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.

Incidence of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents.

This study investigated the real-world incidence rate of serotonin syndrome in patients receiving tedizolid and concomitant serotonergic agents. A retrospective cohort of 479 adult patients was assessed between January 2015 and July 2023. Overall, a rare rate of 0.4% (2/479) of possible serotonin syndrome with tedizolid was identified. Given that concomitant serotonergic agents were commonly used, further study is warranted to determine causality.

Clinical manifestations and treatment outcomes for patients with Pseudomonas endocarditis.

OBJECTIVES: To investigate clinical outcomes of patients with Pseudomonas endocarditis and identify factors associated with treatment failure. METHODS: Adult patients meeting definitive Duke's criteria for Pseudomonas endocarditis at 11 hospitals were identified between May 2000 and February 2024. Failure was defined as death or microbiological failure by day 42. First-line therapy consisted of cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam alone or in combination. RESULTS: Forty-eight patients met inclusion criteria; 29% were persons who inject drugs and 13% were organ transplant recipients. Pseudomonas aeruginosa was the causative species in 98% of cases. Patients who experienced 42 day cure were more likely to be initially managed with first-line ß-lactam agents compared with those who experienced clinical failure (97% versus 62%, P = 0.004). Treatment with first-line ß-lactams was associated with shorter time to treatment initiation and a lower likelihood of infection due to MDR Pseudomonas spp. In the univariate model, patients who experienced 90 day mortality were more likely to have prosthetic valve endocarditis (57% versus 24%, P = 0.02), an intracardiac complication (36% versus 9%, P = 0.04) and a higher median (IQR) Pitt bacteraemia score [2.5 (2-3.8) versus 1 (0-2), P = 0.048]. Combination therapy did not improve clinical outcomes but did increase the rate of adverse effects resulting in drug discontinuation compared with monotherapy, (21% versus 0%, P = 0.08). CONCLUSIONS: This is the largest study of Pseudomonas endocarditis to date. We identified improved clinical outcomes when cefepime, piperacillin/tazobactam, ceftazidime or ceftolozane/tazobactam were used for initial treatment. We did not identify a clinical benefit for combination treatment.

Carbapenem combination therapy versus standard of care for persistent methicillin-susceptible Staphylococcus aureus bacteraemia.

BACKGROUND: Successful use of carbapenems in combination with cefazolin or oxacillin for treatment of MSSA bacteraemia has been described; however, comparative data to standard treatment approaches are lacking. METHODS: This was a multicentre, retrospective study of adult patients with MSSA bacteraemia for >48 h. Standard treatment was considered monotherapy with cefazolin, oxacillin or nafcillin. Combination therapy was defined as the addition of ertapenem or meropenem to standard treatment for at least 24 h. The primary outcome was duration of bacteraemia defined as time from administration of an antibiotic with in vitro activity to first negative blood culture. Time to blood culture sterilization was compared through risk-set matching with aid of a propensity score. RESULTS: Overall, 238 patients were included; 66% (157/238) received standard treatment and 34% (81/238) received combination therapy. The median (IQR) time to carbapenem initiation was 4.7 (3.63-6.5) days. Patients who received combination therapy were younger (P = 0.012), more likely to have endocarditis (P = 0.034) and had longer median duration of bacteraemia (P < 0.001). After applying risk-set matching, patients who received combination therapy experienced faster time to blood culture sterilization compared with control patients [HR = 1.618 (95% CI; 1.119-2.339) P = 0.011]. Using a paired hazard model, 90 day mortality rates were not statistically different among patients who received combination therapy versus matched controls [HR = 1.267 (95% CI; 0.610-2.678), P = 0.608]. DISCUSSION: Carbapenem combination therapy resulted in faster time to blood culture sterilization, but no differences in overall mortality rates. Randomized trials are critical to determine the utility of carbapenem combination therapy.

Clinical outcomes of baloxavir versus oseltamivir in immunocompromised patients.

