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Boceprevir is a protease inhibitor indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination with peginterferon and ribavirin for treatment-naive patients and those who previously failed to improve with interferon and ribavirin treatment.This article provides an overview of the mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of boceprevir.Relevant information was identified through a search of PubMed (1990-July 2012), EMBASE (1990-July 2012), International Pharmaceutical Abstracts (1970-July 2012), and Google Scholar using the key words boceprevir, SCH 503034, non-structural protein 3 (NS3) serine protease inhibitor, and direct-acting antiviral agent (DAA). Additional information was obtained from the US Food and Drug Administration's Web site, review of the reference lists of identified articles, and posters and abstracts from scientific meetings.Clinical efficacy of boceprevir was assessed in 2 Phase III trials, Serine Protease Inhibitor Therapy-2 (SPRINT-2) for treatment-naive patients and Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) for treatment-experienced patients. In SPRINT-2, patients were randomized to receive peginterferon + ribavirin (PR) or peginterferon + ribavirin + boceprevir (PRB); duration of boceprevir therapy varied from 24, 32, to 44 weeks on the basis of HCV RNA results. The primary endpoint was achievement of sustained virologic response (SVR; lower limit of detection, 9.3 IU/mL). The addition of boceprevir was shown to be superior, with overall SVR rates ranging from 63% to 66% compared with 38% with PR (P0.001). Results of SVR in SPRINT-2 were also reorganized to monitor SVRs in black and non-black patients. Treatment-experienced patients were assessed in RESPOND-2; however, null responders were excluded. Patients were again randomized to PR or PRB; duration of boceprevir therapy varied from 32 to 44 weeks on the basis of HCV RNA results. SVR was significantly higher in patients receiving boceprevir (59%-66% vs 21% with PR; P0.001). This benefit was seen in both previous nonresponders (SVR, 40%-52% vs 7% with PR), as well as previous relapsers (SVR, 69%-75% vs 29% with PR). Importantly, SVR could be attained with a shortened course of therapy in almost one half of all treated patients in SPRINT-2 (44%) and RESPOND-2 (46%).Boceprevir was well tolerated in clinical trials and a welcomed addition to our HCV armamentarium.

The emergence of viral resistance is one of the greatest challenges in the treatment of HIV infection. Maraviroc is the first member of a new class of antiretroviral medications, the CCR5-receptor antagonists. It is approved by the US Food and Drug Administration (FDA) for use in combination with other antiretroviral agents in treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.This article provides an overview of the pharmacology, efficacy, and tolerability of maraviroc in the treatment of HIV-1 infection.Relevant information was identified through a search of MEDLINE (January 2000-May 2008) using the terms maraviroc, UK-427,857, and CCR5-receptor antagonist. Also consulted were abstracts from the International AIDS Society Conference, the Conference on Retroviruses and Opportunistic Infections, and other relevant scientific meetings. Additional publications were found by searching the reference lists of the identified articles and the FDA Web site.Maraviroc is a selective, reversible, small-molecule CCR5-receptor antagonist. In vitro, it has potent anti-HIV-1 activity, with a mean 90% inhibitory concentration of 2.0 nmol/L. It is widely distributed, with a V(d) of approximately 194 L. Maraviroc is moderately metabolized in the liver (65.3%), primarily via the cytochrome P450 3A4 isozyme. It has an elimination t(1/2) of 15.9 to 22.9 hours. Until more data are available, maraviroc should be avoided in patients with severe hepatic insufficiency; dose adjustment does not appear to be necessary on the basis of age, sex, or renal function. In 2 Phase IIb/III studies, maraviroc 300 mg PO QD or BID was found to be more efficacious than placebo in reducing the viral load at 48 weeks in treatment-experienced, CCR5-tropic HIV-1-infected patients receiving an optimized background regimen (difference vs placebo-QD arm: -0.89 log(10) copies/mL [97.5% CI, -1.17 to -0.62]; BID arm: -1.05 log(10) copies/mL [97.5% CI, -1.33 to -0.78]). The proportion of patients with a viral load50 copies/mL was 43.2% in the QD arm and 45.5% in the BID arm, compared with 16.7% in the placebo arm (P0.001, both treatment arms vs placebo). In treatment-naive patients infected with CCR5-tropic virus only, maraviroc 300 mg PO BID was not noninferior to oral efavirenz 600 mg QD (difference = -4.2%; lower bound of the 1-sided 97.5% CI, -10.9 [predefined statistical cutoff for noninferiority, -10]). Maraviroc was generally well tolerated in clinical trials. The most frequently reported (or = 5%) adverse events were upper respiratory tract infection (20.0%), cough (12.7%), pyrexia (12.0%), rash (9.6%), musculoskeletal complaints (8.7%), gastrointestinal and abdominal pain (8.2%), dizziness (8.2%), appetite disorders (7.3%), insomnia (7.0%), herpes infection (6.8%), sinusitis (6.3%), joint complaints (6.1%), bronchitis (5.9%), and constipation (5.4%). The recommended dose of maraviroc differs based on concomitant medications, ranging from 150 to 600 mg BID.When used in combination with other antiretroviral agents, maraviroc appears to be a promising agent for treatment-experienced patients infected with multidrug-resistant, CCR5-tropic HIV-1.

