Complicated Gram-positive Infections Research Articles

Continued Dosing of Oritavancin for Complicated Gram-Positive Infections.

Several retrospective and cohort analyses have suggested that continued dosing of oritavancin is both safe and efficacious for complicated Gram-positive infections, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

Oritavancin for the treatment of complicated gram-positive infection in persons who inject drugs

BackgroundTreatment of complicated infections in persons who inject drugs (PWID) and patients experiencing homelessness poses a unique challenge to clinicians. Long-acting lipoglycopeptide antibiotics, such as oritavancin, may facilitate extended courses of outpatient intravenous therapy while avoiding the need for central lines, improving compliance and thus increasing the chance of clinical cure.MethodsRetrospective chart review of adult PWID who received at least one dose of oritavancin for a gram-positive infection between 1/1/17 and 6/30/19 at a large safety net hospital.ResultsTwenty three PWID received 24 courses of at least one dose of oritavancin for a gram-positive infection; 16 were experiencing homelessness at the time of diagnosis. Methicillin resistant Staphylococcus aureus (MRSA) was the most common infecting pathogen and bone or joint the most frequent infection site. Nineteen encounters resulted in clinical cure, including 5 whose conditions improved despite non-adherence to their prescribed regimen. Three patients experienced a non-favorable outcome. Two patients experienced mild adverse drug reactions that did not interfere with therapy; no patients died while on therapy.ConclusionOritavancin may be a clinically effective treatment option for the management of complicated gram-positive infections in PWID and patients experiencing homelessness. Further studies should be performed to validate these results.

Clinical Outcomes and Economic Impact of Oritavancin for Gram-Positive Infections: A Single Academic Medical Center Health System Experience.

BackgroundVancomycin treatment of complicated Gram-positive infections is associated with laboratory monitoring, nephrotoxicity, and multiple daily dosing. Oritavancin, a lipoglycopeptide antibiotic with a once-weekly dosing strategy and similar but slightly broader spectrum of activity, presents several opportunities over vancomycin to improve compliance and convenience for the patient. Minimal real-world clinical and acquisition cost data in the inpatient setting and clinical data surrounding multiple dosing in the outpatient setting have limited oritavancin use despite its potential logistic advantages.ObjectivesWe describe inpatient and outpatient oritavancin administration, clinical outcomes, and economic impact.MethodsThis was a single-center, retrospective case series of patients treated with at least one dose of oritavancin between May 2015 and September 2017 at an academic medical center in the USA. A simplified cost-avoidance analysis was conducted assuming the patient had a national health insurance plan and focused on hospital days prevented.ResultsSeventy-five patients received oritavancin during the study period. The most common use of oritavancin was in patients with acute bacterial skin and skin structure infections (ABSSSI), defined as cellulitis, abscess or non-surgical wounds (n = 25, 33%), followed by surgical wound infections (n = 12, 16%) and osteomyelitis or septic arthritis (n = 10, 13%). Clinical cure or improvement was achieved in 68 patients (93.2%), while five patients (6.8%) failed treatment; adverse reactions were reported in nine patients (12%). Thirty-five patients received oritavancin as inpatients; 20 patients (57%) had at least one hospital day avoided due to inpatient oritavancin administration resulting in a total cost avoidance of US$343,654.ConclusionIn this series of 75 patients with Gram-positive infections, oritavancin treatment resulted in clinical cure or improvement in most patients, and was generally well tolerated. Inpatient administration may avoid costs and outpatient administration is a reasonable consideration for patients in which prolonged antibiotic therapy is necessary.

Pharmacodynamics of ClpP-Activating Antibiotic Combinations against Gram-Positive Pathogens.

It is often difficult to cure endocarditis, osteomyelitis, and device-associated infections caused by Gram-positive pathogens, despite therapy with clinically appropriate antibiotics. This may be due to antibiotic tolerance or resistance development. Acyldepsipeptides (ADEPs) are a class of bactericidal compounds active against a variety of clinically important Gram-positive bacteria, including staphylococci, streptococci, and enterococci. ADEPs activate caseinolytic protease P (ClpP), killing high-density, nondividing cultures of bacteria that are tolerant to approved classes of antibiotics. Acyldepsipeptide analog 4 (ADEP4) was active against a panel of drug-resistant Gram-positive pathogens in MIC assays, with no preexisting resistance detected. Killing of stationary-phase cultures was observed when ADEP4 was combined with multiple classes of approved antibiotics. Additionally, a hollow-fiber infection model was used to assess the effects of ADEP4 antibiotic combinations on bacterial killing and resistance development. These studies were performed on high-density cultures of methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), and vancomycin-resistant Enterococcus faecalis (VRE). None of the approved antibiotics linezolid, ampicillin, and oxacillin tested alone had bactericidal activity under these conditions. ADEP4 initially caused killing, but regrowth of the culture was apparent within 96 h due to resistance. Combinations of ADEP4 with linezolid or oxacillin caused substantially improved killing of MRSA or MSSA cultures, respectively, and no regrowth due to resistance was observed. The combination of ADEP4 and ampicillin eradicated cultures of VRE to the limit of detection within 52 h. These data suggest that combining ClpP activators with traditional antibiotics may be a good strategy to treat complicated Gram-positive infections.

