Susceptible Gram-positive Pathogens Research Articles

Clinical Experience with Telavancin for the Treatment of Patients with Bacteremia and Endocarditis: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BackgroundBacteremia and endocarditis caused by Staphylococcus aureus (S. aureus), particularly methicillin-resistant S. aureus (MRSA), are challenging to treat and are associated with high morbidity and mortality. Telavancin is a lipoglycopeptide antibacterial active against susceptible Gram-positive pathogens, including MRSA.ObjectiveThis registry study assessed the real-world use and clinical outcomes of telavancin in patients with bacteremia or endocarditis enrolled in the Telavancin Observation Use Registry (TOUR™).MethodsThe subset of patients enrolled in TOUR who were diagnosed with endocarditis and/or bacteremia with a known or unknown primary source (N = 151) were analyzed. Data including demographics, infection type, baseline pathogens, prior or concomitant antimicrobial therapy, dosing regimen, clinical response, treatment-emergent adverse events (TEAEs) of interest, and mortality were collected by retrospective medical chart review.ResultsTelavancin was primarily used as a second-line or greater therapy (n = 132, 87.4%). MRSA was present in 87 (57.6%) patients. Median telavancin dose was 740.6 mg (interquartile range (IQR) 206.0 mg) and median duration of therapy was 9.0 days (IQR 24.0 days). Of the 132/151 (87.4%) patients with an available assessment at the end of telavancin therapy, a positive clinical response was achieved in 98/132 (74.2%), while 14/132 (10.6%) failed therapy and 20/132 (15.2%) had an indeterminant outcome. TEAEs occurred in 24 (15.9%) patients. The most frequent TEAE was renal failure (n = 12, 7.9%); seven of these patients were receiving concomitant nephrotoxic medications. There was no change in creatinine clearance for 67/89 (75.3%) patients with values recorded at the beginning and the end of telavancin therapy.ConclusionsIn real-world clinical practice, overall positive clinical outcomes are observed in patients with bacteremia or endocarditis treated with telavancin, including in those patients infected with MRSA or another S. aureus pathogen. Telavancin may be an alternative treatment option for these patients.Trial RegistrationThis trial was registered with clinicaltrials.gov (NCT02288234) on 11 November 2014.Electronic supplementary materialThe online version of this article (10.1007/s40801-020-00191-x) contains supplementary material, which is available to authorized users.

Corrigendum.

[This corrects the article DOI: 10.1177/2049936117690501.].

Evaluation of telavancin dose capping in a large community hospital

BackgroundTelavancin is a bactericidal lipoglycopeptide treat susceptible Gram-positive pathogens including Methicillin-resistant Staphylococcus aureus. Pharmacokinetic studies have shown that obese patients have increased exposure to telavancin compared with non-obese patients. Dose capping of 750 mg was utilized in selected patients with the purpose of minimizing toxicity and decreasing costs without compromising efficacy.MethodsRetrospective case series includes adult patients admitted from 2010–2016 who received at least three doses of telavancin. Data collection includes patient demographics, telavancin dosing, antibiotic indication, length of stay, laboratory and microbiological data, and case mix index (CMI). The primary outcome is to assess the efficacy of capping telavancin doses at 750 mg compared with non-capped doses. Secondary outcomes include safety and financial outcomes, as well as readmission rates.Results333 patients were evaluated with 164 meeting the inclusion criteria. Seventy-three patients in the capped group vs. 91 in the non-capped group. Most common infections included ABSSI, pneumonia and bacteremia. Mean weight 110 kg in capped vs. 108 kg in noncapped, mean age 52 vs. 58, male 63% vs. 70%, fever resolution 83% vs. 60%, CMI 3.19 vs. 3.43 Six patients (8.2%) in the capped group were readmitted and 6 (8.5%) needed additional antibiotics compared with 12 (13.2%) and 9 (9.9%) in the non-capped group, respectively. Seven (9.6%) patients in the capped group experienced nephrotoxicity compared with 21 (23.1%) in the non-capped group (P = 0.04). The capped group experienced 7 (9.6%) incidents of mortality vs. 28 (30.8%) in the non-capped group (P = 0.001). When doses were capped, approximately $1,400 was saved per patient.ConclusionThe use of a capped 750 mg telavancin dose in adult patients appears to be an alternative dosing scheme that maintains efficacy and safety as well as being associated with reduced cost. Additional pharmacokinetic and clinical studies are needed to further investigate the use of capped dosing of telavancin to support the findings of this retrospective case series.Disclosures All authors: No reported disclosures.

