobial agents., Competing Interests: P.B.B.—Speaker’s Bureau: bioMérieux. C.M.B.—Speaker’s Bureau: Merck Pharmaceuticals. Grant Funding: ALK Abello. S.T.K.—Speaker’s Bureau: Melinta Therapeutics. J.A.J.—Speaker’s Bureau: bioMérieux. All other authors report no potential conflicts of interest.

Background: Many direct-acting antivirals (DAAs) have drug-drug interactions (DDIs) with the potential to affect efficacy and safety., Objective: To describe the incidence and severity of DDIs with DAAs identified by the hepatitis C virus (HCV) clinical pharmacist within a Veterans Affairs health care system., Methods: This single-center, retrospective cohort study evaluated patients with HCV treated with DAA therapy. Primary end points included the total number of identified DDIs, percentage of patients with at least 1 DDI, mean number of DDIs per patient, and the number of DDIs by severity category. Additional end points included characterization of interacting drugs, clinical consequence of interaction, intervention recommended, acceptance rate of actionable recommendations, and achievement of sustained virological response 12 weeks after treatment (SVR12)., Results: A total of 300 patients were included. There were 554 identified DDIs, and 80.3% of patients had at least 1 DDI, with an average of 1.85 DDIs per patient; 76% of the DDIs identified were categorized as either a potentially clinically significant or critical interaction. The most common DDIs involved acid suppression agents (20%). Patient monitoring was the most commonly recommended intervention (59%), followed by dose modification of the interacting medication (30%). There was no difference in SVR12 between patients with at least 1 DDI compared with those with no DDIs (94.8% vs 95.8%; P = 0.73). There were a total of 227 actionable recommendations, with an acceptance rate of 84.1%., Conclusions: This study suggests that DDIs are prevalent among patients treated with DAAs for HCV. A HCV clinical pharmacist can help optimize patient care by identifying DDIs and recommending interventions to providers.

Drug-resistant Neisseria gonorrhoeae has become a global health concern that requires immediate attention. Due to increasing resistance to cephalosporins, pursuing novel alternatives for treating N. gonorrhoeae infections is paramount. Whilst new drug development is often cumbersome, reviving antiquated antibiotic agents for treatment of modern infections has become prevalent in clinical practice. Fosfomycin exhibits bactericidal activity through a unique mechanism of action, and a variety of organisms including N. gonorrhoeae are susceptible. In vitro studies have demonstrated that fosfomycin can retain activity against ceftriaxone-resistant N. gonorrhoeae; however, it remains unclear whether there is synergy between fosfomycin and other antibiotics. Clinical investigations evaluating fosfomycin for the treatment of N. gonorrhoeae infections are confounded by methodological limitations, none the less they do provide some perspective on its potential role in therapy. Future studies are needed to establish a safe, convenient and effective fosfomycin regimen for treating N. gonorrhoeae infections., (Published by Elsevier B.V.)

Background: Invasive infections with Pseudomonas aeruginosa (PA) are associated with significant morbidity and mortality. While risk factors for mortality have been identified, their influence on short-term outcomes impacting treatment selection has not been reported., Objectives: The objective of this study was to evaluate the relationship between select patient- and treatment-related factors and short-term outcomes in patients with PA pneumonia and/or bacteremia., Setting: Large academic medical center in the United States., Methods: This IRB-approved single-center, retrospective case-cohort study included patients >18 years of age with culture-confirmed PA bacteremia and/or pneumonia receiving antimicrobial agent(s) active against PA., Main Outcome Measure: Risk of unfavorable short-term treatment result., Results: The population consisted of 117 patients (40 [34 %] and 77 [66 %] in the unfavorable and not-unfavorable groups, respectively). Baseline characteristics including age (mean of 63 years), gender (55 % male), Charlson score, creatinine clearance, and body mass index were comparable between groups. Piperacillin/tazobactam was the most common monotherapy antibiotic (46 and 33 % in unfavorable and not-unfavorable groups, respectively). Combination therapy primarily consisted of a beta-lactam plus ciprofloxacin in both unfavorable (10 %) and not-unfavorable (20 %) outcome groups. The preliminary regression model indicated that SIRS, direct ICU admission, and vasopressor therapy were associated with an unfavorable outcome. In addition, patients who received more than two active antimicrobials had a reduced risk of an unfavorable outcome. The final regression model revealed that vasopressor therapy (odds ratio [OR] 6.0; 95 % confidence interval [95 % CI] 2.3, 17) was associated with an unfavorable outcome, while receipt of greater than two active antibiotics was associated with a reduced risk of an unfavorable outcome (OR 0.26; 95 % CI 0.07, 0.83)., Conclusions: Treatment with more than two agents with activity against PA was associated with a reduced risk of an unfavorable short-term treatment outcome in patients with bacteremia and/or pneumonia.

