Identifying Effective Durations of Antibiotic Therapy for the Treatment of Carbapenem-resistant Enterobacterales Bloodstream Infections: A Multicenter Observational Study.

In a propensity-score-weighted cohort of 183 adults with carbapenem-resistant Enterobacterales bacteremia at 24 US hospitals, patients receiving short courses of active therapy (7-10 days, median 9 days) experienced similar odds of recurrent bacteremia or death within 30 days as those receiving prolonged courses of active therapy (14-21 days, median 14 days).

Rates of resistance to ceftazidime-avibactam and ceftolozane-tazobactam among patients treated for multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia.

Among consecutive patients with multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia we found those treated with ceftazidime-avibactam were more likely to develop resistance (defined as ≥4-fold increased MIC) than those treated with ceftolozane-tazobactam (40% vs. 10%; P=0.002). Ceftazidime-avibactam resistance was associated with new mutations in ampC and efflux regulatory pathways.

Evolving Real-World Effectiveness of Monoclonal Antibodies for Treatment of COVID-19 : A Cohort Study.

BACKGROUND: Treatment guidelines and U.S. Food and Drug Administration emergency use authorizations (EUAs) of monoclonal antibodies (mAbs) for treatment of high-risk outpatients with mild to moderate COVID-19 changed frequently as different SARS-CoV-2 variants emerged. OBJECTIVE: To evaluate whether early outpatient treatment with mAbs, overall and by mAb product, presumed SARS-CoV-2 variant, and immunocompromised status, is associated with reduced risk for hospitalization or death at 28 days. DESIGN: Hypothetical pragmatic randomized trial from observational data comparing mAb-treated patients with a propensity score-matched, nontreated control group. SETTING: Large U.S. health care system. PARTICIPANTS: High-risk outpatients eligible for mAb treatment under any EUA with a positive SARS-CoV-2 test result from 8 December 2020 to 31 August 2022. INTERVENTION: Single-dose intravenous mAb treatment with bamlanivimab, bamlanivimab-etesevimab, sotrovimab, bebtelovimab, or intravenous or subcutaneous casirivimab-imdevimab administered within 2 days of a positive SARS-CoV-2 test result. MEASUREMENTS: The primary outcome was hospitalization or death at 28 days among treated patients versus a nontreated control group (no treatment or treatment ≥3 days after SARS-CoV-2 test date). RESULTS: The risk for hospitalization or death at 28 days was 4.6% in 2571 treated patients and 7.6% in 5135 nontreated control patients (risk ratio [RR], 0.61 [95% CI, 0.50 to 0.74]). In sensitivity analyses, the corresponding RRs for 1- and 3-day treatment grace periods were 0.59 and 0.49, respectively. In subgroup analyses, those receiving mAbs when the Alpha and Delta variants were presumed to be predominant had estimated RRs of 0.55 and 0.53, respectively, compared with 0.71 for the Omicron variant period. Relative risk estimates for individual mAb products all suggested lower risk for hospitalization or death. Among immunocompromised patients, the RR was 0.45 (CI, 0.28 to 0.71). LIMITATIONS: Observational study design, SARS-CoV-2 variant presumed by date rather than genotyping, no data on symptom severity, and partial data on vaccination status. CONCLUSION: Early mAb treatment among outpatients with COVID-19 is associated with lower risk for hospitalization or death for various mAb products and SARS-CoV-2 variants. PRIMARY FUNDING SOURCE: None.

Less Is More? Antibiotic Treatment Duration in Pseudomonas aeruginosa Ventilator-Associated Pneumonia.

Recommended antimicrobial treatment durations for ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa have evolved over the past few decades. In this Viewpoint, we provide a narrative review of landmark trials investigating antimicrobial treatment durations for VAP caused by P. aeruginosa, and appraise iterations of expert consensus guidelines based on these data. We highlight strengths and weaknesses of existing data on this topic and provide recommendations for future avenues of study.

Antibiotic Myths for the Infectious Diseases Clinician.

