Elias B. Chahine

Echinocandins: the newest class of antifungals.

Objective: To review the mechanism of action, antifungal spectrum of activity, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of the echinocandins. Data Sources: A MEDLINE search (1982–May 2009) was conducted for articles published in the English language using the key words caspofungin, micafungin, anidulafungin, and echinocandins. Study Selection and Data Extraction: Medicinal chemistry, in vitro, and animal studies, as well as human trials were reviewed for information on the pharmacodynamics, pharmacokinetics, efficacy, and safety of each echinocandin. Clinical trials were reviewed and included to compare and contrast the available echinocandins. Data Synthesis: Three echinocandin antifungal agents are currently approved for use in the US: caspofungin, micafungin, and anidulafungin. The echinocandins have a unique mechanism of action, inhibiting β-(1,3)-d-glucan synthase, an enzyme that is necessary for the synthesis of an essential component of the cell wall of several fungi. The echinocandins display fungistatic activity against Aspergillus spp. and fungicidal activity against most Candida spp., including strains that are fluconazole-resistant. The echinocandins have been shown to be efficacious for the treatment of esophageal candidiasis, candidemia, and invasive candidiasis. In addition, caspofungin has demonstrated efficacy as empiric treatment of febrile neutropenia and salvage therapy for the treatment of invasive aspergillosis, and it is the only echinocandin approved for use in pediatric patients. Micafungin is the only echinocandin approved for use as prophylaxis against Candida infections in patients undergoing hematopoietic stem cell transplantation. Overall, resistance to echinocandins is still rare, and all agents are well tolerated, with similar adverse effect profiles and few drug–drug interactions. Conclusions: Echinocandins, the newest addition to the arsenal of antifungals, offer potential advantages over other classes of agents. Clinicians should assess their distinguishing characteristics, including route of metabolism, drug interaction profile, and approved indications for use, when determining which agent to include on a formulary.

Bedaquiline A Novel Diarylquinoline for Multidrug-Resistant Tuberculosis

Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and administration of bedaquiline, a novel oral diarylquinoline antimycobacterial agent approved by the Food and Drug Administration for the treatment of adults with pulmonary multidrug-resistant tuberculosis (MDR-TB). Data Sources: A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004-May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included proceedings of the Union World Conference on Lung Health. Study Selection and Data Extraction: Preclinical data as well as Phase 1 and 2 studies published in English were evaluated. Data Synthesis: Bedaquiline possesses a unique mechanism of action that disrupts the activity of the mycobacterial adenosine triphosphate synthase. Clinical trials have been conducted evaluating the use of bedaquiline in combination with a background regimen for the treatment of adults with pulmonary MDR-TB. Bedaquiline has an excellent in vitro activity against Mycobacterium tuberculosis, including multidrug resistant M tuberculosis; however, its side effect profile limits its use against MDR-TB when no other effective regimen can be provided. Bedaquiline carries Black Box warnings for increased risk of unexplained mortality and QT prolongation. Bedaquiline is metabolized via the CYP3A4 isoenzyme and thus interacts with rifamycins and several antiretrovirals. Conclusions: In an era of emerging resistance and given the suboptimal efficacy and toxicity of currently available regimens for MDR-TB, bedaquiline represents a great addition to the existing armamentarium of anti-TB agents particularly in areas of the world where the disease is endemic.OBJECTIVE To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, dosage, and administration of bedaquiline, a novel oral diarylquinoline antimycobacterial agent approved by the Food and Drug Administration for the treatment of adults with pulmonary multidrug-resistant tuberculosis (MDR-TB). DATA SOURCES A search of PubMed (January 2004-May 2013) and International Pharmaceutical Abstracts (January 2004-May 2013) using the search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included proceedings of the Union World Conference on Lung Health. STUDY SELECTION AND DATA EXTRACTION Preclinical data as well as Phase 1 and 2 studies published in English were evaluated. DATA SYNTHESIS Bedaquiline possesses a unique mechanism of action that disrupts the activity of the mycobacterial adenosine triphosphate synthase. Clinical trials have been conducted evaluating the use of bedaquiline in combination with a background regimen for the treatment of adults with pulmonary MDR-TB. Bedaquiline has an excellent in vitro activity against Mycobacterium tuberculosis, including multidrug resistant M tuberculosis; however, its side effect profile limits its use against MDR-TB when no other effective regimen can be provided. Bedaquiline carries Black Box warnings for increased risk of unexplained mortality and QT prolongation. Bedaquiline is metabolized via the CYP3A4 isoenzyme and thus interacts with rifamycins and several antiretrovirals. CONCLUSIONS In an era of emerging resistance and given the suboptimal efficacy and toxicity of currently available regimens for MDR-TB, bedaquiline represents a great addition to the existing armamentarium of anti-TB agents particularly in areas of the world where the disease is endemic.

