Live Biotherapeutic Products for the Prevention of Recurrent Clostridioides difficile Infection.

OBJECTIVE: To review the efficacy, safety, and role of live biotherapeutic products (LBPs) in the prevention of recurrent Clostridioides difficile infection (rCDI). DATA SOURCES: A literature search was performed using PubMed and Google Scholar (through February 2024) with search terms RBX2660, SER-109, and fecal microbiota. Other resources included abstracts presented at recent conferences, national clinical practice guidelines, and manufacturers' websites. STUDY SELECTION AND DATA EXTRACTION: All relevant studies, trial updates, conference abstracts, and guidelines in the English language were included. DATA SYNTHESIS: Two LBPs were recently approved by the Food and Drug Administration for the prevention of recurrence in adults following antibiotic treatment for rCDI. Fecal microbiota, live-jslm is administered rectally as a retention enema, whereas fecal microbiota spores, live-brpk is given orally after bowel preparation. Several phase 2 and phase 3 clinical trials have established the safety and efficacy of these LBPs in reducing rates of rCDI compared with placebo. Patients with severe immunosuppression and those with inflammatory bowel disease were largely excluded from these trials. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Live biotherapeutic products offer a similar mechanism to conventional fecal microbiota transplant (FMT) in preventing rCDI through microbiota restoration. The primary advantages of LBPs over FMT are their standardized composition and donor stool screening processes for transmissible pathogens. Bezlotoxumab is also available for the prevention of Clostridioides difficile infection; however, there are no clinical data available to compare the efficacy of LBPs with bezlotoxumab, and the benefit of simultaneous use of these preventative therapies is unclear. CONCLUSIONS: Live biotherapeutic products provide a safe and effective option for the prevention of rCDI and represent an improvement over conventional FMT. Additional studies are needed to further determine their place in therapy relative to bezlotoxumab and in the setting of immunosuppression and inflammatory bowel disease.

Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV.

OBJECTIVE: To review the efficacy, safety, and role of lenacapavir (LEN) in the treatment of HIV-1 infection. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (through March 2023) with the search term LEN and GS-6207. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, and prescribing information. STUDY SELECTION AND DATA EXTRACTION: All relevant articles, trial updates, and conference abstracts in the English language were included. DATA SYNTHESIS: Lenacapavir represents a new class of antiretrovirals (ARVs) with a novel mechanism of action as a capsid inhibitor and a unique twice-a-year subcutaneous administration schedule. Lenacapavir when combined with other ARVs has proven to benefit heavily treatment-experienced (HTE) patients with HIV-1 infection in achieving viral suppression and immune restoration. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Lenacapavir is a new treatment option that patients who are HTE can consider adding as part of an ARV regimen. CONCLUSIONS: Lenacapavir is an effective and well-tolerated option for HTE patients which is a valuable addition to the arsenal of ARVs.

Cabotegravir: The First Long-Acting Injectable for HIV Preexposure Prophylaxis.

OBJECTIVE: Review the pharmacology, pharmacokinetics, efficacy, safety, and role of long-acting injectable cabotegravir (CAB-LA) in HIV preexposure prophylaxis (PrEP). DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2012 to April 2022) with the search terms cabotegravir, preexposure prophylaxis, and PrEP. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, prescribing information, and review articles. STUDY SELECTION AND DATA EXTRACTION: All English-language articles of studies assessing the efficacy and safety of CAB-LA for PrEP were included. DATA SYNTHESIS: CAB-LA is the first long-acting injectable therapy approved for HIV-1 PrEP in both men and women. It is a suspension given intramuscularly every other month. CAB-LA has been shown to be more effective than daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in preventing HIV-1 infection among high-risk individuals. Two phase 3 trials were stopped early on the basis of superior efficacy of CAB-LA. The most common adverse effects were injection site reactions (ISRs), although they tended to decrease over time, and few participants in clinical trials discontinued use due to ISRs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: CAB-LA may be particularly useful for individuals with known adherence problems to oral therapy, those with renal impairment, and those with decreased bone mineral density. However, CAB-LA is more expensive than generic TDF/FTC and may be associated with weight gain. CONCLUSIONS: CAB-LA is the first long-acting injectable agent for HIV PrEP. It is more effective than oral TDF/FTC, is well-tolerated aside from ISRs, and has few clinically significant drug-drug interactions.