BACKGROUND: Neuraminidase inhibitors, including oseltamivir, are the treatment standard for influenza. Baloxavir, a novel antiviral, demonstrated comparable outcomes to oseltamivir in outpatients with influenza. Baloxavir was equally effective as oseltamivir in a retrospective study of hospitalized patients with influenza at our institution. However, the efficacy of baloxavir in immunocompromised patients is unclear. METHODS: We conducted a retrospective cohort study of immunocompromised adult patients hospitalized with influenza A who received baloxavir from January 2019 to April 2019 or oseltamivir from January 2018 to April 2018. Demographic and clinical outcomes were assessed. Primary outcomes were time from antiviral initiation to resolution of hypoxia and fever. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) care, ICU LOS, and 30-day mortality. RESULTS: Of 95 total patients, 52 received baloxavir and 43 received oseltamivir. Other than younger age (57.5 vs. 65; p = .035) and longer duration between vaccination and symptom onset (114 vs. 86 days; p = .001) in the baloxavir group, baseline characteristics did not differ. H1 was the predominant subtype in the baloxavir group (65.3%) versus H3 in the oseltamivir group (85.7%). When comparing baloxavir to oseltamivir, there was no significant difference in median time from antiviral initiation to resolution of hypoxia (59.9 vs. 42.5 h) and to resolution of fever (21.6 vs. 26.6 h). There were no differences in secondary outcomes. CONCLUSION: Baloxavir was not associated with longer time to resolution of hypoxia or fever in comparison to oseltamivir. Results must be taken in context of variations in seasonal influenza subtype and resistance rates.

In-Class Cross-Reactivity among Hospitalized Patients with Hypersensitivity Reactions to Fluoroquinolones.

Results from this large, multicenter study suggest that patients with a confirmed ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction are likely to tolerate other fluoroquinolones. Avoiding different fluoroquinolones in patients labeled with a ciprofloxacin, moxifloxacin, or levofloxacin allergy may not always be mandatory. This was a study of patients with a ciprofloxacin, moxifloxacin, or levofloxacin hypersensitivity reaction and a documented electronic medical record administration of a different fluoroquinolone. Numerically, the most common reaction risk occurred with a challenge to moxifloxacin (2/19; 9.5%), followed by ciprofloxacin (6/89; 6.3%), and levofloxacin (1/44; 2.2%).

Serratia endocarditis: antimicrobial management strategies and clinical outcomes.

OBJECTIVES: The incidence of Serratia endocarditis is increasing, yet optimal treatment has not been defined. Our objective was to investigate the outcomes of patients with Serratia endocarditis by treatment strategy. METHODS: We reviewed adult patients with definitive Serratia endocarditis at two independent health systems between July 2001 and April 2023. Combination therapy was defined as receipt of ≥2 in vitro active agents for ≥72 h. RESULTS: Seventy-five patients were included; 64% (48/75) were male and 85% (64/75) were people who inject drugs. Compared with monotherapy, receipt of combination therapy was associated with lower rates of microbiological failure (0% versus 15%, P = 0.026) and 90 day all-cause mortality (11% versus 31%, P = 0.049). Antimicrobial discontinuation due to an adverse event was more common among patients receiving combination therapy compared with monotherapy (36% versus 8%, P = 0.058). CONCLUSIONS: In the largest series of Serratia endocarditis to date, combination antibiotic treatment was associated with improved outcomes. However, larger, prospective studies are warranted.

Ceftolozane/tazobactam for refractory P. aeruginosa endocarditis: A case report and pharmacokinetic analysis.

We describe a case of a 48 years old male with left sided endocarditis and septic emboli secondary to a Pseudomonas aeruginosa strain that developed resistance to other ß-lactam antibiotics during therapy resulting in prolonged bacteremia. Blood cultures sterilized within 1 day of initiating ceftolozane/tazobactam 3 g every 8 hours in combination with ciprofloxacin. Steady state free ceftolozane plasma Cmax and Cmin concentrations were calculated to be 122.2µg/mL and 24.3µg/mL, respectively. The multidrug-resistant strain harbored chromosomal ß-lactamases OXA-486 and PDC-3, mutations in ampD and dacB predicted to lead to ampC over-expression, and mutations in OprD predicted to decrease outer membrane permeability. Following completion of a 42 day course and aortic valve replacement, the patient was deemed clinically cured without recurrence of infection at follow up 2 years later. To our knowledge, this is the first reported case to measure ceftolozane concentrations during the treatment of endocarditis which supports dose optimization approaches of severe endovascular disease due to multidrug resistant pathogens.