200. Real-World Experience with Dalbavancin for Complicated Gram-Positive Infections: A Multicenter Evaluation

BackgroundDalbavancin (DAL) received Food and Drug Administration (FDA) approval for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive organisms including Methicillin-resistant Staphylococcus aureus (MRSA). Due to its unique activity and dosing schedule, use in non-FDA approved indications has been increasing. We evaluated the clinical and safety outcomes of patients treated with DAL for various infections.MethodsA multicenter, retrospective observational study was conducted from April 2017 to February 2019. We included adult patients who received 1 dose of DAL for any indication. The primary outcome was clinical success defined as 30-day survival from DAL initiation, resolution of signs and symptoms of infection, and absence of therapy escalation/change. Reasons for DAL therapy selection were also investigated.ResultsA total of 30 patients were included. The median age was 49 (35–58) years, 50% were female and 93.3% were Caucasian. Median APACHE II score was 9 (5–12). Persons who inject drugs (PWID) comprised 50%. Common DAL indications were bacteremia (53.3%), bone and joint infections (33.3%) and ABSSSI (26.7%). Pathogens were MRSA (43.3%), coagulase-negative Staphylococci (23.3%) and methicillin-susceptible S. aureus (MSSA) (13.3%). Previous antibiotics were administered in 93.3% of patients for a median of 9 (7–15) days and (13.3%) received combination antibiotic therapy with DAL. In a subgroup of patients with confirmed microbiological eradication (73.3%), DAL was initiated at a median of 8 days (4–14) after clearance. Clinical success was achieved in 80% of patients and 10% were de-escalated to oral therapy. Rash/pruritus and hypotension occurred in two and one patient, respectively. DAL was selected because of ease of administration (60%), inability to be discharged with a line (43.3%), poor candidacy for outpatient therapy (36.7%), and/or inadequate adherence (30%).ConclusionDAL appears to be well tolerated and results in high clinical success. Larger studies with longer follow would be valuable to more precisely define the role of DAL in complicated Gram-positive infections, particularly in comparison to other long-acting lipoglycopeptides.Disclosures All authors: No reported disclosures.

Efficacy and Safety of Daptomycin in Patients with Renal Impairment: A Multicenter Retrospective Analysis

Daptomycin is a therapeutic option for patients with underlying renal insufficiency who are vulnerable to nephrotoxicity from vancomycin. We evaluated the efficacy and safety of daptomycin in patients with renal impairment. Multicenter, retrospective, observational, case series analysis. Two academic medical centers. One hundred and sixty adults with creatinine clearance (Clcr ) of 50 ml/minute or less who received daptomycin for at least 72 hours for complicated Gram-positive infections from 2008-2011. Clinical and microbiologic outcomes were assessed at the end of daptomycin therapy. Safety evaluations were documented for all patients, and when available, creatine phosphokinase (CPK) levels were recorded. Thirty-eight (23.8%) patients were on hemodialysis, and 122 (76.3%) had a decreased baseline renal clearance not requiring hemodialysis with a median interquartile range (IQR) Clcr of 32.4 ml/minute (24.2-40.4 ml/min). The median (IQR) daptomycin dose was 6.0 mg/kg (5.8-7.8 mg/kg) administered every 24 hours in 68 patients (42.5%) and every 48 hours in 92 patients (57.5%). Daptomycin success, including cure or improvement, (Cure: signs and symptoms resolved and no additional antibiotic therapy required, or infection cleared with negative cultures reported at the end of daptomycin therapy; Improvement: partial resolution of signs and symptoms and additional antibiotic therapy necessary at the end of daptomycin therapy) was achieved in 128 of 160 (80.0%) patients at the end of therapy. Methicillin-resistant Staphylococcus aureus (MRSA) was the most common pathogen (45%) isolated. The most frequent reason for using daptomycin was due to vancomycin-associated nephrotoxicity (20%). Daptomycin therapy was discontinued in six patients (3.8%) because of elevated CPK (median time to onset, 11.5 days). Loss of daptomycin susceptibility occurred in two patients with complex endovascular infections who were on hemodialysis. Daptomycin demonstrated clinical and microbiologic success rates comparable with prior studies. Discontinuation of therapy because of elevated CPK levels may have been avoided in some patients with adjustment to every 48-hour dosing for Clcr less than 30 ml/minute. The relatively early time to onset suggests the need for CPK monitoring more frequently than once/week in renally impaired patients receiving daptomycin. The treatment of bacteremia in patients with renal insufficiency warrants further study.

High‐Dose Daptomycin for Treatment of Complicated Gram‐Positive Infections: A Large, Multicenter, Retrospective Study

To evaluate the clinical response and safety of high-dose daptomycin for treatment of complicated gram-positive infections. Multicenter, retrospective, observational, case series analysis. Five academic medical centers in four major United States cities. Two hundred fifty adults, not undergoing dialysis, who received high-dose daptomycin (≥ 8 mg/kg/day) for at least 72 hours for complicated gram-positive infections between January 1, 2005, and March 1, 2010. Clinical and microbiologic outcomes were assessed at the end of high-dose daptomycin therapy. Safety evaluations were recorded for all patients, and when available, baseline, end-of-therapy, and highest observed serum creatine phosphokinase (CPK) levels were recorded. Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) were the primary organisms isolated. The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0-10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5-16 days) and 13 days (IQR 6-18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy CPK level was 39 U/L (IQR 26-67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level. Daptomycin dosages of 8 mg/kg/day or greater may be safe and effective in patients with complicated gram-positive infections. Further clinical studies are warranted.