Doripenem: a new carbapenem antibiotic.

PURPOSE The chemistry, pharmacology, antimicrobial activity, pharmacokinetics, pharmacodynamics, efficacy and safety in humans, and formulary considerations of doripenem are reviewed. SUMMARY Doripenem, a member of the β-lactam class of antibiotics, is the newest addition to the carbapenems. It exhibits concentration-independent bactericidal activity against gram-positive bacteria; enteric and nonenteric gram-negative bacteria, including extended-spectrum β-lactamase-producing strains; and anaerobic pathogens. Doripenem was found to be noninferior to meropenem in the treatment of complicated intraabdominal infections and noninferior to levofloxacin in the treatment of complicated urinary tract infections including pyelonephritis and was granted marketing approval by the Food and Drug Administration for these two indications. Doripenem was also found to be noninferior to imipenem in the treatment of ventilator-associated pneumonia and noninferior to piperacillin-tazobactam in the treatment of hospital-acquired pneumonia. It has a favorable safety profile, with gastrointestinal complaints and headache being the most common adverse effects and allergic reactions the most serious adverse effects. Doripenem has a relatively low potential to induce seizures. The only known clinically relevant drug interaction is that coadministration with valproic acid may result in reductions of valproic acid serum concentrations. As with most renally eliminated antibiotics, the dose of doripenem should be adjusted according to kidney function. CONCLUSION Doripenem is an injectable carbapenem antibiotic with a spectrum of activity comparable to that of imipenem and meropenem. Its safety is similar to that of other carbapenems.

Prevnar 13, the New 13-Valent Pneumococcal Conjugate Vaccine

Objective: To review the immurtogenicity, efficacy, and safety of the 13-valent pneumococcal conjugate vaccine (PCV13) for use in pediatric patients. Data Sources: A MEDLINE search (2000-September 2011) was conducted using the key words Streptococcus pneumoniae and pneumococcal conjugate vaccine for clinical trials, limited to studies conducted in humans and published in English. Studv Selection And Data Extraction: Randomized, controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of PCV13, Literature on the epidemiology and pathology of pneumococcal Infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. Data Synthesis: PCV13 is approved for routine vaccination of all infants as a 4-dose series at age 2,4,6, and 12–15 months for children who previously received 1 or more doses of the 7-valent pneumococcal conjugate vaccine (PCV7), and for children with underlying medical conditions that increase their risk for pneumococcal disease or its complications. PCV13 has comparable immunogenicity to the serotypes common with PCV7 and also provides protection against 6 additional pneumococcal serotypes. PCV13 has also been shown to have a comparable adverse reaction profile to PCV7. Conclusions: Based on published immunogenicity and safety data, as well as the recent recommendations by the ACIP for routine use in infants and indications for high-risk pediatric patients, PCV13 is a revised formulation of pneumococcal vaccine that should be included on pharmacy formularies.