Background: The incidence of invasive fungal infections (IFIs) caused by opportunistic filamentous molds is increasing, along with emerging fungal resistance. Posaconazole, a structural analogue of itraconazole that was approved for marketing in the United States in 2006, appears to be a promising antifungal agent. Objective: This article provides an overview of the pharmacology, efficacy, and tolerability of posaconazole when used for the prophylaxis and treatment of various common and rare fungal infections. Methods: Relevant information was identified through a search of MEDLINE (1966-April 2007), International Pharmaceutical Abstracts (1970-April 2007), and abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy using the terms posaconazole and SCH 56592 . Additional resources were found by searching the reference lists of the identified articles and the US Food and Drug Administration Web site. Results: Posaconazole is available as an oral suspension. It is highly distributed to various sites, including bone, the central nervous system, and eye tissue. Its Vd is 2447 L when administered in multiple daily doses (up to 800 mg/d) in the presence of a high-fat meal. Because it is excreted mostly as unchanged drug in the feces (77%), posaconazole can be administered to patients with poor renal function without any dose adjustment. Posaconazole has shown in vitro and in vivo activity against a wide variety of fungi, including those that are rare and relatively resistant. Two clinical trials have compared posaconazole with fluconazole or itraconazole for the prophylaxis of IFIs in immunocompromised patients. The first, a randomized, double-blind trial in 600 recipients of hematopoietic stem cell transplants, found that overall rates of IFI did not differ significantly between posaconazole and fluconazole (5% vs 9%, respectively). The other, a randomized, open-label trial in 602 neutropenic patients, reported significantly fewer IFIs in patients receiving posaconazole compared with those receiving fluconazole or itraconazole (>2% vs >8%, respectively; P = 0.001). An additional 2 trials have investigated posaconazole for the treatment of oropharyngeal candidiasis (OPC) in patients with HIV infection. A randomized, controlled, evaluator-blinded study in 350 HIV-infected patients with OPC found similar 14-day clinical success rates with posaconazole and fluconazole (91.7% and 92.5%, respectively; 95% CI, -6.6l to 5.04), whereas an open-label study in 176 HIV-infected patients with a history of refractory OPC reported a 28-day clinical success rate of 75%. Numerous small studies and case reports have described successful posaconazole treatment of zygomycosis, aspergillosis, fusariosis, endemic dimorphic fungal infection, and superficial and subcutaneous fungal infections that were refractory to conventional antifungal agents or in patients who were unable to tolerate these agents. Posaconazole has been well tolerated. The most common complaints have been gastrointestinal in nature, including nausea (7%-8%) and diarrhea (3%-11%), although these have rarely led to permanent discontinuation of therapy. Other common adverse effects have included vomiting (4%-7%), headache (2%-8%), and liver enzyme elevations (2%-3%). Conclusions: Posaconazole suspension administered at up to 800 mg/d is a reasonable alternative to conventional antifungal agents for the prevention and treatment of IFIs in high-risk populations. It may also be suitable in patients with infections caused by rare or relatively resistant fungi, and those who are unable to tolerate long-term therapy with other antifungal agents.