PreHevbrio: A New 3-Antigen Hepatitis B Vaccine for Adults.

OBJECTIVE: The main objective of this article is to review the immunogenicity and safety of the 3-antigen recombinant hepatitis B vaccine (3A-HepB) in adults. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2000 to June 2022) with the search terms hepatitis B vaccine and 3-antigen. Other resources included the Centers for Disease Control and Prevention, conference abstracts of liver meetings, the prescribing information, and the manufacturer's website. STUDY SELECTION AND DATA EXTRACTION: All English-language articles of studies assessing the immunogenicity and safety of 3A-HepB in humans were included. DATA SYNTHESIS: The 3A-HepB is licensed to prevent infection caused by all known subtypes of the hepatitis B virus in adults. It contains 3 hepatitis B surface antigens. The 3A-HepB has been shown to be noninferior to a single-antigen hepatitis B vaccine (1A-HepB). It is administered intramuscularly as a 3-dose series at 0, 1, and 6 months. The most commonly reported local reactions were injection site pain and tenderness, and the most commonly reported systemic reactions were headache, fatigue, and myalgia. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The introduction of 3A-HepB represents another step toward reducing the rates of new hepatitis B infections. However, clinical trials are needed to assess the immunogenicity of 3A-HepB in individuals at high-risk of nonresponse or low response to 1A-HepB, such as those with renal or hepatic impairment and those with altered immunocompetence. CONCLUSIONS: The 3A-HepB represents another vaccine to prevent hepatitis B in adults. It is safe and immunogenic but is associated with more adverse reactions than 1A-HepB.

Antibiotic Approvals in the Last Decade: Are We Keeping Up With Resistance?

OBJECTIVE: To review the spectrum of activity, efficacy, safety, and role in therapy of all antibiotics and related biologics approved by the Food and Drug Administration (FDA) in the last decade. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2010 to end May 2021) with the search terms' name of the antibiotic or the biologic. Data were also obtained from the prescribing information, FDA, and ClinicalTrials.gov websites. STUDY SELECTION: All relevant English-language, late phase clinical trials assessing the safety and efficacy of the identified drugs were included. Review articles and references of retrieved articles were evaluated for relevant data. DATA SYNTHESIS: Antibiotic resistance is a public health crisis, and antibiotic development is imperative to outpace the ability of bacteria to develop resistance. Only 17 new systemic antibiotics and 1 related biologic have been approved by the FDA since 2010. Among these drugs, 14 were approved for common bacterial infections, 1 was approved for Clostridioides difficile infection (CDI), 1 was licensed to prevent CDI recurrence, and 2 were approved for drug-resistant tuberculosis. Very few antibiotics are in clinical development. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The arrival of these new antibiotics was welcomed with great enthusiasm, particularly when they met previously unmet medical needs. Unfortunately, the majority of them represent modifications to existing chemical structures rather than new drug classes. Despite the availability of these antibiotics, managing patients with deep-seated infections and those with extensively resistant gram-negative organisms remains challenging. CONCLUSIONS: The number of new antibiotics and their indications are not keeping up with resistance and the needs of the patients.

A Continuing Education Activity Durably Addressed Knowledge Gaps Related to Penicillin Allergies Among Pharmacists and Pharmacy Technicians.

