Omadacycline in the treatment of community-acquired bacterial pneumonia in patients with comorbidities: a post-hoc analysis of the phase 3 OPTIC trial.

Introduction: The 2019 American Thoracic Society/Infectious Disease Society of America guidelines recommend respiratory fluoroquinolones to treat community-acquired bacterial pneumonia (CABP) in adults with comorbidities. Fluoroquinolones are effective against both typical and atypical pathogens. However, fluoroquinolone treatment has a risk of adverse effects, and the Food and Drug Administration has issued black box safety warnings for their use. Inpatient use of fluoroquinolones has reduced as a result; however, most antibiotic courses are completed as outpatients and discharge prescriptions account for the majority of fluoroquinolone use. As such, a new treatment option is needed to replace fluoroquinolones. Omadacycline is an aminomethylcycline antibiotic with a broad spectrum of activity and is available as a once-daily intravenous or bioequivalent oral formulation. Methods: This study assessed the safety and clinical efficacy of omadacycline compared with moxifloxacin for the treatment of adult CABP patients with Pneumonia Severity Index (PSI) risk class II/III and ≥1 comorbidity through a post-hoc analysis of the phase 3 OPTIC study (NCT02531438). Results: In total, 239 omadacycline- and 222 moxifloxacin-treated patients were assessed. The median age was similar between groups (omadacycline: 57 years; moxifloxacin: 58 years), with 26.0% and 26.6%, respectively, ≥65 years of age. Early clinical response was 91.6% for patients with ≥1 comorbidity treated with omadacycline and 91.4% for those treated with moxifloxacin. Post-treatment evaluation results for overall response were 89.1% in the omadacycline group and 87.4% in the moxifloxacin group. Conclusion: Safety warnings have reduced inpatient use of fluoroquinolones; however, outpatient and discharge prescriptions account for the majority of fluoroquinolone use. Outpatients with comorbidities need an efficacious alternative to fluoroquinolones. Omadacycline maintains the similar efficacy and benefits of fluoroquinolones as a once-daily, monotherapy, bioequivalent oral option with potent in vitro activity against the most common CABP pathogens, including S. pneumoniae and atypical pathogens, but offers a materially different safety profile consistent with its tetracycline heritage. In conclusion, both omadacycline and moxifloxacin exhibited similar efficacy in patients with PSI risk class II/III and comorbidities. Omadacycline fulfills an unmet need as an oral monotherapy treatment option for adult patients with CABP, which will further reduce the use of fluoroquinolones. Clinical trial registration: https://www.clinicaltrials.gov/study/NCT02531438, identifer: NCT02531438; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004071-13, identifier: EudraCT #2013-004071-13.

Omadacycline Oral Dosing and Pharmacokinetics in Community-Acquired Bacterial Pneumonia and Acute Bacterial Skin and Skin Structure Infection.

Omadacycline, a first-in-class aminomethylcycline antibiotic, is approved in the USA as intravenous (IV) and/or oral therapy for treatment of adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI). Phase 1 and 3 studies indicate that omadacycline dose adjustments are not required for any patient group based on age, sex, race, weight, renal impairment, end-stage renal disease, or hepatic impairment. Equivalency of exposure has also been demonstrated for 300 mg oral and 100 mg IV doses. Using an oral loading-dose regimen results in drug exposures exceeding established efficacy targets against the most common CABP and ABSSSI pathogens by Day 2 of treatment, and omadacycline has demonstrated clinical efficacy and is well tolerated. The oral-only dosing regimens provide the potential for treatment of CABP and ABSSSI either within a hospital setting or in the community, which could support earlier hospital discharge and reduced treatment costs.

Clinical Efficacy of Patients With Secondary Bacteremia Treated With Omadacycline: Results From Phase 3 Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia Studies.

In this post hoc analysis of the 63 patients with secondary bacteremia enrolled in the 3 omadacycline phase 3 studies of acute bacterial skin/skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP), we determined that omadacycline is a viable therapeutic option for appropriate patients with secondary bacteremia.

Use of daptomycin in the treatment of vancomycin-resistant enterococcal urinary tract infections: a short case series.