Background: Tinidazole, a structural analogue of metrondazole, is an antiprotozoal agent that has been widely used in Europe and developing countries for >2 decades with established efficacy and acceptable tolerability. It was recently approved by the US Food and Drug Administration for the treatment of trichomoniasis, giardiasis, amebiasis, and amebic liver abscess. Objective: This article reviews the pharmacologicand pharmacokinetic properties and clinical usefulness of tinidazole. Methods: Relevant information was identified through a search of MEDLINE (1966–August 2005), Iowa Drug Information Service (1966–August 2005), and International Pharmaceutical Abstracts (1970–August 2005) using the terms tinidazole, Fasigyn , and nitroimidazole . Results: In vitro, tinidazole exhibits activity againstpathogenic protozoa (eg, Tricbomonas vaginalis, Entamoeba bistolytica, Giardia duodenalis ), a wide range of clinically significant anaerobic bacteria (eg, Bacteroides fragilis, Clostridium difficile ), and the microaerophilic bacterium Helicobacter pylori . In susceptible protozoal and bacterial cells, tinidazole is reduced to cytotoxic intermediates that covalently bind to DNA, causing irreversible damage. In human adults, tinidazole had a bioavailability of 100% and a V d of 50.7 L, was minimally bound to plasma protein (12%), had a plasma elimination t ½ of 12.3 hours, and was eliminated primarily by hepatic metabolism (∼63%). Dose adjustment does not appear to be necessary on the basis of race, sex, or renal function. No data were found on the disposition of tinidazole in patients with hepatic insufficiency; therefore, use of tinidazole in patients with severe hepatic impairment (Child-Pugh class C) is not recommended. Clinical cure rates in patients with trichomoniasis, giardiasis, amebiasis, and amebic liver abscess were generally >90%. In comparative trials, tinidazole was as effective as metronidazole in the treatment of trichomoniasis and was significantly more effective than metronidazole in the treatment of giardiasis ( P P 1%) adverse effects included bitter taste, nausea, abdominal discomfort, anorexia, vomiting, and fatigue. The recommended dosage of tinidazole is a single dose of 2 g for trichomoniasis and giardiasis, and 2 g/d for 3 to 5 days for amebiasis. Conclusions: Tinidazole appears to be a promisingagent for the treatment of trichomoniasis, giardiasis, amebiasis, and amebic liver abscess. Clinical studies are needed to evaluate the use of tinidazole against anaerobic bacteria and H pylori .

Objectives: The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy ofdaptomycin; to explore its safety profile; and to discuss its current and potential roles as an antimicrobial therapy. Methods: A literature search was conducted using the MEDLINE (1966–August 2004) and InternationalPharmaceutical Abstracts (1970–August 2004) databases with the search terms daptomycin, LY146032 , and lipopeptide antibiotics . Abstracts of the Interscience Conference on Antimicrobial Agents and Chemotherapy and documents submitted to the US Food and Drug Administration were also reviewed. Results: Phase III study results suggest no difference in efficacy or tolerability between daptomycin 4 mg/kgIV QD and vancomycin or semisynthetic penicillins for complicated skin and skin-structure infections. Animal studies suggest daptomycin may be useful for the treatment of endocarditis. Daptomycin is not indicated for pneumonia, with poorer outcomes than conventional treatment It is available as an IV medication and exhibits 92% plasma protein binding in vitro. In healthy adult humans, daptomycin has a volume of distribution of 0.1 Ukg and a plasma elimination half-life of ∼9 hours, and is eliminated primarily by renal excretion (∼54%). In patients with reduced renal function, including those receiving hemodialysis and peritoneal dialysis, the dose interval should be 48 hours. No dosage adjustment appears to be necessary for mild to moderate hepatic impairment. The use of daptomycin in patients with severe hepatic impairment has not been assessed. The most commonly reported adverse events include constipation, nausea, injection-site reactions, headache, and diarrhea. Patients should also be monitored regularly for skeletal muscle toxicity. Conclusions: Daptomycin may be useful for complicated skin and skin-structure infections and gram-positive pathogens resistant to conventional antimicrobials. However, limited data are currently available for duration of treatment beyond 14 days and at doses >4 mg/kg QD.

Reports of resistance and intolerance to currently available antifungal agents are increasing. Voriconazole is a broad-spectrum azole antifungal agent structurally derived from fluconazole. It is indicated for the treatment of invasive aspergillosis and serious fungal infections caused by Scedosporium apiospermum and Fusarium species in patients who are unable to tolerate or are refractory to other antifungal therapy.This article reviews the pharmacologic and pharmacokinetic properties and clinical usefulness of voriconazole.Relevant information was identified through a search of MEDLINE (1966-December 2002), Iowa Drug Information Service (1966-December 2002), International Pharmaceutical Abstracts (1970-December 2002), and meeting abstracts of the Infectious Diseases Society of America (1996-2002) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996-2002) using the terms voriconazole and UK-109,495.In head-to-head comparative trials, voriconazole appeared to be as efficacious as amphotericin B for the treatment of invasive aspergillosis and the empiric treatment of fungal infections in patients with febrile neutropenia. In clinical studies, it was as efficacious as fluconazole for the treatment of oropharyngeal and esophageal candidiasis. The results of in vitro susceptibility studies and case reports suggested that voriconazole may be useful against fluconazole- and/or itraconazole-resistant strains of Candida. Although voriconazole may be associated with a lower incidence of serious systemic adverse effects compared with amphotericin B (13.4% vs 24.3% in 1 pivotal clinical study; P = NS), major adverse effects associated with voriconazole include visual abnormalities ( approximately 30%), skin reactions ( approximately 20%), and elevations in hepatic enzymes (or =20%). Voriconazole is available as oral and intravenous formulations. Pharmacokinetically, it has widespread distribution, including penetration into cerebral tissue. However, as 80% of voriconazole is hepatically eliminated, primarily via the cytochrome P450 (CYP) isozymes CYP2C19, CYP3A4, and CYP2C9, voriconazole has a high potential for drug interactions, and dose reduction is recommended in patients with mild to moderate hepatic dysfunction (Child-Pugh class A or B). Oral voriconazole may be preferred in patients with a creatinine clearance50 mL/min due to the potential accumulation of the solubilizing excipient in the parenteral formulation of voriconazole.Voriconazole appears to be a useful alternative to conventional antifungal agents in cases of resistance or intolerance to initial therapy. However, dose adjustment is recommended in patients with hepatic dysfunction, as well as in those receiving medications that may interact with voriconazole via hepatic metabolism.