Background: Penicillin allergy is one of the most frequent self-reported allergies; however, only about 10% of reported allergies are accurate. Objectives: Through the creation of a continuing pharmacy education (CPE) activity, we sought to assess knowledge gaps and comfort levels in the management of penicillin allergies. Methods: A 1-hour enduring-content CPE activity was offered as an interactive course from September 20, 2019, to September 20, 2020. Participants completed 3 surveys (pre-survey, post-survey, and follow-up survey). Participants were pharmacists and pharmacy technicians who completed, at a minimum, the activity and both pre- and post-surveys. The primary outcome was the percentage of participants scoring >80% on knowledge-based questions on the post-survey compared with the pre-survey. Secondary outcomes included pre-post comparisons on knowledge-based questions, participants' self-report of an allergy, and comfort levels dispensing cephalosporins in a patient with a self-reported penicillin allergy. Results: A total of 389 participants completed the CPE activity, with 176 included for analysis. Significantly more participants scored >80% on knowledge-based questions on the post-survey compared with the pre-survey (71.6% vs 22.7%, P < .001). There was no significant difference between the percentage of participants scoring >80% on the post-survey and the follow-up survey (71.6% vs 65%, P = .119). The majority of participants (74%) felt comfortable dispensing a cephalosporin in a patient with a penicillin allergy on the pre-survey, with similar percentages on the post- and follow-up surveys (77% and 90%, respectively). Conclusion: A targeted continuing education program improved overall knowledge, which was sustained for up to 2 months.

High-Dose Inactivated Influenza Vaccine Quadrivalent for Older Adults.

OBJECTIVE: To review the efficacy and safety of the high-dose inactivated influenza vaccine quadrivalent (HD-IIV4) in the prevention of influenza in older adults. DATA SOURCES: A literature search was performed using PubMed and Google Scholar with the search terms high-dose, influenza vaccine, and quadrivalent. Other resources included the Centers for Disease Control and Prevention (CDC), the prescribing information, and the manufacturer's website. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language articles of studies assessing the efficacy and safety of HD-IIV4 were included. DATA SYNTHESIS: HD-IIV4 is licensed by the Food and Drug Administration for the prevention of influenza in adults aged 65 years and older. The safety and immunogenicity of HD-IIV4 was demonstrated in a phase 3 trial, and the efficacy of the trivalent formulation (HD-IIV3) was demonstrated in a phase 3b-4 trial. HD-IIV4 carries a warning regarding the occurrence of Guillain-Barré syndrome. Adverse reactions, including injection-site pain and myalgia, were reported more frequently with HD-IIV4 than with HD-IIV3. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Although the CDC recommends any age-appropriate influenza vaccine for adults aged 65 years and older, HD-IIV4 was associated with improved immunogenicity against the added B strain and HD-IIV3 provided better protection against influenza than the standard-dose vaccine. Other influenza vaccines have weaker evidence of efficacy in older adults. Therefore, HDIIV4 should be recommended as the vaccine of choice in adults aged 65 years and older. CONCLUSION: HD-IIV4 has proven immunogenic, safe, and effective in preventing influenza in older adults and should be recommended as the vaccine of choice in this patient population.

Cabotegravir-Rilpivirine: The First Complete Long-Acting Injectable Regimen for the Treatment of HIV-1 Infection.

OBJECTIVE: To review the efficacy and safety of cabotegravir (CAB) with rilpivirine (RPV) in the treatment of HIV-1 infection. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2010 to January 2021) with the search terms cabotegravir and rilpivirine. Other resources included abstracts presented at recent conferences and the manufacturer's website and prescribing information. STUDY SELECTION: All English-language articles of studies assessing the efficacy and safety of CAB with RPV were included. DATA SYNTHESIS: The combination of CAB, a new integrase strand transfer inhibitor, and RPV, an established nonnucleoside reverse transcriptase inhibitor, is the first long-acting dual therapy approved for the treatment of HIV-1 infection in adults who have achieved viral suppression on a standard antiretroviral therapy (ART). This regimen demonstrated comparable maintenance of viral suppression evaluated up to 160 weeks, with low rates of virological failure. CAB and RPV are available as suspension given intramuscularly in 2 separate injections every 4 weeks. Common adverse effects include injection site reactions, pyrexia, fatigue, and headache. CAB and RPV are also available as tablets given orally for bridging therapy. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This long-acting dual therapy represents an attractive option with a high barrier to resistance for adults who have achieved viral suppression on standard ART and who prefer monthly injections over daily oral therapy. CONCLUSIONS: CAB-RPV is the first complete long-acting injectable that provides a convenient way to maintain viral suppression with no negative effects on renal and bone health and few drug interactions.

Ibalizumab: The First Monoclonal Antibody for the Treatment of HIV-1 Infection.

