Paul P. Belliveau

Experience with a once-daily aminoglycoside program administered to 2,184 adult patients.

Once-daily aminoglycoside (ODA) regimens have been instituted to maximize bacterial killing by optimizing the peak concentration/MIC ratio and to reduce the potential for toxicity. We initiated an ODA program at our institution that utilizes a fixed 7-mg/kg intravenous dose with a drug administration interval based on estimated creatinine clearance: > or = 60 ml/min every 24 h (q24h), 59 to 40 ml/min q36h, and 39 to 20 ml/min q48h. Subsequent interval adjustments are made by using a single concentration in serum and a nomogram designed for monitoring of ODA therapy. Since initiation of the program, 2,184 patients have received this ODA regimen. The median dose was 450 (range, 200 to 925) mg, while the median length of therapy was 3 (range, 1 to 26) days. The median age of the population was 46 (range, 13 to 97) years. Gentamicin accounted for 94% of the aminoglycoside use, and the majority (77%) of patients received the drug q24h. The 36-, 48-, and > 48-h intervals were used for 15, 6, and 2% of this population, respectively. Three patients exhibited clinically apparent ototoxicity. Twenty-seven patients (1.2%) developed nephrotoxicity (the Hartford Hospital historical rate is approximately 3 to 5%) after a median of 7 (range, 3 to 19) days of therapy. On the basis of a prospective evaluation of 58 patients and follow-up of additional patients via clinician reports, we have noted no apparent alterations in clinical response with our ODA program. This ODA program appears to be clinically effective, reduces the incidence of nephrotoxicity, and provides a cost-effective method for administration of aminoglycosides by reducing ancillary service time and serum aminoglycoside determinations.

Tigecycline for the Treatment of Severe Clostridium difficile Infection

Objective: To evaluate the evidence for the use of tigecycline in the treatment of Clostridium difficile infection (CDI). Data Sources: Searches were performed (2004 to June 2011), using the EMBASE and MEDLINE databases, with the terms tigecycline, Tygacil, Clostridium difficile, C. difficile, Clostridium difficile infection, and CDI. Study Selection: Six case reports that described the use of tigecycline for treatment of CDI were included for review. No clinical trials were identified. Data Synthesis: In all case reports except 1, tigecycline (alone or in combination with other CDI therapies) was used for the treatment of CDI that was refractory to metronidazole and/or vancomycin. In 6 of the cases, treatment success was reported following initiation of tigecycline therapy; 1 patient died following a complicated hospitalization. The treatment duration with tigecycline was 2-4 weeks. In the cases with successful outcomes, symptoms began to improve within 1 week. None of these patients experienced recurrence during follow-up of various lengths. In vitro studies demonstrated a 90% minimum inhibitory concentration range for tigecycline of 0.016-0.25 mg/L for all C. difficile isolates. Tgecycline exhibited good fecal penetration because of primary biliary excretion of unchanged drug. Up to 59% of the dose is recovered in feces following administration over 4 days in healthy volunteers. Conclusions: Case reports have suggested that tigecycline may be successful for treatment of severe or severe complicated CDI, when prior therapy has failed. Data demonstrating tigecycline use as initial therapy for CDI are limited; therefore, this option should be reserved for patients in whom other therapeutic options, including metronidazole and vancomycin, have failed. A randomized controlled trial is needed to assess the safety and efficacy of tigecycline in this patient population and better define the drugs role in the treatment of CDI.

Intracellular and extracellular penetration of azithromycin into inflammatory and noninflammatory blister fluid.

The penetration of azithromycin into the blister fluids of six volunteers was analyzed after a 5-day regimen (total of 1.5 g). Differences in drug concentrations in a paper disk and serum and in the mass of azithromycin from inflammatory blister chamber leukocytes and noninflammatory blister chamber leukocytes were significant (P < 0.05).