Background: The mainstays of treatment for nosocomial fungal infections have been amphotericin B and azole derivatives. Caspofungin acetate is a new echinocandin antifungal agent with a mechanism of action that targets a structural component of the fungal cell wall. Objective: This article describes the pharmacologic properties and potential clinical usefulness of caspofungin. Methods: Relevant information was identified through searches of MEDLINE (1966–September 2001), Iowa Drug Information Service (1966–September 2001), and International Pharmaceutical Abstracts (1970–September 2001), as well as meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996–2001), using the terms caspofungin, MK-0991, pneumocandin, echinocandin, candin, and β-(1,3)-glucan inhibitor . Results: In vitro, caspofungin exhibits antifungal activity against an array of clinically important yeasts and molds, including Candida and Aspergillus spp. The proposed susceptibility breakpoint for caspofungin against Candida spp, the most common cause of nosocomial fungal infections, is a minimum inhibitory concentration of ≤1 μg/mL. In humans, caspofungin has a volume of distribution of 9.67 L, is extensively bound to albumin (97%), has a plasma elimination half-life of 9 to 11 hours, and is metabolized to inactive metabolites in the liver. Dose adjustment based on age, sex, race, or renal function does not appear to be necessary, although patients with moderate hepatic insufficiency (Child-Pugh score 7–9) should receive a lower maintenance dose. The results of clinical trials, although somewhat preliminary, suggest that caspofungin is effective in the treatment of esophageal and oropharyngeal candidiasis and invasive aspergillosis. When combined with other antifungal agents, caspofungin produces a synergistic or additive effect against a variety of clinically important fungi. The most commonly reported adverse events with caspofungin have included fever, infusion-related reactions, headache, nausea, elevations in liver transaminase levels, and histamine-type reactions. The recommended dosage in adults is 70 mg IV on day 1 followed by 50 mg/d, with the duration of treatment depending on the severity of the patient's underlying condition and the clinical response. Conclusion: Although additional studies are needed, caspofungin appears to be a promising agent for the treatment of patients with difficult-to-treat or life-threatening fungal infections.

Background: Linezolid is the first oxazolidinone anti-infective agent marketed in the United States. It is indicated for the treatment of nosocomial pneumonia, complicated skin and skin-structure infections caused by methicillin-sensitive or methicillin-resistant Staphylococcus aureus and other susceptible organisms, and vancomycin-resistant Enterococcus faecium infections. It also is indicated for the treatment of uncomplicated skin and skin-structure infections caused by methicillin-sensitive S aureus or Streptococcus pyogenes , and community-acquired pneumonia caused by penicillin-sensitive Streptococcus pneumoniae . Objective: This article reviews the pharmacologic properties and clinical usefulness of linezolid. Methods: Using the terms linezolid, PNU-100766 , and oxazolidinone , we performed a literature search of the following databases: MEDLINE ® (1966 to September 2000), HealthSTAR ® (1993 to September 2000), Iowa Drug Information Service (1966 to September 2000), International Pharmaceutical Abstracts (1970 to September 2000), PharmaProjects (January 2000 version), and meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996 to 2000). Results: Linezolid has a unique structure and mechanism of action, which targets protein synthesis at an exceedingly early stage. Consequently, cross-resistance with other commercially available antimicrobial agents is unlikely. It is primarily effective against gram-positive bacteria. To date, resistance to linezolid has been reported in patients infected with enterococci. The pharmacokinetic parameters of linezolid in adults are not altered by hepatic or renal function, age, or sex to an extent requiring dose adjustment. Linezolid is metabolized via morpholine ring oxidation, which is independent of the cytochrome P450 (CYP450) enzyme system; as a result, linezolid is unlikely to interact with medications that stimulate or inhibit CYP450 enzymes. Compassionate-use trials and other clinical studies involving mainly adult hospitalized patients with gram-positive infections have shown that linezolid administered intravenously or orally is effective in a variety of nosocomial and community-acquired infections, including those caused by resistant gram-positive organisms. Reported adverse effects include thrombocytopenia, diarrhea, headache, nausea, vomiting, insomnia, constipation, rash, and dizziness. Preliminary pharmacoeconomic data indicate that a significantly higher percentage of patients receiving linezolid therapy versus comparator could be discharged from the hospital by day 7 ( P = 0.005). Conclusions: Linezolid appears to be effective while maintaining an acceptable tolerability profile. Due to the risk of bacterial resistance, linezolid should be reserved for the treatment of documented serious vancomycin-resistant enterococcal infections.