Combination Therapy of Chloramphenicol and Daptomycin for the Treatment of Infective Endocarditis Secondary to Multidrug Resistant Enterococcus faecium.

A 38-years-old female with an aortic valve replacement presented to an outside hospital (OSH) with fevers and malaise. Blood cultures revealed VRE which was resistant to linezolid, resistant to ampicillin, non-susceptible to daptomycin (MIC of 8 mcg/mL), and exhibited susceptibility to gentamicin. The patient was therefore initiated on intravenous (IV) daptomycin 6 mg/kg q24h and gentamicin IV 1 mg/kg q8h. However, after 14 days of therapy with daptomycin and gentamicin, the patient was transferred to our institution for the management of cardiogenic shock and hypoxemic respiratory failure. Given the concern for treatment failure, her antimicrobial regimen was changed to IV chloramphenicol 12.5 mg/kg every 6 hours with IV daptomycin 10 mg/kg every 48 hours given an estimated creatinine clearance of 30 mL/minutes. In vitro susceptibilities for chloramphenicol were performed which confirmed susceptibility. A transesophageal echocardiogram revealed a possible abscess at the left coronary cusp and aortic valve dehiscence. The patient underwent aortic valve replacement with aortic root reconstruction. The aortic valve culture grew VRE susceptible to linezolid but resistant to ampicillin and doxycycline. The patient was deemed clinically cured after 42 days of combination therapy with daptomycin and chloramphenicol. After 6 years of follow-up, the patient has not had a recurrent VRE infection. To our knowledge, this is the first case of endocarditis secondary to VRE that was successfully managed with the combination of daptomycin and chloramphenicol.

Renal and Hepatic Toxicity Analysis of Remdesivir Formulations: Does What Is on the Inside Really Count?

It has been postulated that the injectable solution formulation of remdesivir could be more nephrotoxic than the lyophilized powder since it contains twice as much sulfobutylether-ß-cyclodextrin (SBECD). Therefore, we evaluated 1,000 hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who received remdesivir lyophilized powder or solution. A logistic regression model accounting for baseline confounders identified that neither the use of the injectable solution (odds ratio [OR], 1.05; 95% confidence interval [CI], 0.49 to 2.29; P = 0.901) nor a creatinine clearance of <30 ml/min at the time of remdesivir initiation (OR, 1.39; 95% CI, 0.51 to 3.5; P = 0.499) was significantly associated with acute kidney injury. Regarding hepatoxicity, there was no significant difference in early discontinuation of remdesivir due to abnormal liver function tests between patients who received the lyophilized powder versus those who received solution (0.9% versus 2.3%, P = 0.09).

A Valid Warning or Clinical Lore: an Evaluation of Safety Outcomes of Remdesivir in Patients with Impaired Renal Function from a Multicenter Matched Cohort.

Per prescribing guidance, remdesivir is not recommended for SARS-CoV-2 in patients with renal disease given the absence of safety data in this patient population. This study was a multicenter, retrospective chart review of hospitalized patients with SARS-CoV-2 who received remdesivir. Safety outcomes were compared between patients with an estimated creatinine clearance (eCrCl) of <30 ml/min and an eCrCl of ≥30 ml/min. The primary endpoint was acute kidney injury (AKI) at the end of treatment (EOT). Of 359 patients who received remdesivir, 347 met inclusion criteria. Patients with an eCrCl of <30 ml/min were older {median, 80 years (interquartile range [IQR], 63.8 to 89) versus 62 (IQR, 54 to 74); P < 0.001}, were more likely to be on vasopressors on the day of remdesivir administration (30% versus 12.7%; P = 0.003), and were more likely to be mechanically ventilated during remdesivir therapy (27.5% versus 12.4%; P = 0.01) than those with an eCrCl of ≥30 ml/min. Despite these confounders, there was no significant difference in the frequency of EOT AKI (5% versus 2.3%; P = 0.283) or early discontinuation due to abnormal liver function tests (LFTs) (0% versus 3.9%; P = 0.374). Of the 5% of patients who developed EOT AKI on remdesivir with an eCrCl <30 ml/min, no cases were attributable to remdesivir administration per the treating physician. Comparable safety outcomes were observed when 1:1 nearest neighbor matching was applied to account for baseline confounders. In conclusion, remdesivir administration was not significantly associated with increased EOT AKI in patients with an eCrCl of <30 ml/min compared to patients with an eCrCl of ≥30 ml/min.

