Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial

ABSTRACTOritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistantStaphylococcus aureus(MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA.

Download Full-text

Telavancin versus Standard Therapy for Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: FAST 2 Study

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.3.862-867.2006 ◽

2006 ◽

Vol 50 (3) ◽

pp. 862-867 ◽

Cited By ~ 121

Author(s):

Martin E. Stryjewski ◽

Vivian H. Chu ◽

William D. O'Riordan ◽

Brian L. Warren ◽

Lala M. Dunbar ◽

...

Keyword(s):

Standard Therapy ◽

Clinical Success ◽

Therapy Group ◽

Success Rates ◽

Standard Therapy Group ◽

Gram Positive ◽

Double Blind ◽

Skin Structure ◽

Complicated Skin ◽

Cure Rates

ABSTRACT Telavancin is a bactericidal lipoglycopeptide with a multifunctional mechanism of action. We conducted a randomized, double blind, active-control phase II trial. Patients ≥18 years of age with complicated skin and skin structure infections caused by suspected or confirmed gram-positive organisms were randomized to receive either telavancin at 10 mg/kg intravenously every 24 h (q24h) or standard therapy (antistaphylococcal penicillin at 2 g q6h or vancomycin at 1 g q12h). A total of 195 patients were randomized and received at least one dose of study medication. Clinical success rates were similar in all analysis populations at test of cure. In microbiologically evaluable patients with Staphylococcus aureus at baseline (n = 91), 96% of the telavancin group and 90% of the standard-therapy group were cured. Among patients with methicillin-resistant S. aureus (MRSA) at baseline (n = 45), clinical cure rates were also 96% for telavancin and 90% for standard therapy. Microbiologic eradication in patients with S. aureus infection was better with telavancin compared to standard therapy (92% versus 78%, P = 0.07) and significantly better in patients with MRSA (92% versus 68%; P = 0.04). Therapy was discontinued for an adverse event (AE) in 6% and 3% of the patients receiving telavancin and standard therapy, respectively. Except for two cases of rash in the telavancin group, these AEs were similar in type and severity in the two groups. The overall incidences and severities of AEs and laboratory abnormalities were similar between the two groups. These data support the ongoing studies assessing the efficacy and safety of telavancin in the treatment of serious gram-positive infections, particularly involving MRSA.

Download Full-text

Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00551-07 ◽

2007 ◽

Vol 52 (1) ◽

pp. 37-44 ◽

Cited By ~ 120

Author(s):

Gary J. Noel ◽

Richard S. Strauss ◽

Karen Amsler ◽

Markus Heep ◽

Rienk Pypstra ◽

...

Keyword(s):

Confidence Interval ◽

Study Drug ◽

Primary Objective ◽

Gram Positive ◽

Taste Disturbance ◽

Double Blind ◽

Skin Structure ◽

Gram Positive Bacteria ◽

Complicated Skin ◽

Cure Rates

ABSTRACT Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, −4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, −8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n = 17) of the ceftobiprole-treated patients and 6% (n = 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.

Download Full-text

Multicenter, Randomized Study of the Efficacy and Safety of Intravenous Iclaprim in Complicated Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01383-08 ◽

2009 ◽

Vol 53 (7) ◽

pp. 2834-2840 ◽

Cited By ~ 25

Author(s):

D. Krievins ◽

R. Brandt ◽

S. Hawser ◽

P. Hadvary ◽

K. Islam

Keyword(s):

Randomized Study ◽

Efficacy And Safety ◽

Double Blind ◽

Skin Structure ◽

Treatment Groups ◽

Folate Pathway ◽

Complicated Skin ◽

Cure Rates ◽

To Receive ◽

Vancomycin Treatment

ABSTRACT Iclaprim is a novel antibacterial agent that is currently in development for the treatment of complicated skin and skin structure infections (cSSSI). Iclaprim specifically and selectively inhibits bacterial dihydrofolate reductase, a critical enzyme in the bacterial folate pathway, and exhibits an extended spectrum of activity against various resistant pathogens, including methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). The objective of this randomized, double-blind phase II study was to compare the efficacy and safety of iclaprim to those of vancomycin in patients with cSSSI. Patients were randomized to receive 0.8 mg iclaprim/kg of body weight, 1.6 mg/kg iclaprim, or 1 g vancomycin twice a day for 10 days. Clinical cure rates for the 0.8- and 1.6-mg/kg-iclaprim treatment groups were comparable to that for the vancomycin treatment group (26/28 patients [92.9%], 28/31 patients [90.3%], and 26/28 patients [92.9%], respectively). Iclaprim also showed high microbiological eradication rates. Iclaprim exhibited an eradication rate of 80% and 72% versus 59% observed with vancomycin for S. aureus, the pathogen most frequently isolated at baseline. Five MRSA cases were observed, four in the 0.8-mg/kg-iclaprim arm and one in the vancomycin arm, and all were both clinically and microbiologically cured. Iclaprim exhibited a safety profile similar to that of vancomycin, an established drug for the treatment of cSSSI. Results from this study indicate that iclaprim is a promising new therapy for the treatment of cSSSI, in particular those caused by S. aureus, including MRSA.