OBJECTIVE: To review the efficacy and safety of ibalizumab (IBA) in the treatment of HIV-1 infection. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2010 to mid-June 2020) with the search terms TMB-355, TNX-355, and ibalizumab. Other resources included abstracts presented at recent conferences and the manufacturer's website and prescribing information. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language articles of studies assessing the efficacy and safety of IBA were included. DATA SYNTHESIS: IBA is a monoclonal antibody that blocks HIV-1 from infecting CD4+ T cells. IBA is approved by the Food and Drug Administration, in combination with other antiretrovirals (ARVs), for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant (MDR) HIV-1 infection failing their current ARVs. IBA demonstrated significant and sustained antiviral activity in patients with MDR HIV-1 infection who had advanced disease and limited treatment options. It carries a warning regarding the development of immune reconstitution inflammatory syndrome. Common adverse reactions include diarrhea, dizziness, nausea, and rash. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: IBA represents an attractive option for treatment-experienced adults with advanced HIV-1 infection who are no longer able to achieve viral suppression on oral ARV therapy alone and who are able to adhere to an infusion therapy every 2 weeks. As with other biologics, there is a potential for the development of antibodies to IBA that can compromise its efficacy and safety. CONCLUSION: IBA provides a needed treatment option to achieve and maintain viral suppression in heavily treatment-experienced adults with MDR HIV-1 infection.

Lefamulin: The First Systemic Pleuromutilin Antibiotic.

OBJECTIVE: To review the pharmacology, microbiology, efficacy, and safety of lefamulin. DATA SOURCES: A literature search was performed using PubMed and Google Scholar (2010 to end-April 2020) with the search terms BC-3781 and lefamulin. Other resources included abstracts presented at recent conferences, prescribing information, and the manufacturer's and Food and Drug Administration websites. STUDY SELECTION AND DATA EXTRACTION: All relevant English-language articles of studies assessing the efficacy and safety of lefamulin were included. DATA SYNTHESIS: Lefamulin is a pleuromutilin antibiotic with activity against Staphylococcus aureus, Streptococcus pneumoniae, and atypical bacteria. Lefamulin, given at the dose of 150 mg intravenously or 600 mg orally on an empty stomach every 12 hours for 5 to 7 days, was proven noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). Common adverse reactions include injection site reactions, hepatic enzyme elevation, gastrointestinal upset, hypokalemia, insomnia, and headache. Lefamulin is associated with QT prolongation, and concomitant use with CYP3A substrates that prolong the QT interval is contraindicated. Lefamulin may cause fetal harm. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Lefamulin is a novel antibiotic with a unique mechanism of action. It represents an alternative option to ß-lactams and macrolides in the treatment of adults with CABP and an alternative option to amoxicillin and doxycycline in the outpatient setting given the rise in resistance to macrolides and safety concerns with fluoroquinolones. Nausea, vomiting, and diarrhea may limit the tolerability of the oral formulation. CONCLUSIONS: Lefamulin is the first systemic pleuromutilin antibiotic that has proven safe and effective for adults with CABP.

Omadacycline: A New Tetracycline Antibiotic.

OBJECTIVE: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of omadacycline, a new tetracycline antibiotic. DATA SOURCES: A literature search through PubMed, Google Scholar, and clinicaltrials.gov was conducted (2008 to October 2018) using the search terms omadacycline and PTK-0796. Abstracts presented at recent conferences, prescribing information and information from the FDA and the manufacturer's website were reviewed. STUDY SELECTION AND DATA EXTRACTION: Preclinical data and published phase 1, 2, and 3 studies were evaluated. DATA SYNTHESIS: Omadacycline displays in vitro activity against a wide range of bacteria. Clinical trials have shown that omadacycline is noninferior to linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and noninferior to moxifloxacin for the treatment of community-acquired bacterial pneumonia (CABP). A loading dose of 200 mg intravenously (IV) once or 100 mg IV twice or 450 mg orally once is recommended followed by a maintenance dose of 100 mg IV or 300 mg orally once daily. No dosage adjustment is needed in patients with renal or hepatic impairment. Omadacycline is well tolerated, with nausea being a common adverse effect, but is associated with food and drug interactions. Relevance to Patient Care and Clinical Practice: Omadacycline is active against staphylococci, including methicillin-resistant strains, and streptococci, including tetracycline-resistant strains, as well as atypical bacteria. Omadacycline provides clinicians with an additional parenteral and oral option for the treatment of adults with ABSSSI and CABP. CONCLUSION: Omadacycline is an alternative treatment option for ABSSSI and CABP.