Three is a crowd: Clinical outcomes of a twice daily versus a thrice daily metronidazole dosing strategy from a multicenter study.

This was a multicenter, retrospective study of patients with anaerobic bacteremia comparing metronidazole 500 mg every 8 h versus 500 mg every 12 h. Of 782 patients reviewed, 85 met inclusion criteria. There was no significant difference in mortality, length of stay, or escalation of therapy between dosing strategies.

Clinical outcomes of baloxavir versus oseltamivir in patients hospitalized with influenza A.

OBJECTIVES: To date, clinical trials evaluating baloxavir have excluded patients hospitalized with influenza infection and therefore this study sought to evaluate the efficacy of baloxavir in inpatients with influenza A. METHODS: This study was a multicentre, retrospective chart review of adult patients admitted to the hospital within the Yale New Haven Health System who received oseltamivir or baloxavir for the treatment of influenza A. Patients were screened for inclusion between January 2018 and April 2018 in the oseltamivir group, while patients in the baloxavir group were screened for inclusion between January 2019 and April 2019. Influenza A diagnosis was confirmed by RT-PCR using a nasopharyngeal swab specimen. RESULTS: Of the 2392 patients assessed, 790 met the inclusion criteria. There were 359 patients who received baloxavir and 431 patients who received oseltamivir. Patients who received baloxavir were younger compared with those who received oseltamivir [median = 69 (IQR = 57-81) years versus 77 (IQR = 62-86) years; P < 0.001]. Patients who received baloxavir had no significant difference in hospital length of stay [median = 4 (IQR = 3-6) days versus 5 (IQR = 3-6) days; P = 0.45] or 30 day all-cause mortality [12 (3.3%) versus 26 (6%); P = 0.079] compared with those who received oseltamivir. However, patients who received baloxavir had a significantly faster time to hypoxia resolution [median = 51.7 (IQR = 25.3-89.3) h versus 72 (IQR = 37.5-123) h; P < 0.001]. CONCLUSIONS: The results of this study support the use of baloxavir for the treatment of influenza A in hospitalized patients with the potential benefit of a faster time to resolution of hypoxia.

Impact of Delayed Oral Vancomycin for Severe Clostridium difficile Infection.

Background: Treatment of severe Clostridium difficile infection (CDI) with oral vancomycin (VAN) is known to be superior to treatment with metronidazole (MDZ). However, previous studies have not evaluated the impact on patients when oral VAN therapy is delayed after diagnosis of severe CDI. Materials and Methods: This was a single-center, retrospective study of adult patients who were diagnosed with severe CDI. The objective was to compare clinical outcomes for patients treated initially with oral VAN versus patients receiving delayed oral VAN after at least 48 hours of initial treatment with MDZ. The primary outcome was all-cause in-hospital mortality. Results: There were 101 patients who comprised the initial oral VAN group, while 20 patients comprised the delayed oral VAN group. There was no significant difference in all-cause in-hospital mortality for patients in the initial oral VAN treatment group compared to those who had delayed oral VAN therapy (4.95% vs 15.00%, P = 0.13). Patients who were initially treated with oral VAN experienced a significantly higher rate of clinical cure (49.50% vs 20.00%, P = 0.02), shorter median postinfection length of hospitalization (7.0 days vs 13.0 days, P < 0.001), shorter median time to resolution of leukocytosis (3.9 days vs 10.4 days, P = 0.01), and were less likely to have an end of treatment serum creatinine greater than 1.5 times their baseline (8.7% vs 29.4%, P = 0.03). Conclusion: Patients who receive oral VAN as their initial treatment for severe CDI experience improved clinical outcomes compared to patients receiving delayed oral VAN after being initially treated with MDZ.