Antimicrobials are commonly prescribed and often misunderstood. With more than 50% of hospitalized patients receiving an antimicrobial agent at any point in time, judicious and optimal use of these drugs is paramount to advancing patient care. This narrative will focus on myths relevant to nuanced consultation from infectious diseases specialists, particularly surrounding specific considerations for a variety of antibiotics.

Monoclonal Antibodies for Treatment of SARS-CoV-2 Infection During Pregnancy : A Cohort Study.

BACKGROUND: Monoclonal antibody (mAb) treatment decreases hospitalization and death in high-risk outpatients with mild to moderate COVID-19. However, no studies have evaluated adverse events and effectiveness of mAbs in pregnant persons compared with no mAb treatment. OBJECTIVE: To determine the frequency of drug-related adverse events and obstetric-associated safety outcomes after treatment with mAb compared with no mAb treatment of pregnant persons, and the association between mAb treatment and a composite of 28-day COVID-19-related hospital admission or emergency department (ED) visit, COVID-19-associated delivery, or mortality. DESIGN: Retrospective, propensity score-matched, cohort study. SETTING: UPMC Health System from 30 April 2021 to 21 January 2022. PARTICIPANTS: Persons aged 12 years or older with a pregnancy episode and any documented positive SARS-CoV-2 test (polymerase chain reaction or antigen test). INTERVENTION: Bamlanivimab and etesevimab, casirivimab and imdevimab, or sotrovimab treatment compared with no mAb treatment. MEASUREMENTS: Drug-related adverse events, obstetric-associated safety outcomes among persons who delivered, and a risk-adjusted composite of 28-day COVID-19-related hospital admission or ED visit, COVID-19-associated delivery, or mortality. RESULTS: Among 944 pregnant persons (median age [interquartile range (IQR)], 30 years [26 to 33 years]; White (79.5%; n = 750); median Charlson Comorbidity Index score [IQR], 0 [0 to 0]), 552 received mAb treatment (58%). Median gestational age at COVID-19 diagnosis or treatment was 179 days (IQR, 123 to 227), and most persons received sotrovimab (69%; n = 382). Of those with known vaccination status, 392 (62%) were fully vaccinated. Drug-related adverse events were uncommon (n = 8; 1.4%), and there were no differences in any obstetric-associated outcome among 778 persons who delivered. In the total population, the risk ratio for mAb treatment of the composite 28-day COVID-19-associated outcome was 0.71 (95% CI, 0.37 to 1.4). The propensity score-matched risk ratio was 0.61 (95% CI, 0.34 to 1.1). There were no deaths among mAb-treated patients compared with 1 death in the nontreated control patients. There were more non-COVID-19-related hospital admissions in the mAb-treated persons in the unmatched cohort (14 [2.5%] vs. 2 [0.5%]; risk ratio, 5.0; 95% CI, 1.1 to 21.7); however, there was no difference in the propensity score-matched rates, which were 2.5% mAb-treated vs. 2% untreated (risk ratio, 1.3; 95% CI, 0.58% to 2.8%). LIMITATIONS: Drug-related adverse events were patient and provider reported and potentially underrepresented. Symptom severity at the time of SARS-CoV-2 testing was not available for nontreated patients. CONCLUSION: In pregnant persons with mild to moderate COVID-19, adverse events after mAb treatment were mild and rare. There was no difference in obstetric-associated safety outcomes between mAb treatment and no treatment among persons who delivered. There was no difference in 28-day COVID-19-associated outcomes and non-COVID-19-related hospital admissions for mAb treatment compared with no mAb treatment in a propensity score-matched cohort. PRIMARY FUNDING SOURCE: No funding was received for this study.

Isavuconazole Is as Effective as and Better Tolerated Than Voriconazole for Antifungal Prophylaxis in Lung Transplant Recipients.