The purpose of this paper is to review the rationale for a new class of nonsteroidal anti-inflammatory drugs (NSAIDs) known as selective cyclooxygenase (COX)-2 inhibitors and to present preliminary clinical data on 2 COX-2 inhibitors that are approved for use in the United States. The primary mechanism of NSAIDs in the treatment of inflammation is the inhibition of COX, which exists in 2 forms. COX-I appears to regulate many normal physiologic functions, and COX-2 mediates the inflammatory response. Theoretically, an NSAID that inhibits COX-2 selectively should decrease inflammation but not influence normal physiologic functions and thus should cause fewer gastrointestinal side effects. Preliminary data suggest that celecoxib, a highly selective COX-2 inhibitor, is superior to placebo and similar to traditional NSAIDs in the short-term treatment of pain due to osteoarthritis, although it has been associated with adverse effects such as headache, change in bowel habits, abdominal discomfort, and dizziness. Celecoxib also has been shown to be as effective as traditional NSAIDs in the treatment of rheumatoid arthritis, but it may cause fewer adverse effects, including endoscopically documented ulcers. Celecoxib is metabolized in the liver by the cytochrome P-450 isozyme CYP2C9, and thus serious drug interactions are possible. In the treatment of osteoarthritis, rofecoxib has been shown to be as effective as traditional NSAIDs and may cause fewer endoscopically documented ulcers, but its complete adverse-effect profile is not known. Until the selective COX-2 inhibitors are widely used and more clinical as well as pharmacoeconomic studies are published, the exact role of COX-2 therapy cannot be determined. words: cyclooxygenase, celecoxib, rofecoxib, rheumatoid arthritis, osteoarthritis.

Background Ceftaroline is a cephalosporin with expanded gram-positive activity recently approved for clinical uses by the US Food and Drug Administration. Objective This article provides an overview of the in vitro and in vivo activities, mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of ceftaroline. Methods Relevant information was identified through a search of PubMed (1990–April 2011), EMBASE (1990–April 2011), International Pharmaceutical Abstracts (1970–April 2011), and Google Scholar using the key words ceftaroline, PPI-0903, PPI-0903M, T-91825, and TAK-599 . A review of the reference lists of identified articles, a search of the US Food and Drug Administration Web site, and posters and abstracts from scientific meetings yielded additional publications. Results In vitro, ceftaroline exhibits activity against most aerobic gram-positive isolates, common aerobic gram-negative respiratory pathogens, and some gram-positive anaerobes. The MIC range for most Staphylococcus aureus isolates, including vancomycin-resistant strains was between ≤0.008 and 4 μg/mL. In Phase III studies (CANVAS 1 and CANVAS 2), ceftaroline was found to be noninferior to vancomycin + aztreonam for the treatment of complicated skin and skin-structure infections, with a clinical cure rate of 91.6% among clinically evaluable patients (ceftaroline versus vancomycin + aztreonam: difference, −1.1; 95% CI, −4.2 to 2.0; P = NS). Ceftaroline's efficacy has also been assessed for the treatment of community-acquired pneumonia in 2 Phase III studies (FOCUS 1 and FOCUS 2) and was equivalent to ceftriaxone, with cure rates of 84.3% and 77.7%, respectively, among clinically evaluable patients in the combined analysis (ceftaroline versus ceftriaxone: difference, 6.7; 95% CI, 1.6 to 11.8). The recommended dosage for patients 18 years and older is 600 mg IV every 12 hours. Dosage adjustment is necessary in patients with renal impairment (creatinine clearance ≤50 mL/min). The pharmacokinetic properties of ceftaroline in patients with hepatic impairments are currently unavailable. Ceftaroline appeared to be well tolerated generally. The most frequently (>3%) reported adverse events were nausea, headaches, diarrhea, pruritus, rash, and insomnia; all were usually mild to moderate, self-limiting, and of little clinical significance. Conclusions Ceftaroline is a cephalosporin with broad gram-positive activity, including Methicillin-resistant S aureus and vancomycin-resistant S aureus . Its gram-negative activity includes common respiratory pathogens and members of the Enterobacteriaceae. Clinical trials have reported that ceftaroline was noninferior to ceftriaxone, and vancomycin + aztreonam for the treatment of community-acquired pneumonia and complicated skin and skin-structure infections, respectively.