BACKGROUND: Vancomycin-resistant enterococci are a leading cause of hospital-acquired urinary tract infection and a growing concern for the clinician. The aim of this study was to evaluate the effectiveness of daptomycin in the treatment of patients with vancomycin-resistant enterococcal urinary tract infection treated in our 200-bed community-based institution. METHODS: Patients with confirmed symptomatic vancomycin-resistant enterococcal urinary tract infection identified by infectious disease consultation between January 1, 2007, and December 8, 2009, vancomycin-resistant enterococci-positive urine culture, and urinary symptoms and/or pyuria on urinalysis, and treated with daptomycin, were included in this case series. Daptomycin was generally administered at a planned dosage regimen of ≥ 5 mg/kg every 24 hours in patients with normal to moderately impaired kidney function or every 48 hours in patients with severe kidney disease. Microbiologic cure was defined as eradication of vancomycin-resistant enterococci in urine cultures taken after the completion of daptomycin treatment. Clinical cure was defined by symptom resolution, as assessed by the infectious disease clinician caring for the patient. RESULTS: Included in this case series are 10 patients who received daptomycin for confirmed vancomycin-resistant enterococcal urinary tract infection. Patients had a history of extensive hospital stays. Chart review revealed that all levels of kidney function (3, 2, 3, and 2 patients with kidney disease classified as normal, mild, moderate, and severe/kidney failure, respectively) were represented in the sample and that patients with (n = 5) or without (n = 5) previous urinary tract infection and with (n = 3) or without (n = 7) Foley catheters were included. Treatment with daptomycin achieved clinical cure and vancomycin-resistant enterococcal eradication in all cases in this series. CONCLUSION: Treatment with daptomycin was well tolerated and effective in all patients in this series, regardless of renal function, history of urinary tract infection, or Foley catheter use. This study adds to emerging clinical evidence that daptomycin is a valuable treatment for vancomycin-resistant enterococcal urinary tract infection.

Multicenter evaluation of the clinical outcomes of daptomycin with and without concomitant ß-lactams in patients with Staphylococcus aureus bacteremia and mild to moderate renal impairment.

Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of ß-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant ß-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a ß-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with ß-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.

Safety and clinical outcomes when utilizing high-dose (> or =8 mg/kg) daptomycin therapy.

BACKGROUND: Daptomycin is approved for the treatment of skin and skin-structure infections (4 mg/kg) and Staphylococcus aureus bacteremia, including right-sided endocarditis (6 mg/kg). In vitro and animal studies have reported increased activity with increased daptomycin doses. There are limited clinical data on use of daptomycin at doses greater than 6 mg/kg. OBJECTIVE: To evaluate the safety and efficacy of higher doses (> or =8 mg/kg) of daptomycin when administered for a variety of gram-positive infections. METHODS: Data were collected retrospectively as part of an ongoing registry (the Cubicin Outcomes Registry and Experience database) for the 2005-2007 program years. For the purpose of this study, the safety and efficacy of daptomycin were evaluated in patients who received doses of 8 mg/kg or higher. RESULTS: Ninety-four (2.6%) of 3617 patients received daptomycin doses of 8 mg/kg or higher; 18 (19%) of those patients received doses of 10 mg/kg or higher. The most common infections were bacteremia (30/94), skin and skin-structure infections (22/94), and endocarditis (15/94). The most common pathogens were Enterococcus spp. (37/94; 57% vancomycin-resistant) and S. aureus (28/94; 68% methicillin-resistant). Fifty-one percent of the patients were male, 39% were aged 66 years or older, 27% had an initial creatinine clearance less than 30 mL/min, and 17% were on dialysis. The median duration of daptomycin therapy was 15 days (minimum 1, maximum 90). Six (6.4%) of the 94 patients experienced 1 or more adverse events or abnormal laboratory value changes possibly related to daptomycin; in 2 (2.1%) of the 94 patients, daptomycin was discontinued due to treatment-related adverse events. Seventy-four (79%) patients were considered evaluable for efficacy. The overall clinical success rate was 89% (bacteremia, 91%; skin and skin-structure infections, 88%; endocarditis, 67%). CONCLUSIONS: Daptomycin was well tolerated and effective at doses of 8 mg/kg or higher in patients with gram-positive infections. Further prospective and comparative studies of daptomycin at doses greater than 6 mg/kg are warranted.

Adverse reactions to trimethoprim/sulfamethoxazole in AIDS.

OBJECTIVE: To report the case of a woman with AIDS who developed tremor, acute pancreatitis, and elevated serum creatinine levels while receiving trimethoprim/sulfamethoxazole (TMP/SMX). CASE SUMMARY: A 37-year-old Puerto Rican woman with AIDS, HIV nephropathy, and a recent history of disseminated histoplasmosis presented with fever, nonproductive cough, pancytopenia, and elevated transaminase and alkaline phosphatase levels. Serum creatinine was near her baseline level of 2.9 mg/dL. Treatment was started with amphotericin B lipid complex for histoplasmosis and intravenous TMP/SMX for presumed Pneumocystis carinii pneumonia. Two days later, the patient developed a high-frequency tremor and severe abdominal pain, and serum creatinine increased to 5.6 mg/dL. TMP/SMX was discontinued, after which the patient's symptoms resolved within 72 hours and serum creatinine returned to baseline levels. DISCUSSION: A high incidence of adverse reactions to TMP/SMX has been reported among HIV-infected persons. Toxic sulfamethoxazole metabolites may elicit hypersensitivity reactions. Trimethoprim can inhibit renal creatinine secretion, leading to high serum creatinine levels. Trimethoprim also inhibits dihydrofolate reductase, causing decreased dopamine production, which may lead to parkinsonian symptoms. Use of the Naranjo probability scale indicated a probable relationship between the adverse effect and TMP/SMX. CONCLUSIONS: The high frequency and wide range of potential adverse effects associated with the use of TMP/SMX in HIV-infected persons require that clinicians consider drug toxicity as a cause of new symptoms in patients receiving this medication.