BACKGROUND: Invasive fungal infections (IFIs) are common following lung transplantation. Isavuconazole is unstudied as prophylaxis in organ transplant recipients. We compared effectiveness and tolerability of isavuconazole and voriconazole prophylaxis in lung transplant recipients. METHODS: A single-center, retrospective study of patients who received isavuconazole (September 2015-February 2018) or voriconazole (September 2013-September 2015) for antifungal prophylaxis. IFIs were defined by EORTC/MSG criteria. RESULTS: Patients received isavuconazole (n = 144) or voriconazole (n = 156) for median 3.4 and 3.1 months, respectively. Adjunctive inhaled amphotericin B (iAmB) was administered to 100% and 41% of patients in the respective groups. At 1 year, 8% of patients receiving isavuconazole or voriconazole developed IFIs. For both groups, 70% and 30% of IFIs were caused by molds and yeasts, respectively, and breakthrough IFI (bIFI) rate was 3%. Outcomes did not significantly differ for patients receiving or not receiving iAmB. Independent risk factors for bIFI and breakthrough invasive mold infection (bIMI) were mold-positive respiratory culture and red blood cell transfusion >7 units at transplant. Bronchial necrosis >2 cm from anastomosis and basiliximab induction were also independent risk factors for bIMI. Isavuconazole and voriconazole were discontinued prematurely due to adverse events in 11% and 36% of patients, respectively (P = .0001). Most common causes of voriconazole and isavuconazole discontinuation were hepatotoxicity and lack of oral intake, respectively. Patients receiving ≥90 days prophylaxis had fewer IFIs at 1 year (3% vs 9%, P = .02). IFIs were associated with increased mortality (P = .0001) and longer hospitalizations (P = .0005). CONCLUSIONS: Isavuconazole was effective and well tolerated as antifungal prophylaxis following lung transplantation.

New Perspectives on Antimicrobial Agents: Cefiderocol.

Bacterial resistance to carbapenem agents has reached alarming levels. Accordingly, collaborative efforts between national and international organizations and the pharmaceutical industry have led to an impressive expansion of commercially available ß-lactam agents in recent years. No available agent comes close to the broad range of activity afforded by cefiderocol, a novel siderophore-cephalosporin conjugate. The novelty of and need for cefiderocol are clear, but available clinical data are conflicting, leaving infectious diseases specialists puzzled as to when to prescribe this agent in clinical practice. After a brief overview of cefiderocol pharmacokinetics and pharmacodynamics, safety data, cefiderocol susceptibility testing, and putative mechanisms of cefiderocol resistance, this review focuses on determining cefiderocol's role in the management of specific pathogens, including carbapenem-resistant Acinetobacter baumannii complex, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacterales, and less commonly identified glucose-nonfermenting organisms such as Stenotrophomonas maltophilia, Burkholderia species, and Achromobacter species. Available preclinical, clinical trial, and postmarketing data are summarized for each organism, and each section concludes with our opinions on where to position cefiderocol as a clinical therapeutic.

Isavuconazole for treatment of refractory coccidioidal meningitis with concomitant cerebrospinal fluid and plasma therapeutic drug monitoring.

Coccidioidal meningitis (CM) is a life-threatening infection with limited treatment options. Small series have reported success with isavuconazole; however, limited data exist on cerebrospinal fluid (CSF) penetration. Paired plasma and CSF isavuconazole concentrations were measured. Eleven CSF levels were tested, (7 ventricular, 4 lumbar) in three CM patients. Ventricular CSF levels were undetectable despite detectable plasma levels. All lumbar CSF levels were detectable (mean 1.00 µg/ml). Three pairs of lumbar CSF/plasma concentrations taken within 1 h of each other yielded a mean CSF/plasma ratio of 0.31. Isavuconazole was detectable in lumbar but not ventricular CSF in three patients treated for refractory CM. LAY SUMMARY: Isavuconazole is a triazole antifungal that has been used as salvage therapy in the treatment of coccidioidal meningitis (CM). Few data exist characterizing its concentration in the cerebrospinal fluid (CSF). We report tandem plasma and CSF concentrations of isavuconazole in three patients with CM.

Early Experience With Meropenem-Vaborbactam for Treatment of Carbapenem-resistant Enterobacteriaceae Infections.