The Rise and Fall of Metronidazole for Clostridium difficile Infection.

Clostridium difficile is posing urgent health threats. Older studies have shown that metronidazole and vancomycin are equally effective in the treatment of Clostridium difficile infection (CDI). Given its inexpensive cost and low propensity to select antimicrobial resistant organisms, metronidazole became rapidly the drug of choice despite its pharmacokinetic limitations in the treatment of CDI. However, newer studies demonstrated that metronidazole is inferior to vancomycin, prompting clinicians to change their long-standing position on using metronidazole for mild to moderate infections and on reserving vancomycin for severe infections. Moving forward, metronidazole will fall out of favor in the treatment of CDI.

Providing Additional "Muscle" for Older Adults Through Optimal Influenza Vaccine Selection.

Immunization is the best strategy to protect individuals from influenza; however, older adults tend to respond less favorably to vaccines because of immunosenescence. The Centers for Disease Control and Prevention states that any licensed, recommended, and age-appropriate influenza vaccine may be used in older adults despite reasonable evidence suggesting that the high-dose and, to a lesser extent, the adjuvanted and recombinant influenza vaccines provide better protection than the standard-dose vaccines in this vulnerable population. In this era of precision medicine, clinicians can preferentially recommend these contemporary vaccines to equip their older patients with the best possible protection against influenza.

Shingrix: The New Adjuvanted Recombinant Herpes Zoster Vaccine.

OBJECTIVES: To review the immunogenicity, efficacy, and safety of the herpes zoster subunit vaccine (HZ/su) for use in adult patients for the prevention of shingles. DATA SOURCES: A literature search through PubMed was conducted (June 2008 to October 2017) using the terms shingles vaccine and varicella zoster virus. References from retrieved articles and the prescribing information were also reviewed for any additional material. STUDY SELECTION/DATA EXTRACTION: The literature search was limited to human studies published in English. Randomized controlled, multicenter trials were reviewed and included to evaluate the safety and efficacy of HZ/su. Literature on the epidemiology and pathology of herpes zoster virus infections and recommendations from the Advisory Committee on Immunization Practices (ACIP) were also reviewed. DATA SYNTHESIS: HZ/su is a new adjuvanted recombinant vaccine approved by the Food and Drug Administration for the prevention of herpes zoster in adults 50 years of age and older. HZ/su significantly reduced the risk of developing herpes zoster by more than 90% as compared with placebo and displayed a comparable adverse effect profile. The most common local adverse events were injection site pain, redness, and swelling, and the most common systemic adverse events were myalgia, fatigue, and headache. The ACIP recommends the routine use of HZ/su as the preferred vaccine for the prevention of herpes zoster in immunocompetent adults 50 years of age and older. CONCLUSIONS: Based on published immunogenicity, efficacy, and safety data, as well as the recent recommendations by the ACIP, HZ/su should be included on both hospital and community pharmacy formularies and recommended to all immunocompetent patients older than 50 years to prevent herpes zoster.

Sofosbuvir/Velpatasvir/Voxilaprevir: A Pan-Genotypic Direct-Acting Antiviral Combination for Hepatitis C.