Background: Besifloxacin is a topical ophthalmic fluoroquinolone that was approved by the US Food and Drug Administration (FDA) in May 2009 for the treatment of bacterial conjunctivitis caused by susceptible bacterial strains. Objective: This article provides an overview of the pharmacology, clinical efficacy, and tolerability of ophthalmic besifloxacin when used for the treatment of bacterial conjunctivitis. Methods: Relevant reports pertaining to the pharmacology, efficacy, and tolerability of besifloxacin were identified through a search of MEDLINE (1985–December 2009) and International Pharmaceutical Abstracts (1985–December 2009) using the terms besifloxacin, BOL-303224-A, ophthalmic fluoroquinolones, and bacterial conjunctivitis. Additional publications were identified by reviewing the reference lists of identified articles and searching the FDA Web site. Results: Besifloxacin has potent in vitro inhibitory activity against most common ocular bacterial pathogens (MIC90 values generally ≤4 μg/mL), including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. In an ocular pharmacokinetic study in 64 healthy volunteers, the Cmax in tears (mean [SD], 610 [540] μg/mL) was reached 10 minutes after a single ocular instillation of besifloxacin; concentrations ≥1.6 μg/g of tear were sustained for at least 24 hours; and the elimination t1/2 was ~3.4 hours. In a study in 24 patients with a clinical diagnosis of bilateral bacterial conjunctivitis, systemic exposure (Cmax) after administration of besifloxacin ophthalmic suspension 3 times daily for 5 days was

Tigecycline, the first glycylcycline to be approved by the US Food and Drug Administration, is a structural analogue of minocycline that was designed to avoid tetracycline resistance mediated by ribosomal protection and drug efflux. It is indicated for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections and is available for intravenous administration only.This article summarizes the in vitro and in vivo activities and pharmacologic and pharmacokinetic properties of tigecycline, and reviews its clinical efficacy and tolerability profile.Relevant information was identified through a search of MEDLINE (1966-April 2006), Iowa Drug Information Service (1966-April 2006), and International Pharmaceutical Abstracts (1970-April 2006) using the terms tigecycline, GAR-936, and glycylcycline. Also consulted were abstracts and posters from meetings of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2006) and documents provided for formulary consideration by the US manufacturer of tigecycline.Like the tetracyclines, tigecycline binds to the 30S subunit of bacterial ribosomes and inhibits protein synthesis by preventing the incorporation of amino acid residues into elongating peptide chains. In vitro, tigecycline exhibits activity against a wide range of clinically significant gram-positive and gram-negative bacteria, including multidrug-resistant strains (eg, oxacillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae), and anaerobes (eg, Bacteroides spp). In pharmacokinetic studies in human adults, tigecycline had a large Vd (7-9 L/kg), was moderately bound to plasma protein (71%-89%), had an elimination t(1/2) of 42.4 hours, and was eliminated primarily by biliary/fecal (59%) and renal (33%) excretion. Dose adjustment did not appear to be necessary based on age, sex, renal function, or mild to moderate hepatic impairment (Child-Pugh class A-B). In patients with severe hepatic impairment (Child-Pugh class C), the maintenance dose should be reduced by 50%. In 4 Phase III clinical trials in patients with complicated skin and skin-structure infections and complicated intra-abdominal infections, tigecycline was reported to be noninferior to its comparators (vancomycin + aztreonam in 2 studies and imipenem/cilastatin in 2 studies), with clinical cure rates among clinically evaluable patients of80% (P0.001 for noninferiority). The most frequently reported (or =5 %) adverse events with tigecycline were nausea (28.5%), vomiting (19.4%), diarrhea (11.6%), local IV-site reaction (8.2%), infection (6.7%), fever (6.3%), abdominal pain (6.0%), and headache (5.6%). The recommended dosage of tigecycline is 100 mg IV given as a loading dose, followed by 50 mg IV g12h for 5 to 14 days.In clinical trials, tigecycline was effective for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections. With the exception of gastrointestinal adverse events, tigecycline was generally well tolerated. With a broad spectrum of activity that includes multidrug-resistant gram-positive and gram-negative pathogens, tigecycline may be useful in the treatment of conditions caused by these pathogens.