Oritavancin: An investigational lipoglycopeptide antibiotic

PURPOSE The pharmacology, unique pharmacokinetic-pharmacodynamic profile, and potential future role of oritavancin in combating multidrug-resistant infections are reviewed, with an emphasis on efficacy data from Phase II and III clinical trials. SUMMARY Oritavancin has been shown to have potent in vitro activity against vancomycin-resistant enterococci (VRE) and staphylococci, methicillin-resistant Staphylococcus aureus (MRSA), and gram-positive anaerobic bacteria. Oritavancin exhibits excellent tissue penetration and concentrates well in macrophages; its prolonged plasma half-life (195.4 hours) and extended in vitro postantibiotic effect (2.4- 7.7 hours for MRSA and 1.9-4.3 hours for VRE) might allow once-daily or alternate-day dosing. Oritavancin has been shown to have synergistic activity with several antibiotics (e.g., ampicillin, gentamicin, linezolid) against certain infections. In two Phase III clinical trials involving a total of about 1800 patients with complicated skin and skin structure infections (cSSSIs), i.v. oritavancin therapy was shown to have bactericidal activity and a safety profile comparable to those of i.v. vancomycin (plus optional oral cephalexin stepdown therapy) while requiring a significantly shorter duration of therapy; however, the compiled evidence was considered insufficient to justify marketing approval by the Food and Drug Administration, which requested additional safety and efficacy data. Two ongoing Phase III trials evaluating oritavancin for the treatment of acute bacterial SSSIs are expected to be completed in early 2013. During the clinical trials to date, the most commonly reported adverse effects among oritavancin users were headache, nausea, constipation, and phlebitis. CONCLUSION Oritavancin is an investigational semisynthetic antibiotic classified as a second-generation lipoglycopeptide, with promising activity against multidrug-resistant gram-positive pathogens.

Pharmacist involvement in medical missions: Planning, execution, and assessment

The motto of the Lloyd L. Gregory School of Pharmacy at Palm Beach Atlantic University is “pharmacy with faith,” and its vision is “excellence with character.” The school strives to develop “servant-leaders” who are patient care advocates fully committed to raising the standards of

Ceftolozane/Tazobactam A New Cephalosporin and β-Lactamase Inhibitor Combination

Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of ceftolozane/tazobactam, a new antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. Data Sources: A literature search through clinicaltrials.gov and PubMed was conducted (January 2007-May 2015) using the search terms ceftolozane, ceftolozane/tazobactam, FR264205, CXA-101/tazobactam, and CXA-201. References from retrieved articles and abstracts presented at recent meetings were reviewed to identify additional material. The prescribing information was also reviewed. Study Selection and Data Extraction: Preclinical data as well as phase 1, 2, and 3 studies published in English were evaluated. Data Synthesis: Ceftolozane/tazobactam displays enhanced potency against Pseudomonas aeruginosa in vitro. Clinical trials have shown that ceftolozane/tazobactam is noninferior to levofloxacin for the treatment of complicated urinary tract infections (76.9% vs 68.4%, 95% CI = 2.3-14.6) and when used in combination with metronidazole is noninferior to meropenem for the treatment of complicated intra-abdominal infections (83% vs 87.3%, 95% CI = −8.91 to 0.54). An alternate antibiotic should be considered in patients who have a severe β-lactam allergy or an estimated creatinine clearance between 30 and 50 mL/min. Ceftolozane/tazobactam is well tolerated, with few drug interactions and no effects on the cytochrome P450 system. Conclusions: In an era of increasing resistance to antimicrobials, ceftolozane/tazobactam provides clinicians with an additional treatment option for infections caused by multidrug-resistant Gram-negative organisms, including extended-spectrum β-lactamase–producing bacteria and Pseudomonas aeruginosa.

Engaging Pharmacy Students, Residents, and Fellows in Antimicrobial Stewardship

Antimicrobial stewardship programs are mainly established by infectious diseases physicians and infectious diseases-trained clinical pharmacists with the goal of optimizing patients’ outcomes while halting antimicrobial resistance, decreasing adverse events, and controlling health care cost. The role of the infectious diseases-trained clinical pharmacist in antimicrobial stewardship is well established; however, there are not enough formally trained pharmacists to assume the challenging responsibilities of the steward coordinator. The purpose of this article was to review the available literature and resources and propose a model to engage introductory pharmacy practice experience students, advanced pharmacy practice experience students, postgraduate year (PGY) 1 pharmacy residents, PGY2 infectious diseases pharmacy residents, and PGY2 or PGY3 infectious diseases pharmacy fellows in antimicrobial stewardship. Further studies are needed to assess and document the impact of pharmacy students and postgraduate trainees on antimicrobial stewardship programs.