Boceprevir: A Protease Inhibitor for the Treatment of Chronic Hepatitis C

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of boceprevir, a novel oral hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor for the treatment of chronic HCV infection, specifically, genotype 1. Data Sources: A literature search was conducted through MEDLINE and EMBASE (1966-May 2011) using the terms boceprevir and SCH 503034. Data from the package insert, abstracts obtained from conferences, and unpublished Phase 2-3 clinical trials, obtained through clinicaltrials.gov, were also reviewed. Study Selection And Data Extraction: All English-language articles identified from the data sources were evaluated. References from selected articles were used to identify other pertinent citations. Article selection focused on pharmacology, clinical trials, safety analyses, and resistance. Preference was given to human data. Data Synthesis: Boceprevir is an oral protease inhibitor that binds to the NS3 protein of HCV, ultimately inhibiting viral intracellular replication. Boceprevir displays linear pharmacokinetics and is rapidly absorbed upon oral administration. In clinical studies of treatment-naïve and treatment-experienced patients, boceprevir, in combination with standard of care (pegylated interferon [Peg-IFN]-α-2b with or without ribavirin) achieved greater sustained viral response (SVR) rates compared to standard of care. Safety analyses showed an increased incidence of adverse effects when boceprevir was used with Peg-IFN-α-2b and ribavirin. The most common adverse events reported include fatigue, headache, nausea, dysguesia, and anemia; the incidence of the latter 2 adverse effects may be increased it boceprevir is added to standard therapy. Additional Phase 2 and 3 studies are currently enrolling participants. Conclusions: Boceprevir should be used in combination with Peg-IFN-α-2b and ribavirin in the treatment of chronic HCV genotype 1 infection. The improved response rates achieved with that combination will make boceprevir a viable option compared with other developing and approved NS3 protease inhibitors for treatment-naïve and treatment-experienced nonresponders/relapsers. Additional data are needed to clarify the potential for resistance and drug interactions.

Vigabatrin for Infantile Spasms

Infantile spasms describe a pediatric epilepsy syndrome characterized by frequent clusters of brief symmetric muscle contractions; the condition is often associated with developmental delay. When infantile spasms are accompanied by hypsarrhythmia on electroencephalogram, the condition is labeled West syndrome. The mainstay of treatment for infantile spasms is adrenocorticotropic hormone; however, vigabatrin, a vinyl derivative of 7‐aminobutyric acid, has been used for the treatment of infantile spasms in Europe since 1989. In 2009, vigabatrin was approved by the United States Food and Drug Adminstration (FDA) for use as monotherapy in the treatment of infantile spasms in patients aged 1 month‐2 years when the benefits of treatment outweigh the risks. Results from numerous trials examining the role of vigabatrin in infantile spasms have been published; many of these trials were small, open‐label, or noncontrolled. Although clinical trials have provided some insight into the utility of vigabatrin for the treatment of infantile spasms, these studies have notable limitations. In addition, vigabatrin is associated with a black‐box warning that describes the potential for permanent bilateral concentric visual field defects. Currently, vigabatrin is available through a manufacturer‐sponsored program in accordance with its FDA‐approved Risk Evaluation and Mitigation Strategy. Although several guidelines recommend vigabatrin as a first‐line therapy for infantile spasms, specifically infantile spasms related to tuberous sclerosis, it is still unclear whether vigabatrin should supersede hormone therapy as first‐line therapy. Further research comparing the two therapies is needed.

Excretion of Antimicrobials Used to Treat Methicillin‐Resistant Staphylococcus aureus Infections During Lactation: Safety in Breastfeeding Infants

Community‐acquired strains of methicillin‐resistant Staphylococcus aureus(MRSA) have become a common cause of skin and soft tissue infections in the United States. These infections sometimes require treatment with antibiotics, and with the increasing resistance of pathogens to these agents, choosing the appropriate drug can be difficult. In lactating women who develop these infections, selecting an antibiotic is even more challenging, as clinicians need to be aware of risks to the infant from the drug excreted during lactation. To our knowledge, no review has addressed the safety of antibiotics in breastfeeding infants when the drugs are used to treat maternal skin and soft tissue infections from MRSA. Thus, we performed a literature search of the PubMed‐MEDLlNE and EMBASE databases (1974‐March 2009), reviewed reference citations from identified publications, researched antibiotic prescribing information, and corresponded with drug manufacturers. Case reports, case series, and both in vivo and in vitro clinical trials were evaluated for the following antibiotics: clindamycin, daptomycin, linezolid, quinupristin‐dalfopristin, rifampin, tetracycline, doxycycline, minocycline, tigecycline, trimethoprim‐sulfamethoxazole, and vancomycin. lnformation for the newer antibiotics (linezolid, quinupristin‐dalfopristin, tigecycline, and daptomycin) was limited. Despite heterogeneity in the data for the older antibiotics (clindamycin, rifampin, tetracyclines, trimethoprim‐sulfamethoxazole, and vancomycin), all appear to be relatively safe in the minimal quantities nursing infants ingest through breast milk. Although the risk to infants seems to be relatively low for most of the agents we explored, the paucity of data indicates a need for close monitoring of breastfed infants whose mothers are receiving an antibiotic for an MRSA skin and soft tissue infection.

Use of Daptomycin to Treat Infections With Methicillin-Resistant Staphylococcus aureus Isolates Having Vancomycin Minimum Inhibitory Concentrations of 1.5 to 2 µg/mL

Objective: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL. Data Sources: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013).Study Selection and Data Extraction: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included. Data Synthesis: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d). Conclusions: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area.