OBJECTIVES: To review the efficacy and safety of sofosbuvir/velpatasvir/voxilaprevir in the treatment of hepatitis C virus (HCV) infection. DATA SOURCES: A literature search through PubMed was conducted (August 2010 to August 2017) using the terms GS-9857, voxilaprevir, and NS3/4A protease inhibitor. STUDY SELECTION/DATA EXTRACTION: Studies of sofosbuvir/velpatasvir/voxilaprevir were identified. DATA SYNTHESIS: Sofosbuvir/velpatasvir/voxilaprevir is indicated for adult patients with chronic HCV without cirrhosis or with compensated cirrhosis who have (1) genotype 1 through 6 and have previously been treated with an NS5A inhibitor or (2) genotype 1a or 3 and have previously been treated with sofosbuvir without an NS5A inhibitor. POLARIS-1 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 12 weeks was highly effective in patients with HCV genotype 1 through 6 who had prior exposure to an NS5A inhibitor. POLARIS-2 failed to demonstrate that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was noninferior to sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 6 who had no prior exposure to direct-acting antivirals (DAAs). POLARIS-3 demonstrated that sofosbuvir/velpatasvir/voxilaprevir for 8 weeks was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 3 and compensated cirrhosis who had no prior exposure to DAAs. POLARIS-4 demonstrated that sofosbuvir/velpatasvir/voxilaprevir was as effective as sofosbuvir/velpatasvir for 12 weeks in patients with HCV genotype 1 through 3 who had prior exposure to DAAs but not an NS5A inhibitor. The most common adverse reactions were headache, fatigue, diarrhea, and nausea. CONCLUSIONS: Sofosbuvir/velpatasvir/voxilaprevir is safe and effective to treat HCV in patients who have previously been treated with DAAs.

Bezlotoxumab for the Prevention of Clostridium difficile Recurrence.

OBJECTIVE: To review the pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosing, and administration of bezlotoxumab (BEZ), as well as its place in the prevention of Clostridium difficile infection (CDI) recurrence. DATA SOURCES: A search of PubMed and Google Scholar using the terms "bezlotoxumab," "CDB1," "MDX-1388," and "MK-6072" was performed. The manufacturer's website was also reviewed to further identify relevant information. STUDY SELCTION: All English-language articles from 2006 to May 2017 appearing in these searches were reviewed for relevance to this paper. In addition, their bibliographies were reviewed to identify any articles not identified in the searches. DATA SYNTHESIS: BEZ is a human monoclonal antibody that binds to Clostridium difficile toxin B. It is approved by the Food and Drug Administration to reduce CDI recurrence in adult patients who are receiving antibiotic therapy for CDI and are at high risk for CDI recurrence. It is given as a single dose of 10 mg/kg via an intravenous infusion. It is eliminated by catabolism. Phase III clinical trials demonstrated that BEZ was associated with significantly lower rates of CDI recurrence, compared with placebo. The most common adverse events reported during clinical trials were diarrhea and nausea. There is a warning regarding the use of BEZ in patients with a history of congestive heart failure. The most common adverse reactions associated with BEZ are nausea, pyrexia, and headache. CONCLUSION: BEZ has been proven safe and effective in preventing CDI recurrence. Given its high cost, it should be reserved for patients at high risk for CDI recurrence.

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.

Small bowel in vivo bioengineering using an aortic matrix in a porcine model.

OBJECTIVE: To evaluate the feasibility of an in vivo small bowel bioengineering model using allogeneic aortic grafts in pigs. BACKGROUND: The best treatment for short bowel syndrome is still unclear. Intestinal transplantation, as well as lifelong parenteral nutrition is associated with a 5-year survival rate of less than 50 %. We have already used allogeneic arterial segments to replace the upper airway in sheep. The results were encouraging with an induced transformation of the aortic wall into tracheo-bronchial bronchial-type tissue. METHODS: Seven young mini-pigs were used. A 10-cm-diameter, allogeneic, aortic graft was interposed in an excluded small bowel segment and wrapped by the neighboring omentum. Animals were autopsied at 1 (n = 2), 3 (n = 3), and 6 months (n = 2), respectively. Specimens were examined macroscopically and microscopically. RESULTS: The overall survival rate of the animals was 71.4 %. No anastomotic leak occurred. Histologic analysis revealed intestinal-like wall transformation of the aortic graft in the surviving animals. CONCLUSION: Aortic-enteric anastomosis is feasible in a porcine model. Moreover, in vivo, bioengineered, intestinal-like transformation of the vascular wall was identified.

Ceftolozane/Tazobactam: A New Cephalosporin and ß-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 ß-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 ß-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 ß-lactamase-producing bacteria and Pseudomonas aeruginosa.