Comparative In Vitro Activities of Oritavancin, Dalbavancin, and Vancomycin against Methicillin-Resistant Staphylococcus aureus Isolates in a Nondividing State.

Antibacterial agents that kill nondividing bacteria may be of utility in treating persistent infections. Oritavancin and dalbavancin are bactericidal lipoglycopeptides that are approved for acute bacterial skin and skin structure infections in adults caused by susceptible Gram-positive pathogens. Using time-kill methodology, we demonstrate that oritavancin exerts bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) isolates that are maintained in a nondividing state in vitro, whereas dalbavancin and the glycopeptide vancomycin do not.

Tedizolid: a novel oxazolidinone with potent activity against multidrug-resistant gram-positive pathogens.

Tedizolid phosphate is a novel oxazolidinone prodrug (converted to the active form tedizolid by phosphatases in vivo) that has been developed and recently approved (June 2014) by the United States FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by susceptible Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Tedizolid is an oxazolidinone, but differs from other oxazolidinones by possessing a modified side chain at the C-5 position of the oxazolidinone nucleus which confers activity against certain linezolid-resistant pathogens and has an optimized C- and D-ring system that improves potency through additional binding site interactions. The mechanism of action of tedizolid is similar to other oxazolidinones and occurs through inhibition of bacterial protein synthesis by binding to 23S ribosomal RNA (rRNA) of the 50S subunit of the ribosome. As with other oxazolidinones, the spontaneous frequency of resistance development to tedizolid is low. Tedizolid is four- to eightfold more potent in vivo than linezolid against all species of staphylococci, enterococci, and streptococci, including drug-resistant phenotypes such as MRSA and vancomycin-resistant enterococci (VRE) and linezolid-resistant phenotypes. Importantly, tedizolid demonstrates activity against linezolid-resistant bacterial strains harboring the horizontally transmissible cfr gene, in the absence of certain ribosomal mutations conferring reduced oxazolidinone susceptibility. With its half-life of approximately 12 h, tedizolid is dosed once daily. It demonstrates linear pharmacokinetics, has a high oral bioavailability of approximately 90 %, and is primarily excreted by the liver as an inactive, non-circulating sulphate conjugate. Tedizolid does not require dosage adjustment in patients with any degree of renal dysfunction or hepatic dysfunction. Studies in animals have demonstrated that the pharmacodynamic parameter most closely associated with the efficacy of tedizolid is fAUC(0-24h)/MIC. In non-neutropenic animals, a dose-response enhancement was observed with tedizolid and lower exposures were required compared to neutropenic cohorts. Two Phase III clinical trials have demonstrated non-inferiority of a once-daily tedizolid 200 mg dose for 6-10 days versus twice-daily 600 mg linezolid for the treatment of ABSSSIs. Both trials used the primary endpoint of early clinical response at 48-72 h; however, one trial compared oral formulations while the other initiated therapy with the parenteral formulation and allowed oral sequential therapy following initial clinical response. Throughout its development, tedizolid has demonstrated that it is well tolerated and animal studies have shown a lower propensity for neuropathies with long-term use than its predecessor linezolid. Data from the two completed Phase III clinical trials demonstrated that the studied tedizolid regimen (200 mg once daily for 6 days) had significantly less impact on hematologic parameters as well as significantly less gastrointestinal treatment-emergent adverse effects (TEAEs) than its comparator linezolid. As with linezolid, tedizolid is a weak, reversible MAO inhibitor; however, a murine head twitch model validated to assess serotonergic activity reported no increase in the number of head twitches with tedizolid even at doses that exceeded the C max in humans by up to 25-fold. Tyramine and pseudoephedrine challenge studies in humans have also reported no meaningful MAO-related interactions with tedizolid. With its enhanced in vitro activity against a broad-spectrum of Gram-positive aerobic bacteria, convenient once-daily dosing, a short 6-day course of therapy, availability of both oral and intravenous routes of administration, and an adverse effect profile that appears to be more favorable than linezolid, tedizolid is an attractive agent for use in both the hospital and community settings. Tedizolid is currently undergoing additional Phase III clinical trials for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilated nosocomial pneumonia (VNP).