Download Full-text

TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00712-12 ◽

2012 ◽

Vol 56 (11) ◽

pp. 5476-5483 ◽

Cited By ~ 22

Author(s):

Martin E. Stryjewski ◽

Peter D. Potgieter ◽

Yu-Ping Li ◽

Steven L. Barriere ◽

Allan Churukian ◽

...

Keyword(s):

Clinical Success ◽

Study Medication ◽

Gram Positive ◽

Double Blind ◽

Content Type ◽

Skin Structure ◽

Complicated Skin ◽

The Difference ◽

Vancomycin Group ◽

Cure Rates

ABSTRACTTD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistantStaphylococcus aureusat baseline (n= 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n= 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.

Download Full-text

The Use of Anthelmintics in the Treatmenlt of Ascariasis

Paediatrica Indonesiana ◽

10.14238/pi16.9-10.1976.391-5 ◽

2019 ◽

Vol 16 (9-10) ◽

pp. 391-5

Author(s):

Djauhar Ismail ◽

Utomo Utomo ◽

Sugeng Yuwono ◽

Noerhayati S.

Keyword(s):

Single Dose ◽

Treatment Groups ◽

Pyrantel Pamoate ◽

Cure Rates

Ninety-seven children with Ascariasis were treated at randomly with Piperazine, Tetramisole, and Pyrantel pamoate in a single dose with cure rates of 59%, 62%, and 88%, respectively. In the children who were not cured, a reduction in egg count of nearly 80% was found in all three treatment groups. The results of this study showed that Pyrantel pamoate is the most effective of the three drugs.

Download Full-text

Safety and Pharmacokinetics of Recombinant Human Plasma Gelsolin in Patients Hospitalized for Nonsevere Community-Acquired Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00579-20 ◽

2020 ◽

Vol 64 (10) ◽

Author(s):

Abla Tannous ◽

Susan L. Levinson ◽

James Bolognese ◽

Steven M. Opal ◽

Mark J. DiNubile

Keyword(s):

Placebo Recipient ◽

Single Dose ◽

Human Plasma ◽

Unmet Need ◽

Community Acquired Pneumonia ◽

Comfort Care ◽

Plasma Gelsolin ◽

Treatment Groups ◽

Dosing Regimens ◽

Severe Community Acquired Pneumonia

ABSTRACT There remains an unmet need to address the substantial morbidity and mortality associated with severe community-acquired pneumonia (sCAP). Recombinant human plasma gelsolin (rhu-pGSN) improves disease outcomes in diverse animal models of infectious and noninfectious inflammation. This blinded dose-escalation safety study involved non-intensive care unit (ICU) patients admitted for mild CAP and randomized 3:1 to receive adjunctive rhu-pGSN or placebo intravenously. Thirty-three subjects were treated: 8 in the single-dose phase and 25 in the multidose phase. For the single-dose phase, rhu-pGSN at 6 mg/kg of body weight was administered once. For the multidose phase, a daily rhu-pGSN dose of 6, 12, or 24 mg/kg was given on 3 consecutive days. Adverse events (AEs) were generally mild in both treatment groups irrespective of dose. The only serious AE (SAE) in the single-dose phase was a non-drug-related pneumonia in a rhu-pGSN recipient who died after institution of comfort care. One single-dose placebo recipient had a drug-related AE (maculo-papular rash). In the multidose phase, there were 2 SAEs in 1 placebo recipient, including a fatal pulmonary embolism. In the 18 rhu-pGSN recipients in the multidose phase, there were no serious or drug-related AEs, and nausea and increased blood pressure were each reported in 2 patients. The median rhu-pGSN half-life exceeded 17 h with all dosing regimens, and supraphysiologic levels were maintained throughout the 24-h dosing interval in the 2 highest dosing arms. Rhu-pGSN was well tolerated overall in CAP patients admitted to non-ICU beds, justifying a larger proof-of-concept trial in an ICU population admitted with sCAP. (This study has been registered at ClinicalTrials.gov under identifier NCT03466073.)