Daptomycin use in pediatric patients

PURPOSE Currently available evidence on the use of daptomycin in pediatric patients is reviewed and evaluated. SUMMARY Although guidelines on the treatment of methicillin-resistant Staphylococcus aureus infections recommend daptomycin for use in pediatric patients, that recommendation is primarily based on expert opinion. A literature search for articles on pediatric daptomycin use identified three pharmacokinetic studies, three case reports, and one retrospective review. The limited body of published evidence indicates that pediatric patients may require higher daptomycin doses than adult patients in order to attain therapeutic serum concentrations. Pharmacokinetic studies in pediatric patients demonstrated faster daptomycin clearance (CL) and a decreased area under the concentration-time curve (AUC) relative to values reported in adults. Daptomycin appears to have a shorter half-life in patients 2-6 years of age relative to those 12-17 years of age. A retrospective review of 16 cases in which pediatric patients were treated with daptomycin for invasive gram-positive infections indicated positive outcomes after the addition of daptomycin to standard therapy. Overall, daptomycin appears to be well tolerated in pediatric patients. CONCLUSION Due to the limited nature of the available literature, use of daptomycin in pediatric patients should be limited to situations in which other options are not viable due to toxicity, local susceptibility patterns, or likely treatment failure. As a result of faster drug CL and lower AUC values, higher doses may be necessary in pediatric patients to achieve serum concentrations similar to those seen with adult dosing.

Inhaled Aztreonam Lysine for Cystic Fibrosis Pulmonary Disease–Related Outcomes

OBJECTIVE: To evaluate the pharmacology, clinical efficacy, and safety of aztreonam lysine for inhalation (AZLI) for cystic fibrosis (CF)–related signs and symptoms of pulmonary disease. DATA SOURCES: Literature was searched in MEDLINE through PubMed and cross-referenced with EMBASE (1980-June 2012). The key search terms used were aztreonam lysine, nebulized, inhaled, and cystic fibrosis. Bibliographies of selected articles were used to identify additional references. Ongoing trials were identified through a review of Web site trial registries. STUDY SELECTION AND DATA EXTRACTION: Articles were limited to those written in English about studies conducted in humans. Studies included in this review examined both adult and pediatric patients with CF. DATA SYNTHESIS: Aztreonam lysine is an inhaled monocyclic β-lactam antibiotic approved for use in the CF population. Four completed clinical trials with peer-reviewed published data were reviewed to assess the efficacy and safety of single-course AZLI; a fifth trial assessed the safety and efficacy of repeat courses of AZLI. None of these trials compared AZLI in a head-to-head manner with tobramycin for inhalation. In patients with moderate to severe pulmonary disease, AZLI administration improved forced expiratory volume in 1 second measurements, decreased sputum bacterial Pseudomonas aeruginosa density, and improved symptoms. Adverse effects in clinical trials were generally mild and similar to those with placebo. CONCLUSIONS: AZLI is safe and effective for management of pulmonary-related symptoms in patients with CF who are colonized with P. aeruginosa and have moderate to severe pulmonary disease. Additional trial data comparing AZLI with tobramycin are warranted to further establish the place of AZLI in therapy.

Elevated creatine phosphokinase levels associated with linezolid therapy

PURPOSE A case of elevated creatine phosphokinase (CPK) levels associated with linezolid therapy in a patient on chronic antihyperlipidemic therapy is presented. SUMMARY A 79-year-old Caucasian man with a primary diagnosis of acute hemoptysis secondary to pneumonia was admitted to the medical-surgical intensive care unit. A chest radiograph showed a large, right, lower-lobe infiltrate with alveolar consolidation. The patients medical history included hyperlipidemia that was chronically treated with lovastatin and gemfibrozil. Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was suspected and confirmed. Vancomycin 1 g i.v. every 12 hours was administered for approximately 10 days into the admission and switched to linezolid 600 mg i.v. every 12 hours after a lack of response to vancomycin. On hospital day 11, the patients CPK concentration was 47 units/L. Seven days later, his CPK concentration was 2584 units/L and his lovastatin and gemfibrozil were discontinued on that day. The patients CPK concentration peaked at 5369 units/L on the following day, and linezolid was discontinued at that point. One week later, his CPK concentration was 28 units/L. Approximately two weeks after the patients CPK levels normalized, he developed numerous complications. The patient died as a result of respiratory failure 11 days after being extubated, which occurred about 38 days after his admission. Although concomitant use of statins and gemfibrozil is known to increase the risk for CPK elevations, the continued rise in CPK levels after discontinuation of antihyperlipidemic therapy and the rapid time course for normalization after linezolid discontinuation are more consistent with an event associated with linezolid initiation. CONCLUSION A patient on chronic antihyperlipidemic therapy developed elevated CPK levels after receiving linezolid for the treatment of MRSA pneumonia.