Objective: To evaluate the efficacy and safety of administering vancomycin as a continuous infusion., Data Sources: Literature was accessed through MEDLINE (1977-September 2012), Embase (1977-September 2012), and Google Scholar, using the terms vancomycin, continuous, discontinuous, infusion, pharmacokinetics, pharmacodynamics, and nephrotoxicity. In addition, reference citations from publications identified were reviewed., Study Selection and Data Extraction: All English-language articles identified from the data sources were evaluated. Studies including more than 30 adults were included in the safety and efficacy review., Data Synthesis: Infections due to methicillin-resistant Staphylococcus aureus (MRSA) carry a significant risk of morbidity and mortality. Vancomycin is commonly prescribed for invasive MRSA infections and has been traditionally administered as an intermittent infusion. Administering vancomycin as a continuous infusion is a novel approach to improving its efficacy and safety profile. Fourteen clinical trials were reviewed (2 prospective, 1 meta-analysis, 11 retrospective). The pharmacodynamic profiles between continuous-infusion vancomycin and intermittent-infusion vancomycin were comparable. Continuous-infusion therapy did not significantly improve the efficacy of vancomycin in the treatment of invasive MRSA infections. Conflicting results exist regarding the safety profile of continuous-infusion compared with intermittent-infusion vancomycin. The only published prospective randomized clinical trial comparing continuous infusion with intermittent therapy found no significant difference in the rates of nephrotoxicity. The data from retrospective studies are heterogeneous and show variable rates of nephrotoxicity. In general, compatibility information for administering vancomycin as a continuous infusion is unavailable., Conclusions: Overall, currently available evidence is insufficient to conclude whether an improvement in vancomycin efficacy exists when it is administered as a continuous infusion. The risk of nephrotoxicity associated with continuous-infusion vancomycin requires further investigation in prospective randomized trials. Specific patient populations that would benefit from continuous-infusion vancomycin have yet to be determined.

Cephalosporins have been widely used over the last few decades (often as first-line antibiotic therapy) for numerous infections, owing primarily to their broad spectrum of microbiologic activity and favorable safety profile. Current Infectious Diseases Society of America guidelines identify a third-generation cephalosporin in combination with a macrolide antibiotic as an option for treatment of hospitalized adult patients with community-acquired pneumonia (CAP) outside the intensive care unit setting. Although ceftriaxone is a frequently used agent for CAP, increasing incidence of multidrug-resistant Streptococcus pneumoniae and concerns regarding poor outcomes associated with ineffective therapy have prompted the search for a well-tolerated treatment alternative that is effective against bacteria that can cause CAP. Ceftaroline fosamil, the prodrug of ceftaroline, is a new extended-spectrum cephalosporin that exhibits time-dependant bactericidal activity against numerous Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. pneumoniae. Notable exceptions include Pseudomonas spp. and Gram-negative organisms that produce extended-spectrum β-lactamases or carbapenemases. Two large Phase III clinical trials (FOCUS 1 and 2) reported that ceftaroline fosamil was well tolerated, with a clinical cure rate of CAP that was noninferior to that with ceftriaxone in nonintensive care unit adult inpatients with moderately severe (Pneumonia Outcomes Research Team score of III or IV) community-acquired pneumonia.