Drug resistance continues to be a major challenge in the treatment of HIV-1 infection. Virtually all currently available antiretroviral medications inhibit the viral reverse transcriptase or protease. Enfuvirtide is the first fusion inhibitor approved by the US Food and Drug Administration for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced patients.This paper describes the pharmacologic properties and clinical usefulness of enfuvirtide.Relevant information was identified through searches of MEDLINE (1990 to October 2003), International Pharmaceutical Abstracts (1970 to October 2003), and meeting abstracts of major HIV/AIDS conferences (1996-2003) using the search terms enfuvirtide, pentafuside, T-20, DP-178, and fusion inhibitor.In vitro, enfuvirtide exhibits activity against HIV-1 isolates that are resistant to all other classes of anti-retroviral medications. Enfuvirtide blocks the entry of HIV-1 into host cells by interfering with virus-cell fusion, making it unique among licensed antiretroviral medications. In human adults, enfuvirtide has a volume of distribution of 5.48 L, is highly bound to plasma protein (92%), has a plasma elimination half-life of 3.8 hours, and is catabolized by peptidases and proteinases in various tissues. Dose adjustment does not appear necessary on the basis of age, race, or body weight, but may be warranted in women weighing50 kg. A literature review did not identify any data on the disposition of enfuvirtide in patients with hepatic or renal insufficiency. Clinical trials suggest that enfuvirtide reduces plasma HIV-1 RNA levels in highly treatment-experienced patients taking an optimized antiretroviral regimen. Pivotal trials indicated a mean change in HIV-1 RNA of -1.48 log(10) copies/mL in the enfuvirtide arm at week 48, compared with -0.63 log(10) copy/mL in the control arm ( P0.001 ). The mean absolute increase on CD4 cell count was 46 cells/mm(3) (91 cells/mm(3)) in the enfuvirtide arm vs 45 cells/mm(3) in the control arm; P0.001 ). The most commonly reported (15 cases per 100 patient-years of exposure) adverse events (AEs) in clinical trials included injection-site reactions, diarrhea, nausea, fatigue, insomnia, peripheral neuropathy, headache, vomiting, and fever. The most commonly reported (or =2%) laboratory abnormalities (grade III or IV) were eosinophilia, anemia, and increases in amylase, lipase, triglycerides, creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase. In clinical trials, serious AEs leading to study discontinuation occurred in 12.9% ( 114/885 ) of patients in the enfuvirtide arm, compared with 10.7% ( 12/112 ) in the control arm ( P = NS ). The recommended dosage of enfuvirtide is 90 mg SC BID in adults and 2 mg/kg SC BID in children. Efficacy studies in children are ongoing.Although additional studies are needed, enfuvirtide appears to be a promising agent, in combination with other antiretroviral agents, for the treatment of HIV infection in treatment-experienced patients.

Background: Tenofovir disoproxil fumarate (DF) is the first nucleotide reverse transcriptase inhibitor approved for use in combination with other antiretroviral agents in the treatment of HIV-1 infection in the United States. Unlike the nucleoside reverse transcriptase inhibitors, which must undergo 3 intracellular phosphorylation steps for activation, nucleotide analogues such as tenofovir require only 2 such steps. This reduction in the phosphorylation requirement has the potential to produce more rapid and complete conversion of the drug to its pharmacologically active metabolite. Objective: This article describes the pharmacologic properties and potential clinical usefulness of tenofovir DF. Methods: Relevant information was identified through searches of MEDLINE (1996–April 2002), Iowa Drug Information Service (1996–April 2002), and International Pharmaceutical Abstracts (1970–April 2002), as well as from meeting abstracts of major HIV/AIDS conferences (1996–2002), using the search terms enofovir, tenofovir disoproxil fumarate, PMPA, bis(POC)PMPA, GS-4331-05, acyclic nucleoside phosphonate , and nucleotide reverse transcriptase inhibitor . Additional information was obtained from material submitted to the US Food and Drug Administration by the manufacturer of tenofovir DF in support of its New Drug Application. Results: In vitro, tenofovir DF has exhibited anti-HIV activity in various HIV-infected cell lines and has produced a synergistic or additive effect against HIV when combined with other antiretroviral agents. In adult humans, tenofovir has a volume of distribution of 0.813 L/kg, is minimally bound to plasma protein (7.2%), has a plasma elimination half-life of 12.0 to 14.4 hours, and is mainly excreted unchanged in urine (70%–80%). Dose adjustment based on sex or body weight does not appear to be necessary, although dose reduction may be necessary in the elderly; there are currently no data on tenofovir DF in renal or hepatic insufficiency. The results of clinical trials suggest the efficacy of tenofovir DF in reducing plasma levels of HIV-1 RNA when used as an add-on to a stable antiretroviral regimen. The most commonly (⪢3%) reported adverse events in clinical trials have included nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdominal pain, and anorexia. The most commonly (⪢2%) reported laboratory abnormalities (grade III or IV) included increases in creatine kinase, triglycerides, amylase, aspartate aminotransferase, and alanine aminotransferase, as well as hyperglycemia and glucosuria. Serious adverse events leading to discontinuation of tenofovir DF were infrequent (5%), occurring with an incidence similar to that with placebo (8%). The recommended dosage of tenofovir DF in adults is 300 mg/d PO; pharmacokinetic and efficacy studies in children are ongoing. Conclusion: Although additional studies are needed, tenofovir DF appears to be a promising agent for the treatment of HIV infection.