Download Full-text

Grepafloxacin Versus Cefixime as Single-Dose Therapy for Uncomplicated Gonorrhea in Women

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/s1064744997000677 ◽

1997 ◽

Vol 5 (6) ◽

pp. 370-375 ◽

Cited By ~ 2

Author(s):

T. F. Mroczkowski ◽

E. W. Hook III ◽

R. B. Jones ◽

W. M. McCormack ◽

D. H. Martin

Keyword(s):

Single Dose ◽

Transmitted Disease ◽

The United States ◽

Response To Therapy ◽

Sexually Transmitted ◽

Treatment Groups ◽

Cure Rates ◽

Study Participants ◽

Oral Doses ◽

Uncomplicated Gonorrhea

Objective:To compare the efficacy and tolerance of single-dose grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in women.Methods:Women attending nine sexually-transmitted-disease clinics in the United States who had suspected uncomplicated gonorrhea were enrolled in an open study. Participants were randomized to receive single oral doses of grepafloxacin (400 mg) or cefixime (400 mg), and efficacy was evaluated in those who returned for follow-up assessment 5 to 10 days later. The primary measure of efficacy was microbiological response to therapy as determined by pre- and posttreatment culture results forNeisseria gonorrhoeae.Results:Of 380 patients enrolled, 124 in the grepafloxacin group and 131 in the cefixime group were evaluated for microbiological response. Cervical gonococcal infections were eradicated in 99% of patients in both treatment groups, with only one persistent infection in each group. All pharyngeal (n = 15) and rectal (n = 32) gonococcal infections treated with grepafloxacin were cured, whereas 5 of 16 (31%) pharyngeal and 1 of 38 (3%) rectal infections failed to respond to cefixime. Although a third (123 of 386) ofN. gonorrhoeaepretreatment isolates were resistant to penicillin or tetracycline, this had no impact on cure rates. Both drugs were well tolerated, with vaginitis being the most common treatment-related adverse event in each group.Conclusions:This study shows that single-dose grepafloxacin is at least as effective as cefixime for treating women with uncomplicated cervical gonorrhea. Grepafloxacin also appears to be highly effective against extragenital infections.

Download Full-text

443. The CHROME Study, a Real-World Experiential Registry of the Use of Oritavancin for Treatment of Gram-Positive Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.516 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S219-S219

Author(s):

Mark Redell ◽

Miguel Sierra-Hoffman ◽

Maha Assi ◽

Markian Bochan ◽

David Chansolme ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Dose Group ◽

Clinical Success ◽

Gram Positive ◽

Skin Structure ◽

Joint Infections ◽

Medical Evaluation ◽

Co Morbidity ◽

Long Acting

Abstract Background Oritavancin (ORI) is a long-acting lipoglycopeptide antibiotic indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused or suspected to be caused by susceptible Gram-positive (GP) pathogens. Methods Data collected from a retrospective observational registry program (2014–2017), Clinical and Historic Registry and Orbactiv Medical Evaluation (CHROME), describe the utilization, outcomes, and adverse events (AEs) associated with ORI in 440 patients treated at 26 US sites. Results Mean (SD) age was 58 (16) years; 37% of patients were = 65 years old (range, 18–98). Mean (SD) BMI was 32.8 (9.0) (range, 14–65). At least 1 co-morbidity was observed in 85% of patients. Patients were treated for cellulitis (61%), wound infection (15%) or abscess (15%); 32 patients received ORI to treat other infections, such as bone and joint. Ten patients received single-dose ORI for completion of osteomyelitis therapy. Of recovered GP isolates, MRSA was the most common (46%). Infusion of ORI was mostly in infusion center settings (72%). Clinical success was 88% in the single-dose group (387 patients) and 86% in the multi-dose group (51 patients). A cohort of 32 patients received 2 to 10 ORI doses separated by no more than 14 days for complicated GP infections. Clinical success was observed in 30 of 32 patients (94%), including 10 of 11 (91%) patients with bone and joint infections and 7 of 8 (88%) patients with osteomyelitis. AEs were observed for 29 of 440 (6.6%) of patients; there was a single serious AE. Six (1.4%) patients discontinued ORI infusions due to an AE. Conclusion The CHROME program confirms that ORI is an effective and well-tolerated long-acting lipoglycopeptide antibiotic for the treatment of a range of Gram-positive infections. Disclosures All authors: No reported disclosures.

Download Full-text

Phase 2, Randomized, Double-Blind, Dose-Ranging Study Evaluating the Safety, Tolerability, Population Pharmacokinetics, and Efficacy of Oral Torezolid Phosphate in Patients with Complicated Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00076-10 ◽

2010 ◽

Vol 55 (2) ◽

pp. 583-592 ◽

Cited By ~ 71

Author(s):

P. Prokocimer ◽

P. Bien ◽

J. Surber ◽

P. Mehra ◽

C. DeAnda ◽

...