The ATTAIN Trials: Efficacy and Safety of Telavancin Compared with Vancomycin for the Treatment of Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia

Hospital-acquired bacterial pneumonia (HABP) is the second most common nosocomial infection in the USA and the leading cause of mortality among hospital-acquired infections. An increasing proportion of HABP cases are the result of infection with methicillin-resistant Staphylococcus aureus (MRSA). Telavancin is a once-daily injectable, semisynthetic lipoglycopeptide antimicrobial with bactericidal activity against susceptible Gram-positive pathogens, including MRSA. The two methodologically identical Phase III ATTAIN studies demonstrated that telavancin was noninferior to vancomycin for the treatment of HABP, including ventilator-associated bacterial pneumonia, due to S. aureus (including methicillin-sensitive S. aureus and MRSA). Telavancin showed a similar safety profile to vancomycin, except that in patients with moderate-to-severe renal impairment, there was increased mortality, which warrants caution when using telavancin in this population. Now approved in the USA for the treatment of HABP, including ventilator-associated bacterial pneumonia, caused by susceptible isolates of S. aureus when other alternatives are not suitable, telavancin offers another therapeutic option.

Daptomycin in the Treatment of Patients with Infective Endocarditis: Experience from a Registry

Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) is a first-in-its-class cyclic lipopeptide approved for the treatment of patients with complicated skin and skin-structure infections due to susceptible gram-positive pathogens and recently approved for Staphylococcus aureus bloodstream infections including right-sided infective endocarditis. The clinical experience of patients registered in the Cubicin Outcomes Registry and Experience (CORE) 2004 database with daptomycin-treated infective endocarditis is described. The registry data were collected retrospectively by trained investigators to document real-world clinical experience. Study limitations included uncontrolled diagnostic criteria, noncomparative data, and lack of follow-up assessments. A total of 49 patients had a diagnosis of endocarditis: 38 with left-sided or both left-sided and right-sided endocarditis, and 11 with right-sided endocarditis alone. Renal failure was the most common comorbid condition. In all, 27 (55%) of the 49 patients had an initial creatinine clearance of ≤30 mL/min, and 14 (29%) were supported by dialysis. Staphylococcus aureus (59%; 83%, methicillin resistant) and enterococci (29%; 43%, vancomycin resistant) were the most commonly identified pathogens. In most instances, patients received gram-positive therapy before receiving daptomycin (43 of 49 [88%]). The median starting dose of daptomycin was 6 mg/kg (range, 4 to 7 mg/kg); 27 (55%) of the patients received a dose of ≥6 mg/kg. Daptomycin therapy was successful for 31 (63%) of the patients: cure was seen in 18 (37%) and improvement in 13 (27%). Therapy failed in 4 (8%) of the patients, and 14 (29%) of the cases were nonevaluable. The median duration of therapy in successful cases was 27 days. No differences in clinical response were observed based on baseline renal function, primary pathogen, or site of endocarditis. The results from the CORE 2004 database suggest that daptomycin should be considered a possible treatment for patients with right-sided infective endocarditis involving S aureus. Further studies are needed to extend daptomycin’s experience in left-sided or enterococcal endocarditis.

Pharmacokinetics of dalbavancin in plasma and skin blister fluid

Dalbavancin is a novel lipoglycopeptide antibiotic in development for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria. The aim of the present study was to assess the penetration of dalbavancin into skin blister fluid. Nine healthy subjects (five males; ranging in age from 26 to 57 years) were administered a single 30 min intravenous infusion of dalbavancin at a dose of 1000 mg. Skin blisters were induced by application of cantharidin ointment. Plasma and blister fluid samples were collected over 7 days post-dose, and concentrations of dalbavancin were assessed by a validated LC/MS/MS assay. Pharmacokinetics were determined by non-compartmental methods, and drug penetration was assessed based on the ratio of area under the curve (AUC) in the blister fluid versus plasma for each subject. The mean (SD) peak concentration of dalbavancin in plasma and blister fluid was 285 (31.1) and 67.3 (18.2) mg/L, respectively; the corresponding AUC(Day 7) values were 10 806 (1926) and 6438 (1238) mg . h/L, respectively. The mean (SD) penetration of dalbavancin into blister fluid was 59.6% (6.3%). By Day 7, the mean concentration of dalbavancin in plasma and blister fluid was 46.5 and 30.3 mg/L, respectively. Dalbavancin concentrations in blister fluid remained well above the MIC90 values for pathogens commonly implicated in cSSSIs such as Staphylococcus aureus, including methicillin-resistant S. aureus (MIC90 = 0.06 mg/L) and beta-haemolytic streptococci (MIC90 = 0.03 mg/L) through Day 7. These pharmacokinetic data support the use of dalbavancin in the treatment of cSSSIs caused by susceptible Gram-positive pathogens.