This paper reviews the pharmacologic properties and clinical usefulness of amprenavir, a new human immunodeficiency virus type 1 (HIV-1) protease inhibitor.Amprenavir, the most recent HIV-1 protease inhibitor to receive marketing approval from the US Food and Drug Administration, is a potent competitive inhibitor of HIV-1 protease and a relatively weak inhibitor of HIV-2 protease. Inhibition of the HIV-1 protease enzyme results in immature and noninfectious viral particles. Amprenavir is rapidly absorbed following oral administration. The time to peak concentration (Tmax) in adults is between 1 and 2 hours, the area under the plasma concentration versus time curve is roughly proportional to the dose, the half-life is approximately 8 hours, and the volume of distribution is approximately 430 L. The Tmax in children 4 to 12 years of age is between 1.1 and 1.4 hours. The bioavailability of the solution is 86% relative to the capsule formulation. It is metabolized by the cytochrome P-450 isozyme CYP3A4 and to a lesser extent by CYP2D6 and CYP2C9.We searched MEDLINE (1966 to January 2000), AIDSLINE (1980 to January 2000), International Pharmaceutical Abstracts (1970 to January 2000), PharmaProjects (January 2000 version), and Web sites of major HIV/acquired immunodeficiency syndrome conferences for appropriate published references (1996 to February 2000).Data reported to date indicate that amprenavir is efficacious in the treatment of HIV disease in patients with primary HIV infection, antiretroviral-naïve patients, protease inhibitor-naïve patients, protease inhibitor-experienced patients, and pediatric patients. Adverse effects were usually of early onset (range, 2 to 21 days) and transient (range, 3 to 46 days), although the incidence of metabolic abnormalities such as lipodystrophy, hyperlipidemia, and diabetes mellitus has not yet been defined. Amprenavir should be avoided in patients with a known sulfonamide allergy. Concomitant use of other medications that are CYP3A4 inducers or inhibitors should be done cautiously and only if the potential benefit clearly outweighs potential risk. The dose should be reduced in patients with significant hepatic impairment (Child-Pugh score,or = 5). Amprenavir probably should not be administered with rifabutin, rifampin, astemizole, midazolam , triazolam, bepridil, dihydroergotamine, ergotamine, or cisapride. The recommended adult dose is 1200 mg twice daily. For patients between 4 and 12 years of age or between 13 and 16 years of age who weigh50 kg, the recommended dosage of the capsule form is 20 mg/kg (22.5 mg/kg for oral solution) twice daily or 15 mg/kg (17 mg/kg for oral solution) 3 times a day to a maximum dose of 2400 mg (2800 mg for oral solution). Patients should not take vitamin E supplements because amprenavir is formulated with a large amount of vitamin E (109 IU/capsule and 46 IU/mL oral solution) to improve oral absorption. Amprenavir may be administered with or without food, but a high-fat meal (67 g fat) should be avoided.Published clinical data are limited, but amprenavir appears to be efficacious and generally well tolerated in patients with HIV infection. Pharmacoeconomic data are not yet available. The introduction of amprenavir appears to be important, since it provides an additional treatment option as a component of both initial and salvage combination therapies for patients with HIV.

Toxoplasma gondii is an obligate intracellular parasitic protozoan that infects a variety of warm-blooded animals, including humans. Infection is usually asymptomatic in immunocompetent individuals but may be devastating in immunocompromised individuals such as those with acquired immunodeficiency syndrome (AIDS). Clinical manifestations of infection in immunocompromised patients include the development of encephalitis. It has been estimated that approximately 30% of patients with AIDS who are latently infected will eventually develop toxoplasmic encephalitis. The most common regimen used to treat toxoplasmic encephalitis is a combination of pyrimethamine 50 to 100 mg/d and sulfadiazine 4 to 8 g/d, with or without folinic acid 10 mg/d. This regimen, however, commonly leads to adverse effects or relapses. Other pharmacologic approaches include the use of clindamycin rather than sulfadiazine, the macrolide antibiotics, atovaquone, 5-fluorouracil, trimethoprim/sulfamethoxazole, minocycline or doxycycline, trimetrexate with folinic acid, dapsone, rifabutin, pentamidine, and diclazuril. None of these alternative regimens has been proven to be more effective than the standard pharmacologic therapy. An evolving approach is the use of immunotherapy, such as interleukin-2, -6, and -12; interferon-gamma; and alpha-tumor necrosis factor. Restoring a competent immune system may be the only cure for toxoplasmosis and other opportunistic infections.