Twenty patients with carbapenem-resistant Enterobacteriaceae infections were treated with meropenem-vaborbactam. Thirty-day clinical success and survival rates were 65% (13/20) and 90% (18/20), respectively. Thirty-five percent of patients had microbiologic failures within 90 days. One patient developed a recurrent infection due to meropenem-vaborbactam-nonsusceptible, ompK36 porin mutant Klebsiella pneumoniae.

Achievement of clinical isavuconazole blood concentrations in transplant recipients with isavuconazonium sulphate capsules administered via enteral feeding tube.

BACKGROUND: Isavuconazole is a triazole antifungal available in IV and capsule formulation. Prescribing information states that capsules should not be chewed, crushed, dissolved or opened because the drug was not studied in this manner. However, considering the pharmacokinetics of the capsules, we theorized opening and sprinkling the contents into an enteral feeding tube (EFT) would result in adequate absorption and systemic concentrations of isavuconazole. OBJECTIVES: To determine whether patients receiving isavuconazonium sulphate capsules via EFT would achieve clinical blood concentrations of isavuconazole. METHODS: Nineteen solid organ and HCT recipients receiving isavuconazole via EFT for prevention or treatment of invasive fungal infection (IFI) were prospectively identified at four academic medical centres in the USA. Patients were included in this evaluation if they received isavuconazole via EFT for at least 5 days and therapeutic drug monitoring (TDM) was performed. RESULTS: TDM was performed after a median of 7 days (range 6-17) following EFT administration and 15 days (range 7-174) of isavuconazole therapy overall. Median isavuconazole concentration was 1.8 µg/mL (range 0.3-5.2). Median isavuconazole concentrations in patients with or without prior IV administration were 1.8 µg/mL (range 0.3-5.2) and 2.2 µg/mL (range 0.8-3.6; P = 0.896), respectively. Concentrations achieved with the EFT route were similar to or greater than the corresponding concentrations via the IV route in six patients who had TDM performed during both routes of administration. CONCLUSIONS: It is reasonable to consider opening isavuconazonium sulphate capsules and administering the contents enterally for prevention and treatment of IFI.

Impact of Triazole Therapeutic Drug Monitoring Availability and Timing.

Therapeutic drug monitoring (TDM) is an established strategy to optimize antifungal therapy with certain triazoles. While established relationships exist between concentration and safety or efficacy, the impact of TDM timing on outcomes is unknown. We report clinical outcomes, including antifungal exposure and mortality, in patients receiving institutional versus reference laboratory TDM. The availability of in-house triazole assays reduced the time to drug concentration result (12 versus 68 h; P < 0.001) and time to achieve therapeutic serum concentrations (10 versus 31 days; P < 0.001). Subtherapeutic concentrations were associated with higher patient mortality (32% versus 13.3%; P = 0.036).

High-Dose Acyclovir for Cytomegalovirus Prophylaxis in Seropositive Abdominal Transplant Recipients.

BACKGROUND: Following abdominal solid organ transplant (aSOT), valganciclovir (VGC) is recommended for cytomegalovirus (CMV) prophylaxis. This agent is associated with efficacy concerns, toxicity, and emergence of ganciclovir resistance. OBJECTIVE: To evaluate the incidence of high-dose acyclovir (HD-A) prophylaxis failure in seropositive aSOT recipients (R+). METHODS: This was a retrospective, single-center study of R+ transplanted without lymphocyte-depleting induction between January 1, 2000, and June 30, 2013, discharged with 3 months of HD-A prophylaxis (800 mg 4 times daily). The primary outcome was incidence of prophylaxis failure. Secondary outcomes were incidence of biopsy-proven tissue-invasive disease and prophylaxis failure for each allograft subgroup. RESULTS: A total of 1525 patients met inclusion criteria: 944 renal (RTX), 108 simultaneous pancreas-kidneys (SPK), 462 liver (LTX), and 11 pancreas (PTX) transplant recipients. The composite rate of HD-A prophylaxis failure was 7%; incidence of tissue-invasive disease was 0.4%. Failure rates were 4.5%, 6.1%, 11%, and 20% in the RTX, SPK, LTX, and PTX populations, respectively; tissue-invasive disease rates were 0.2%, 0%, 0.7%, and 10%. Failure occurred more frequently in the LTX and PTX populations ( P < 0.0001, HR = 2.6; P = 0.04 HR = 4.4). Incidence of tissue-invasive disease was minimal and not different in the RTX, LTX and SPK populations ( P = 0.34). When evaluating recipients of seronegative allografts (D-), the composite failure rate was 3.4% with no significant difference between allograft subgroups ( P = 0.45). CONCLUSION: HD-A may be a reasonable prophylaxis alternative for D-/R+ recipients, in the absence of lymphocyte-depleting induction, if low incidence viremia is tolerable. Future studies are needed to determine the long-term impact of CMV viremia in the setting of this prophylaxis approach.

