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Horatio B Fung

Publications and source records attributed to Horatio B Fung.

11 recordsLinked to original sources
PubMed2006

Tigecycline: a glycylcycline antimicrobial agent.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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 of >80% (P < 0.001 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. CONCLUSIONS: 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.

Animals↗
PubMed2005

Tinidazole: a nitroimidazole antiprotozoal agent.

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 pharmacologic and 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 against pathogenic 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((1/2)) of 12.3 hours, and was eliminated primarily by hepatic metabolism (approximately 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 < 0.05) and amebiasis (P < 0.05). The most commonly reported (>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 promising agent 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.

Antiprotozoal Agents↗
PubMed2004

Daptomycin: a cyclic lipopeptide antimicrobial agent.

OBJECTIVES: The aims of this article were: to summarize the pharmacology, pharmacokinetics, and efficacy of daptomycin; 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 International Pharmaceutical 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/kg IV 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 L/kg and a plasma elimination half-life of approximately 9 hours, and is eliminated primarily by renal excretion (approximately 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.

Animals↗
PubMed2004

Enfuvirtide: a fusion inhibitor for the treatment of HIV infection.

BACKGROUND: 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. OBJECTIVE: This paper describes the pharmacologic properties and clinical usefulness of enfuvirtide. METHODS: 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. RESULTS: 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 weighing <50 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 ( P<0.001 ). 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; P<0.001 ). 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. CONCLUSION: 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.

Clinical Trials as Topic↗
PubMed2004

Fatal lactic acidosis associated with coadministration of didanosine and tenofovir disoproxil fumarate.

Lactic acidosis is an uncommon but potentially life-threatening adverse effect of didanosine. When given concomitantly with tenofovir disoproxil fumarate (DF), the area under the concentration-time curve of didanosine is increased by 48-60%. A 63-year-old man with human immunodeficiency virus (HIV) infection tolerated several didanosine-containing antiretroviral regimens. He developed generalized weakness, loss of appetite, weight loss, nausea, and vomiting 1.5 years after tenofovir DF was added to his didanosine-containing regimen. He was diagnosed with lactic acidosis and died after a 13-day hospital stay, when his lactate level increased to 189.7 mg/dl and his arterial blood gas pH value fell to 6.75. Health care providers should maintain a high index of suspicion for lactic acidosis in patients with HIV infection who receive didanosine and tenofovir DF concurrently. For patients receiving antiretroviral regimens containing this drug combination, it would be prudent to monitor lactate levels periodically. This is especially important when patients experience symptoms suggestive of lactic acidosis, such as weakness, abdominal pain, weight loss, nausea and vomiting, and shortness of breath.

Acidosis, Lactic↗
PubMed2003

Voriconazole.

BACKGROUND: 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. OBJECTIVE: This article reviews the pharmacologic and pharmacokinetic properties and clinical usefulness of voriconazole. METHODS: 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. RESULTS: 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 clearance <50 mL/min due to the potential accumulation of the solubilizing excipient in the parenteral formulation of voriconazole. CONCLUSIONS: 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.

Animals↗
PubMed2003

A practical guide to the treatment of complicated skin and soft tissue infections.

Complicated skin and soft tissue infections (SSTIs) remain a common reason for hospitalisation. Optimal management of complicated SSTIs begins with a physical examination, and obtaining the complete social and medical history of the patient. Empirical intravenous antibacterial therapy is guided by expected pathogens, patient factors and diagnostic procedure reports, such as the Gram-stained smear of discharge or exudates. The majority of community-acquired SSTIs are caused by Staphylococcus aureus and beta-haemolytic streptococci. On the basis of recent surveillance data, 80-90% of these pathogens remain susceptible to cefazolin or oxacillin. Consequently, a first generation cephalosporin or an antistaphylococcal penicillin remains the first line empirical therapy for community-acquired skin and soft tissue infections. Vancomycin may be an appropriate alternative when vancomycin-resistant S. aureus is highly suspected on the basis of patient history and co-morbid conditions. With the global emergence and spread of macrolide-resistant S. aureus and beta-haemolytic streptococci, clindamycin rather than a macrolide is the recommended agent for empirical antibacterial therapy of community-acquired SSTIs in penicillin-allergic patients. Nosocomial complicated SSTIs are predominantly caused by S. aureus, Pseudomonas aeruginosa, Enterococcus spp., Escherichia coli and other Enterobacteriaceae. Piperacillin/tazobactam with or without vancomycin is the preferred agent for empirical treatment depending on local resistance statistics. The newer fluoroquinolones may have a role in the treatment of complicated SSTIs, especially in penicillin-allergic patients. More clinical studies are needed before a formal recommendation can be made. Many of the newer antimicrobial agents such as the carbapenems, oxazolidinones and streptogramins have been shown to be effective for the treatment of complicated SSTIs. However, because of their proven activity against highly resistant organisms including methicillin-resistant S. aureus and vancomycin-resistant enterococci (oxazolidinones and streptogramins), and Gram-negative bacilli producing extended spectrum beta-lactamases (carbapenems), these antibacterials should be reserved for life-threatening situations and/or when resistant pathogens are suspected. Complicated skin and soft tissue infections are often associated with exudates, ulcerations, fluid collections or abscesses. Adequate debridement of devitalized tissues and drainage of abscesses and fluid collections in addition to systemic antibacterial therapy is an integral part of appropriate management.

Animals↗
PubMed2002

Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection.

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 tenofovir 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.

Adenine↗
PubMed2002

Caspofungin: an echinocandin antifungal agent.

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 beta-(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 < or =1 microg/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.

Aged↗