Alan D. Tice

Practice Guidelines for Outpatient Parenteral Antimicrobial Therapy

These guidelines were formulated to assist physicians and other health care professionals with various aspects of the administration of outpatient parenteral antimicrobial therapy (OPAT). Although there are many reassuring retrospective studies on the efficacy and safety of OPAT, few prospective studies have been conducted to compare the risks and outcomes for patients who receive treatment as outpatients rather than as inpatients. Because truly evidence-based studies are lacking, the present guidelines are formulated from the collective experience of the committee members and advisors from related organizations.

Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial.

BACKGROUND Diabetic foot infections are a common and serious problem, yet few randomised trials of adequate quality have compared the efficacy of the various antibiotic regimens available for their treatment. Our aim was to assess the efficacy and safety of ertapenem versus piperacillin/tazobactam for foot infections. METHODS We did a randomised, double-blinded, multicentre trial in adults (n=586) with diabetes and a foot infection classified as moderate-to-severe and requiring intravenous antibiotics. We assigned patients intravenous ertapenem (1 g daily; n=295) or piperacillin/tazobactam (3.375 g every 6 h; n=291) given for a minimum of 5 days, after which oral amoxicillin/clavulanic acid (875/125 mg every 12 h) could be given for up to 23 days. Investigators retained the option to administer vancomycin to patients in either group to ensure adequate coverage for potentially antibiotic resistant Enterococcus spp and meticillin-resistant Staphylococcus aureus (MRSA). Our primary outcome was the proportion of patients with a favourable clinical response (cure or improvement) on the day that intravenous antibiotic was discontinued. Analyses were by an evaluable-patient only approach. This study is registered with , number NCT00229112. FINDINGS Of the 576 patients treated, 445 were available for assessment at the end of intravenous therapy. Both baseline characteristics and favourable clinical response rates were similar for the 226 who received ertapenem and the 219 who received piperacillin/tazobactam (94%vs 92%, respectively; between treatment difference 1.9%, 95% CI -2.9 to 6.9). Rates of favourable microbiological responses (eradication rates and clinical outcomes, by pathogen) and adverse events did not differ between groups. INTERPRETATION Clinical and microbiological outcomes for patients treated with ertapenem were equivalent to those for patients treated with piperacillin/tazobactam, suggesting that this once-daily antibiotic should be considered for parenteral therapy of diabetic foot infections, when deemed appropriate.

Ceftriaxone Once Daily for Four Weeks Compared with Ceftriaxone Plus Gentamicin Once Daily for Two Weeks for Treatment of Endocarditis Due to Penicillin-Susceptible Streptococci

This randomized, multicenter, open-label study compared the efficacy and safety of monotherapy with 2 g of intravenous ceftriaxone once daily for 4 weeks with those of combination therapy with 2 g of intravenous ceftriaxone and 3 mg of intravenous gentamicin/kg once daily for 2 weeks as therapy for endocarditis due to penicillin-susceptible streptococci. Sixty-one patients were enrolled in the study. Clinical cure was observed for 51 evaluable patients both at termination of therapy and at the 3-month follow-up: 25 (96.2%) of 26 monotherapy recipients and 24 (96%) of 25 combination therapy recipients. Of the 23 patients in each treatment group who were microbiologically evaluable, 22 (95.7%) in each group were considered cured. No patient had evidence of relapse. Fourteen patients (27.5%) required cardiac surgery after initiation of treatment, including five monotherapy recipients and nine combination therapy recipients. Adverse effects were minimal in both treatment groups. We conclude that 2 g of ceftriaxone once daily for 4 weeks and 2 g of ceftriaxone in combination with 3 mg of gentamicin/kg once daily for 2 weeks are both effective and safe for the treatment of streptococcal endocarditis.

Outcomes of osteomyelitis among patients treated with outpatient parenteral antimicrobial therapy

PURPOSE To examine the effects of diabetes, vascular disease, age, and antimicrobial therapy on clinical outcomes, including amputation rates, in patients with osteomyelitis treated in the outpatient setting. METHODS We performed a retrospective chart review of patients treated with intravenous antimicrobial therapy for osteomyelitis at an outpatient infectious diseases practice. All patients were followed for at least 6 months. RESULTS Four hundred and fifty-four patients qualified for inclusion, with follow-up information available for up to 10 years. One hundred and thirty-nine patients (31%) had recurrences and 27 (6%) had amputations. Of the recurrences, 108 (78%) occurred within 6 months and 132 (95%) within 1 year. In univariate analyses, peripheral vascular disease, diabetes, and the combination were all associated with the risk of recurrence; age (>70 years) was not. For osteomyelitis due to Staphylococcus aureus, the relative risk of recurrence, using a Cox regression model, was 0.8 for ceftriaxone (95% confidence interval [CI]: 0.4 to 1.5; P = 0.53), 1.1 for cefazolin (95% CI: 0.5 to 2.2; P = 0.80), and 2.5 for vancomycin (95% CI: 1.1 to 5.6; P = 0.04), as compared with the use of a penicillinase-resistant penicillin. CONCLUSION Diabetes and peripheral vascular disease are important factors in determining the prognosis of patients with osteomyelitis, but age is not. Almost all recurrences of osteomyelitis occur within 1 year. Recurrence rates with osteomyelitis associated with S. aureus appear to be higher with the use of vancomycin, whereas ceftriaxone and cefazolin appear to be similar to penicillinase-resistant penicillins.