Top 10 Myths Regarding the Diagnosis and Treatment of Cellulitis.

BACKGROUND: Cellulitis is commonly treated in the emergency department (ED). Patients who present with cellulitis incur significant health care costs and may be overtreated with antibiotics. The accurate diagnosis and treatment of cellulitis plays an important role in cost-effective, high-quality medical care, as well as appropriate antibiotic utilization. OBJECTIVE: We aim to describe common fallacies regarding cellulitis. We present 10 myths that result in misdiagnosis, overtreatment, or inappropriate empiric management of cellulitis. Clinical presentation, including swelling and redness, is explored in depth, along with incidence of community-acquired methicillin-resistance Staphylococcus aureus, management of tick bites, and effective antibiotic therapy for cellulitis. DISCUSSION: Patients are often treated for cellulitis unnecessarily or inappropriately. Awareness of these myths will help guide providers in clinical decision making in order to effectively tailor treatment for these infections. CONCLUSIONS: Cellulitis is not as simple as it might seem, and is commonly misdiagnosed in the ED. Noninfectious causes of local symptoms, including lymphedema, venous stasis, and deep vein thrombosis need to be considered. Cellulitis should be treated with empiric antimicrobial therapy based on patient risk factors and regional susceptibility patterns. This review will assist providers in managing cellulitis and avoiding treatment errors that lead to high costs, unwanted side effects for patients, and overuse of antibiotics.

Vancomycin Combined With Clindamycin for the Treatment of Acute Bacterial Skin and Skin-Structure Infections.

BACKGROUND: Acute bacterial skin and skin-structure infections (ABSSSIs) are common causes of hospital admissions. These infections are often caused by methicillin-resistant Staphylococcus aureus; therefore, vancomycin remains a commonly used therapy. The purpose of this study was to compare hospital length of stay (LOS) in patients treated with vancomycin monotherapy vs combination therapy with clindamycin for ABSSSIs. METHODS: This was a retrospective analysis of 269 patients admitted with ABSSSIs to a 941-bed hospital in northern Alabama. Patients who received either vancomycin monotherapy or vancomycin in combination with clindamycin were included. The primary outcome was hospital LOS; secondary outcomes included 90-day readmission rate and the impact of the following on the primary outcome: organisms cultured, presence of abscess, incision and debridement (I&D), failure of a trial of outpatient antibiotics, and presence of diabetes. RESULTS: Hospital LOS was similar between groups when evaluating all ABSSSIs (3.7 ± 1.5 days vs 4.0 ± 2.0 days, P = .192, combination and monotherapy, respectively). In patients with abscesses, combination therapy was significantly associated with decreased LOS by 18.2% compared with monotherapy (95% confidence interval [CI], 0.818 [.679 to .985]; P = .034). Among the entire population, significantly fewer patients in the combination group were readmitted within 90 days (5.3% vs 15.3%; P = .006; odds ratio [OR], 3.2; 95% CI [1.35 to 7.66]). The 90-day readmission rates were significantly lower among patients with abscesses as well (2.0% vs 24.3%; P = .0001; OR, 14.6; 95% CI [2.98 to 71.37]). CONCLUSIONS: Combination therapy with vancomycin and clindamycin was associated with decreased hospital LOS for patients with an abscess. The 90-day hospital readmission rates for those with ABSSSIs may be reduced when combination therapy is utilized. A larger, prospective, multicentered study is needed to validate these findings.