Sofosbuvir/Velpatasvir: The First Pangenotypic Direct-Acting Antiviral Combination for Hepatitis C.

Objectives: To review the pharmacology, efficacy, and safety of sofosbuvir/velpatasvir in the treatment of patients with hepatitis C virus (HCV) infection. Data Sources: A literature search through PubMed was conducted (June 2008 to August 2016) using the terms GS-5816, velpatasvir, and sofosbuvir. References from retrieved articles and the prescribing information were reviewed for any additional material. Study Selection/Data Extraction: The literature search was limited to human studies published in English. Phase I, II, and III studies of sofosbuvir/velpatasvir for HCV were identified. Data Synthesis: Sofosbuvir/velpatasvir is indicated for adult patients with chronic HCV genotype 1 through 6. It is given without ribavirin in patients with or without compensated cirrhosis and with ribavirin in patients who have decompensated cirrhosis. The ASTRAL-1 study demonstrated that sofosbuvir 400 mg plus velpatasvir 100 mg for 12 weeks was effective at achieving high sustained virological response (SVR12) rates in patients with HCV genotype 1, 2, 4, 5, or 6. The ASTRAL-2 and ASTRAL-3 studies demonstrated that the same regimen was effective at achieving high SVR12 rates in patients with HCV genotype 2 or 3. The ASTRAL-4 study demonstrated that the same regimen plus ribavirin was effective at achieving high SVR12 rate in patients with decompensated cirrhosis. The most common adverse reactions (≥10% of patients) associated with sofosbuvir/velpatasvir were headache and fatigue. Conclusions: Sofosbuvir/velpatasvir is safe and effective to treat HCV genotypes 1, 2, 3, 4, 5, and 6 in patients with or without compensated cirrhosis. The addition of ribavirin is recommended in patients with decompensated cirrhosis.

Cethromycin: A New Ketolide Antibiotic

OBJECTIVE To review the pharmacology, chemistry, microbiology, in vitro susceptibility, mechanism of resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, dosage, and administration of cethromycin, a new ketolide antibiotic. DATA SOURCES Literature was obtained through searching PubMed (1950-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and a bibliographic review of published articles. Search terms included cethromycin, ABT-773, ketolide antibiotic, and community-acquired pneumonia. STUDY SELECTION AND DATA EXTRACTION All available in vitro and preclinical studies, as well as Phase 1, 2, and 3 clinical studies published in English were evaluated to summarize the pharmacology, chemistry, microbiology, efficacy, and safety of cethromycin in the treatment of respiratory tract infections. DATA SYNTHESIS Cethromycin, a new ketolide, has a similar mechanism of action to telithromycin with an apparently better safety profile. Cethromycin displays in vitro activity against selected gram-positive, gram-negative, and atypical bacteria. The proposed indication of cethromycin is treatment of mild to moderate community-acquired bacterial pneumonia in patients aged 18 years or older. Based on clinical studies, the recommended dose is 300 mg orally once a day without regard to meals. Cethromycin has an orphan drug designation for tularemia, plague, and anthrax prophylaxis. The Food and Drug Administration denied approval for the treatment of community-acquired pneumonia in 2009; a recent noninferiority trial showed comparable efficacy between cethromycin and clarithromycin. Preliminary data on adverse effects suggest that cethromycin is safe and gastrointestinal adverse effects appear to be dose-related. CONCLUSIONS Cethromycin appears to be a promising ketolide for the treatment of mild to moderate community-acquired pneumonia. It was denied approval by the FDA in 2009 pending more evidence to show its efficacy, with more recent studies showing its noninferiority to antibiotics for the same indication.