Keyword(s):

Geometric Mean ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Phase 2 ◽

Gram Positive ◽

Double Blind ◽

Skin Structure ◽

Complicated Skin ◽

Cure Rates ◽

Dose Levels

ABSTRACTTorezolid (TR-700) is the active moiety of the prodrug torezolid phosphate ([TP] TR-701), a second-generation oxazolidinone with 4- to 16-fold greater potency than linezolid against Gram-positive species including methicillin-resistantStaphylococcus aureus(MRSA). A double-blind phase 2 study evaluated three levels (200, 300, or 400 mg) of oral, once-daily TP over 5 to 7 days for complicated skin and skin structure infections (cSSSI). Patients 18 to 75 years old with cSSSI caused by suspected or confirmed Gram-positive pathogens were randomized 1:1:1. Of 188 treated patients, 76.6% had abscesses, 17.6% had extensive cellulitis, and 5.9% had wound infections.S. aureus, the most common pathogen, was isolated in 90.3% of patients (139/154) with a baseline pathogen; 80.6% were MRSA. Cure rates in clinically evaluable patients were 98.2% at 200 mg, 94.4% at 300 mg, and 94.4% at 400 mg. Cure rates were consistent across diagnoses, regardless of lesion size or the presence of systemic signs of infection. Clinical cure rates in patients withS. aureusisolated at baseline were 96.6% overall and 96.8% for MRSA. TP was safe and well tolerated at all dose levels. No patients discontinued treatment due to an adverse event. Three-stage hierarchical population pharmacokinetic modeling yielded a geometric mean clearance of 8.28 liters/h (between-patient variability, 32.3%), a volume of the central compartment of 71.4 liters (24.0%), and a volume of the peripheral compartment of 27.9 liters (35.7%). Results of this study show a high degree of efficacy at all three dose levels without significant differences in the safety profile and support the continued evaluation of TP for the treatment of cSSSI in phase 3 trials.

Download Full-text

Once daily nebulized beclomethasone is effective in maintaining pulmonary function and improving symptoms in asthmatic children

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2007.507 ◽

2016 ◽

Vol 67 (1) ◽

Author(s):

S. La Grutta ◽

G. Nicolini ◽

C. Capristo ◽

S.C. Bellodi ◽

G.A. Rossi

Keyword(s):

Single Dose ◽

Pulmonary Function ◽

Beclomethasone Dipropionate ◽

Tolerability Profile ◽

Multicentric Study ◽

Diurnal Variability ◽

Once Daily ◽

Treatment Groups ◽

Asthmatic Children ◽

Daily Dose

Background and Aim. Compliance with long-term inhaled therapy in asthma is often poor, but it is likely to be improved with a simplified administration, once daily.The present study was designed to assess whether, in childhood asthma, a single dose of nebulized beclomethasone dipropionate once daily was as effective and safe as the same total daily dose administered twice daily. Methods. Asthmatic children, not treated with inhaled steroids for at least a month preceding the study and using short-acting bronchodilators more than once a week were enrolled in a double-blind, double dummy, randomised, multicentric study. After a two week run-in period on nebulised twice daily 400 mcg beclomethasone dipropionate, patients were randomly assigned to twelve weeks of treatment with 800 mcg nebulised beclomethasone dipropionate daily, either in single dose (o.d. group) or divided into two 400 mcg doses (b.i.d. group). Results. 65 children (mean age 8.6 years, mean FEV1 81% of predicted), were valuable for intention to treat. During the run-in period, a significant improvement in FEV1, FVC, morning and evening PEF values and clinical scores was observed. Children then entered the randomised trial: 32 were included in the o.d. group and 33 in the b.i.d. group. During the twelve week treatment period, the observed improvement in pulmonary function parameters was maintained in both treatment groups. Morning and evening PEF showed a progressive slight increase as well as PEF diurnal variability showed a progressive reduction in the two treatment groups during the whole study period without reaching statistical significance. Moreover, in both treatment groups a similar progressive increase in symptom free nights and days and in the percentage of children achieving total asthma symptoms control was detected. Finally, no significant changes in urinary cortisol/creatinine ratio were observed throughout the study period and between groups. Conclusions. A daily dose of 800 mcg of beclomethasone, administered for twelve weeks with a nebuliser either once or twice daily provide similar efficacy in maintaining pulmonary function and symptoms of asthmatic children, with a good tolerability profile.

Download Full-text