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Cubicin (daptomycin)Comment
Daptomycin is the first of a new class of antibiotics, the cyclic lipopeptides. It exerts bactericidal action via depolarization of the cell membrane in a rapid (<1 hour) and concentration-dependent manner with a post-antibiotic effect. It possesses broad activity against Gram-positive pathogens, such as Streptococcus, Staphylococcus (including methicillin-resistant isolates), and Enterococcus faecalis/E. faecium (including vancomycin-resistant isolates). Daptomycin is currently approved by FDA for the treatment of 1) complicated skin and skin structure infections (4 mg/kg/day) caused by S. aureus (including methicillin-resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiaesubspecies equisimilis, and Enterococcus faecalis (vancomycin-susceptible isolates only), and 2) S. aureus bacteremia (6 mg/kg/day), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates. Because daptomycin is inactivated by surfactant in the lung, so it should not be used for the treatment of respiratory infections. Daptomycin has no interaction with P450 cytochrome. It is mainly excreted unchanged in the urine, and the dosing interval should be increased from 24 h to 48 h in patients with a creatinine clearance below 30 ml/min. The specific adverse drug reaction of daptomycin is its reversible elevation of creatinine phosphokinase (CPK) isoenzymes released by the skeletal muscle. At 4 mg/kg/day, the reported incidence of CPK elevation was 2.5% and myopathy 0.2%. Weekly CPK level monitoring is recommended in patients receiving daptomycin.
Clinical Trials
Daptomycin is as effective and safe as vancomycin and semisynthetic penicillins for the treatment of SSTIs while fewer patients with complicated SSTI receiving daptomycin required prolonged treatment and had faster clinical cure in 2 of the 4 analyzed studies.
Daptomycin demonstrated concentration-dependent killing in vitro, and this study presented the safety of daptomycin at a mean dose of 8 mg/kg for a median duration of 25 days.
This retrospective study showed comparable microbiological cure rates, relapse rates and mortality of vancomycin-resistant enterococcal bacteremia between linezolid and daptomycin.
Once daily dosing of daptomycin is an attractive choice in the community setting, and this study provided the evidence for the outpatient daptomycin use in patients with S. aureus bacteremia and infective endocarditis.
Compared with vancomycin/gentamicin, daptomycin performed comparably well as the therapeutic agent for patients with MRSA bacteremia and right-sided endocarditis (success rates 44.4% vs. 32.6%, p>0.05).
Review This paper extensively reviewed recent in vitro antimicrobial susceptibility of vancomycin-resistant enterococci (VRE) and clinical trials/case series of new antibiotic treatments for infection due to VRE, and suggested daptomycin and tigecycline have promising role in treatment of VRE infection.
The article summarized ongoing trials of daptomycin and compared daptomycin with other new anti-Gram-positive antibiotics.
This paper reviewed current clinical evidence of daptomycin as the therapeutic agent for the treatment of staphylococcal infections.
Adverse Drug Reactions and Warnings
Zmax or Zithromax (azithromycin)
Commentary Azithromycin belongs to macrolides and exerts antibacterial activity through inhibition of microbial protein synthesis by binding to the 50S ribosomal subunit of susceptible pathogens. Azithromycin has oral immediate release or intravenous formulations as Zithromax®. Zmax® is a novel extended-release oral formulation of azithromycin, and allows for single-dose administration. Zmax® is pharmacokinetically bioequivalent to and interchangeable with the immediate-release oral Zithromax®. Zmax® achieves higher intracellular concentrations in mononuclear and polymorphonuclear leukocyte and alveolar cells, and higher tissue/fluid concentrations in lung serum, tissue and epithelial lining fluid than in serum. Additionally, azithromycin concentrations of Zmax® in these compartments are generally higher than those achieved with the immediate-release oral Zithromax®.
Zmax® is FDA approved for 1) mild to moderate acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae, and 2) community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in adults and pediatrics aged 6 months and over deemed appropriate for oral therapy.