P1830 Susceptibility of Gram-positive pathogens to daptomycin and other antimicrobial agents: first results from the DAPTOGERM Surveillance Study

Revised Abstract Objectives: Drug resistance in Gram-positive bacteria has become an increasing problem over the past 20 years. New antibacterial agents such as the lipopeptide daptomycin (DAP), which was recently approved in the EU, have been developed to address this problem. Shortly after the approval, a surveillance study was started by a network of clinical microbiology laboratories to monitor the susceptibility of Gram-positive pathogens to DAP in Germany. This report comprises the results of isolates of five frequently encountered Gram-positive species collected in 49 laboratories from March to June 2006. Methods: A total of 1,520 isolates including oxacillin-susceptible Staphylococcus aureus (MSSA, n=360), oxacillin-resistant S. aureus (MRSA, n=286), Staphylococcus epidermidis (Se, n=262), Enterococcus faecalis (Es, n=209), Enterococcus faecium (Em, n=208), and Streptococcus pyogenes (Sp, n=195) were tested against DAP, linezolid (LZD), vancomycin (VAN) and other drugs. First isolates obtained from hospitalized patients with skin and soft tissue infections, respiratory tract infections, foreign body/catheter infections, or sepsis were included. MICs were determined in a central laboratory using the broth microdilution procedure according to the standard of the German DIN (Deutsches Institut fur Normung) 58940 guidelines. MICs of DAP were interpreted by the EUCAST criteria. Results: The majority of isolates was recovered from wound swabs (57.7%), blood samples (21.9%) and respiratory tract specimens (8.2%). MIC50/90 values of DAP for MSSA, MRSA, and Se each were 0.5/1 mg/L. All strains were inhibited by DAP at the EUCAST breakpoint of ≤1 mg/L. LZD and VAN were also active against all staphylococci. However, based on MIC50/90 values, DAP was up to 4fold more active than LZD or VAN. Of the Em isolates, 23 (11.1%) were resistant to VAN. In contrast, none of the Es isolates exhibited resistance to VAN. DAP inhibited all strains at 4 mg/L. MIC50/90 values of DAP for either enterococcal species were 2/4 mg/L. One Es strain was resistant to LZD (MIC 32 mg/L). DAP was more active than LZD or VAN against Sp. MIC50/90 values were 0.125/0.25 for DAP compared to 0.25/0.5 and 1/1 for VAN and LZD, respectively. The highest MICs of DAP for Sp isolates were 0.5 mg/L. Conclusion: DAP demonstrated excellent in vitro activity against frequently encountered Gram-positive species including multi-resistant isolates such as MRSA and VRE. Resistant strains were not detected.

Daptomycin: The First Approved Lipopeptide Antimicrobial

To review the literature concerning the first Food and Drug Administration-approved lipopeptide antimicrobial, daptomycin. A PUBMED search was conducted to identify pertinent English-language journal articles between 1985 and November 2003, and additional references were obtained from the bibliographies of these articles. Abstracts from the Interscience Conference on Antimicrobial Agents and Chemotherapy meetings from 1985 through 2003 also were reviewed. All studies evaluating any aspect of daptomycin. Daptomycin is a semisynthetic lipopeptide, the first such antimicrobial agent to reach the marketplace. Its mechanism of action differs from that of the related agent vancomycin in that much of its effect is not because of inhibition of peptidoglycan biosynthesis, but instead is a result of alterations in cell-membrane electrical charge and transport. It exhibits a broad spectrum of activity against gram-positive aerobes and anaerobes, including methicillin-, penicillin-, aminoglycoside-, and vancomycin-resistant strains. In subjects with normal renal function, the terminal disposition half-life is about 7 to 10 hours. It is principally eliminated as unchanged drug in the urine. Available clinical trial data demonstrate efficacy in complicated skin and skin-structure infections resulting from susceptible gram-positive pathogens, but not in pneumonia. The principal adverse event of concern, although rare, is myotoxicity, manifested by muscle pain and/or weakness and elevated serum creatine phosphokinase (CPK) concentrations. The approved dosage regimen is 4 mg/kg intravenously over 30 minutes once daily for 7 days to 14 days. Studies are underway evaluating doses of up to 8 mg/kg once daily. Daptomycin, the first lipopeptide antimicrobial to be marketed, exhibits activity against multiresistant gram-positive pathogens, including linezolid- and quinupristindalfopristin-resistant strains. As such, it is a potentially valuable agent to treat infections resulting from such pathogens. To preserve its utility, it should not be used indiscriminately for infections resulting from pathogens sensitive to other antimicrobials. It is probably best used with restricted access and used only for multiresistant gram-positive pathogens where alternative agents cannot be employed. If used, careful monitoring for the signs and symptoms of myotoxicity, including obtaining weekly serum CPK levels, is mandatory. In addition, bacterial sensitivities to this agent should be prospectively monitored by national antimicrobial surveillance programs like SENTRY, TRUST, and LIBRA.