Potential role of broad-spectrum azoles as therapy for Malasezzia bloodstream infection.

Amphotericin B is the currently recommended therapy for Malassezia invasive infection (MII), but this drug requires intravenous administration and is associated with significant toxicity. The role of broad-spectrum azoles in managing MII is not clear. We describe two cases of MII due to M. pachydermatis and M. furfur that were successfully treated with posaconazole and reviewed the literature to assess the position of posaconazole in treating MII.

Epidemiology and Clinical Outcomes of Non-HACEK Gram-Negative Infective Endocarditis.

Background: The objectives of this study were to describe the changing epidemiology of gram-negative infective endocarditis (GNIE) and to identify factors associated with treatment failure and death. Methods: Adult patients with GNIE were included if they met modified Duke criteria for definitive infective endocarditis (IE) between April 2010 and December 2021. Patients were identified using Boolean search terms. Clinical failure was a defined as a composite of all-cause 42-day mortality or microbiologic failure. All analyses were performed using Stata, version 15.1. Results: One-hundred twenty-three patients were included. The most common pathogens were Serratia spp. (43%), Pseudomonas aeruginosa (21%), and Klebsiella spp. (14%). Fifty-two percent of cases were among persons who injection drugs (PWID; n = 64), for whom Serratia spp. (70%) was the most common cause of GNIE. Overall, patients infected with P. aeruginosa had higher microbiologic failure rates than other patients (23% vs 6%; P = .004). Patients who received combination therapy (n = 53) had comparable median lengths of stay (23 vs 19.5 days; P = .412), microbiologic failure rates (11.3% vs 7.1%; P = .528), clinical failure rates (18.9% vs 22.9%; P = .592), and 90-day mortality rates (13.2% vs 25.7%; P = .088) as those treated with monotherapy. After applying stepwise logistic regression, male gender, Pitt Bacteremia Score, and not receiving surgical intervention despite a surgical indication were associated with clinical failure. Conclusions: This is the first study to identify Serratia spp. as the most common etiology of GNIE, which was particularly true among PWID. Microbiologic failures occurred most commonly among P. aeruginosa, and use of combination antimicrobial therapy did not improve clinical outcomes.

Microbiologic and Clinical Description of Postoperative Central Nervous System Infection After Endoscopic Endonasal Surgery.

BACKGROUND: Consensus guidelines for antibiotic prophylaxis in endoscopic endonasal surgery (EES) have not been developed. The study objective was to define the microbiologic and clinical characteristics of post-EES central nervous system (CNS) infections. METHODS: This was a single-center retrospective study of patients >18 years of age who underwent EES between January 2010 and July 2021 at a high-volume skull base center. Patients with confirmed CNS infection within 30 days of EES were included. During the study period, the standard prophylaxis regimen was ceftriaxone 2 g every 12 hours for 48 hours. For patients with a documented penicillin allergy, vancomycin plus aztreonam was recommended. RESULTS: In total, 2440 EES procedures were performed on 2005 patients; the CNS infection rate was 1.8% (37/2005). CNS infections were more common among patients with a history of previous EES (6.5%; 20/307) compared with those who did not (1%; 17/1698; P < 0.001). The median time from EES to CNS infection was 12 (6-19) days. Thirty-two percent (12/37) of CNS infections were polymicrobic, which was more common among patients without previous EES (52.9%; 9/17) compared with those with previous EES (15%; 3/20; P = 0.03). Across all cases, Staphylococcus aureus (n = 10) and Pseudomonas aeruginosa (n = 8) were commonly isolated pathogens. Among those with confirmed methicillin-resistant Staphylococcus aureus (MRSA) nares colonization before EES, 75% (3/4) developed MRSA CNS infections compared with 6.1% (2/33) of noncolonized patients (P = 0.005). CONCLUSIONS: CNS infection after EES is rare and causative pathogens vary. Further studies are needed to identify the impact of MRSA nares screening on antimicrobial prophylaxis before EES.