Zithromax® is indicated in adults for infection of 1) lower respiratory tract (acute bacterial exacerbations of chronic obstructive pulmonary disease and community-acquired pneumonia of mild severity in patients appropriate for outpatient oral therapy); 2) upper respiratory tract (streptococcal pharyngitis/tonsillitis); 3) uncomplicated skin and skin structure infections; 4) sexually transmitted diseases (urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae; genital ulcer disease in men due to Haemophilus ducreyi); 5) prophylaxis and treatment of disseminated Mycobacterium avium complex (MAC) Disease. For pediatric patients, Zithromax® is indicated for acute otitis media and community-acquired pneumonia in patients appropriate for outpatient oral therapy. Bacteria acquire resistance to azithromycin via efflux of the drug from the cell (mutations in the mefA gene) or alterations in the drug target site (mutations in the ermB gene). Generally, bacteria that are resistant to erythromycin are cross-resistant to azithromycin. In various US surveillance studies, S. pneumonia azithromycin resistance rates were 27.5%-31%, similar to that of erythromycin and clarithromycin. Compared with other macrolides, azithromycin does not interact with drugs metabolized by CYP3A4, and this applies to both Zmax® and Zithromax®. The most frequent adverse events are diarrhea or loose stools.
Clinical Trials This trial enrolled 358 children and adult and 80% of them were culture confirmed cases. Both azithromycin and gatifolxacin had equivalent safety and efficacy in terms of resolution of fever and overall treatment success (90.7% vs. 91%) while the cost of azithromycin was higher in Vietnam. This prospective, randomized and open-label multicentre clinical trial demonstrated that an intravenous-to-oral regimen of ceftriaxone/azithromycin had equivalent efficacy and safety as the comparator regimen did. The mean length of hospital stay was shorter for patients receiving ceftriaxone/azithromycin if the identified pathogens were atypical or atypical and conventional.
In this a retrospective cohort study of pregnant women with genital chlamydial infection, rates of test-of-cure was significantly higher in those treated with azithromycin than erythromycin, and no difference existed in complications for women or infants between azithromycin and other regimens. In this large, randomized, controlled trial, patients in azithromycin arm had equivalent eradication rate and no bacterial recurrence as those in erythromycin group did, but had less nausea, vomiting, and diarrhea.
Review Articles Macrolides beyond the conventional antimicrobials: a class of potent immunomodulators. Giamarellos-Bourboulis EJ. Int J Antimicrob Agents. 2008 Jan;31(1):12-20. Epub 2007 Nov 1.This article summarized the anti-inflammatory modes of actions of macrolies and reviewed experimental studies and clinical trials that evaluated the effects of macrolides on chronic inflammatory disorders of the lower respiratory tract, such as cystic fibrosis, and acute inflammatory conditions. Azithromycin extended release: a review of its use in the treatment of acute bacterial sinusitis and community-acquired pneumonia in the US. Swainston Harrison T, Keam SJ. Drugs. 2007;67(5):773-92.The article comprehensively reviewed the pharmacodynamic and pharmacokinetic profiles, clinical trials and indications, and tolerability of azithromycin extended release formulation. Its role in treatment of acute bacterial sinusitis and community-acquired pneumonia in the US was also discussed. In this review, compared with fluoroquinolones, azithromycin significantly reduced clinical failure and duration of hospital stay in patients with uncomplicated enteric fever, including those with multiple-drug-resistant or nalidixic acid-of resistant strains of S. Typhi or S. Paratyphi. Compared with ceftriaxon, azithromycin significantly reduced relapse.
This review described recent changes in the burden of pertussis, its different clinical presentations in infants and adolescents, performance of diagnostic tools, and prophylaxis and treatment. Azithromycin and clarithromycin, instead of erythromycin, were recommended as first-line treatment due to equivalent efficacy and better tolerance with improved compliance. Prevention and treatment of sexually transmitted diseases: an update. Van Vranken M. Am Fam Physician. 2007 Dec 15;76(12):1827-32. Review.This article summarized the recent changes in The Centers for Disease Control and Prevention revised guidelines for the prevention and treatment of sexually transmitted diseases. Currently, azithromycin (Zithromax) is recommended as a first-line treatment for Chlamydia trachomatis infection during pregnancy and close follow-up is required if azithromycin is used as an alternative treatment in the management of primary or secondary syphilis due to increasing resistance.