Practice Guidelines for Community-Based Parenteral Anti-Infective Therapy

This is the fourth in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of this guideline is to provide assistance to clinicians when making decisions on when and how to best administer parenteral antimicrobial therapy. The targeted providers are internists, pediatricians, family practitioners, and other providers of outpatient antiinfective therapy. Criteria for selecting the appropriate patients and settings to deliver therapy in the community are described. Panel members represented experts in adult and pediatric infectious diseases. The guidelines are evidence-based. A standard ranking system is used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary and tables highlight the major recommendations.

Albinterferon Alfa-2b Was Not Inferior to Pegylated Interferon-α in a Randomized Trial of Patients With Chronic Hepatitis C Virus Genotype 1

BACKGROUND & AIMS The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b. METHODS In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 μg every week, or albIFN 900 or 1200 μg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μg to 900 μg because of increased pulmonary adverse events (AEs) in the 1200-μg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72). RESULTS Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. The primary objective of showing noninferiority of albIFN 900 μg (P < .001) and 1200 μg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-μg groups. CONCLUSIONS albIFN 900 μg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1.

Staphylococcus aureus: Methicillin-Susceptible S. aureus to Methicillin-Resistant S. aureus and Vancomycin-Resistant S. aureus

The evolution of methicillin-resistant and vancomycin-resistant Staphylococcus aureus has demanded serious review of antimicrobial use and development of new agents and revised approaches to prevent and overcome drug resistance. Depending on local conditions and patient risk factors, empirical therapy of suspected S. aureus infection may require coverage of drug-resistant organisms with newer agents and novel antibiotic combinations. The question of treatment with inappropriate antibiotics raises grave concerns with regard to methicillin-resistant S. aureus selection, overgrowth, and increased virulence. Several strategies to reduce the nosocomial burden of resistance are suggested, including shortened hospital stays and outpatient parenteral antimicrobial therapy of the most serious infections.

Clinical predictors of treatment failure for diabetic foot infections: Data from a prospective trial

To aid clinicians in selecting the appropriate approach for treating patients with diabetic foot infections, we investigated whether any baseline clinical findings predicted an unfavourable clinical outcome. Using data from a large, prospective treatment trial of diabetic foot infections (SIDESTEP), we assessed the association between clinical treatment failure and baseline history, physical and laboratory findings, by univariate and multivariate logistic regression analyses. Among 402 patients clinically evaluable 10 days after completing antibiotic therapy, baseline factors significantly (P < 0·05) associated by univariate analysis with treatment failure were ‘severe’ (versus ‘moderate’) University of Texas (UT) wound grade; elevated white blood cell count, C‐reactive protein or erythrocyte sedimentation rate; high wound severity score; inpatient treatment; low serum albumin; male sex; and skin temperature of affected foot >10°C above that of unaffected foot. By multivariate logistic regression only severe UT wound grade (odds ratio 2·1) and elevated white blood cell count [odds ratio 1·7 for a 1 standard deviation (2971 cells/mm3) increase] remained statistically significant. Clinical failure rates were 46% for patients with both risk factors compared with 10% for patients with no risk factors and 16–17% for patients with one risk factor. Increased white blood cell count and severe UT wound grade at baseline, but not other features, were significant independent and additive risk factors for clinical failure in patients treated for a diabetic foot infection.

Evaluation of the efficacy and safety of outpatient parenteral antimicrobial therapy for infections with methicillin-sensitive Staphylococcus aureus.

Objectives: As increasing numbers of patients are being treated with outpatient parenteral antimicrobial therapy (OPAT), it becomes ever more important to ascertain the risks and benefits of such treatment for patients. Methods: We conducted a retrospective analysis of 1,515 patients with methicillin-sensitive Staphylococcus aureus infections who were treated with outpatient parenteral antimicrobial monotherapy. All patients were included in the adverse drug reaction analysis; 1,252 were evaluable for purposes of evaluating treatment efficacy. Results: The six antibiotics most frequently used in this study (ceftriaxone, cefazolin, vancomycin, oxacillin, nafcillin, and clindamycin) appeared to be equivalent in achieving the desired efficacy outcome. Conclusions: Vancomycin was associated with a significantly greater number of side effects than was ceftriaxone, cefazolin, or oxacillin, and nafcillin was associated with a significantly greater number of adverse events than ceftriaxone.

Cost perspectives for outpatient intravenous antimicrobial therapy.

Intravenous antimicrobial therapy often continues after a patient is discharged from the hospital or it begins in the outpatient setting. Reimbursement for this therapy varies by payer. The United States Outpatient Parenteral Antibiotic Therapy (OPAT) Outcomes Registry is a valuable resource for quantifying cost by payer, as well as for describing practice patterns and adverse events related to intravenous antimicrobial therapy. To describe the reimbursement structure and cost of intravenous vancomycin home care therapy for four different types of payers, a survey of home infusion companies was done. Also surveyed were infusion programs participating in the OPAT Outcomes Registry, representing four different types of payers, to determine the cost of outpatient intravenous therapy. A retrospective cohort study of these infusion programs was conducted to describe practice patterns and to identify adverse events that resulted from intravenous vancomycin. We found that the cost of outpatient therapy was substantial, although nonuniform, across payer types. Alternative outpatient therapies associated with lower risks for adverse events and lower costs should be considered.