Adverse Drug Reactions and Warnings FDA Information Manufacturer/Distributor Product Information ISENTRESS (raltegravir)
Commentary Raltegravir is the first approved HIV integrase inhibitor, and is indicated in the treatment of HIV infection in combination with other antiretroviral agents in treatment-naive patients and treatment-experienced patients with evidence of HIV replication despite ongoing antiretroviral therapy. Raltegravir is active against HIV-2 and a wide range of wild-type and drug-resistant HIV-1isolates, including both CCR5 coreceptor–using strains and CXCR4 coreceptor–using strains. Additive to synergistic activity against HIV-1 was observed when raltegravir was combined with other antiretroviral agents. Raltegravir is metabolized through glucuronidation, and drugs inducing glucuronidation enzyme, UGT1A1, such as rifampin, significantly reduce raltegravir concentration and should not be used. Phenytoin and Phenobarbital also have similar effects, but this has not been well investigated. Despite interactions between raltegravir and selected antiretroviral drugs, such as tenoovir, efaviranz, etravirine, atazanavir, ritonavir, tipranavir, none of these interactions are thought be clinical significant. It has been confirmed that significant resistance to raltegravir is the consequence of multiple integrase gene substitutions. Three main drug-resistance pathways associated with treatment failure has been demonstrated. Although clinical data on cross-resistance to other integrase inhibitor, such as elvitegravir, are lacking, certain resistance pathways produce high-level phenotypic resistance to both drugs. The most common adverse events were transient mild-to-moderate headache and fatigue. A higher percentage of grade 3 and 4 creatine phosphokinase elevations while less significant changes in lipid levels has been reported in the raltegravir arm than in the efavirenz arm over 96 weeks. To date, no strong evidence supports raltegravir is associated with the development of malignancies despite mildly higher incidence of cancer in the early report.
Clinical Trials Compared with placebo plus optimized background regimen, raltegravir plus optimized background regimen demonstrated significantly better efficacy on sustained virologic suppression and comparable incidence of serious drug-related adverse events, death, and cancer through week 96 in triple class–resistant HIV-infected patients.
Substituting raltegravir for enfuvirtide demonstrated noninferiority in maintenance of virologic suppression and lower incidence of great III/IV laboratory abnormalities and adverse events through week 24 following switch. Switching from stable lopinavir/ritonavir-based to raltegravir-based combination antiretroviral therapy improved lipid profiles but did not show non-inferior virologic efficacy. Compared with placebo plus optimized background regimen, raltegravir plus optimized background regimen demonstrated significantly greater efficacy on sustained virologic suppression and similar incidence of serious drug-related adverse events through week 48 in triple class–resistant HIV-infected patients.
Review Articles This article concisely summarized current publications of raltegravir regarding its clinical pharmacology, drug interactions, clinical trials, safety, toxicities, drug resistances, and clinical uses. Development of malignancies has been a concern of raltegravir use, and this extensive review demonstrated no difference in risk for cancer in HIV-positive patients treated with raltetravir or other antiretroviral therapy by summarizing the cancer rates from available data of multiple clinical studies.
Adverse Drug Reactions and Warnings
Manufacturer/Distributor Product Information
VFEND (voriconazole)
Commentary Voriconazole is a synthetic second generation, broad-spectrum triazole derivative of fluconazole. It exerts antifungal activities by inhibiting the cytochrome P450 (CYP)-dependent enzyme 14-α-sterol demethylase, and subsequently disrupting the cell membrane and halting fungal growth. Its FDA indications include 1) invasive aspergillosis caused by Aspergillus fumigatus or species of Aspergillus other than A. fumigatus; 2) candidemia in nonneutropenic patients and disseminated candidiasis in skin and infections in abdomen, kidney, bladder wall, and wounds; 3) esophageal candidiasis; and 4) serious fungal infections caused by Scedosporium apiospermum (asexual form of Pseudallescheria boydii) and Fusarium spp., including Fusarium solani, in patients intolerant of, or refractory to, other therapy. Voriconazole is fungicidal against Aspergillus species, and also shows excellent activity against A. terreus. Voriconazole demonstrated superior to amphotericin B deoxycholate as the first-line treatment of invasive aspergillosis in a nonblind and noninferiority trial. Voriconazole exhibits fungistatic but excellent activity against most Candida spp. which is mostly better than anti-Candida activity of fluconazole. In addition, voriconazole also has good activity against C. glabrata, C. krusei, and C. guilliermondii. Voriconazole has good to excellent in vitro activity against Fusarium spp. and Scedosporim spp. However, it has little or no activity against zygomycetes. Voriconazole exhibits nonlinear pharmacolinetics, and undergoes metabolism by hepatic CYP2C19 (major), CYP3A4 and CYP2C9 isonezymes. Accordingly, liver disease, age, genetic polymorphism of CYP2C19, and concurrent medications may greatly affect voriconazole metabolism. Voriconazole has demonstrated approximately 100-fold variability in drug levels for individuals receiving the same dosage. Recent clinical observations have suggested that such variability may be associated with decreased efficacy or toxicity, raising the importance of voriconazole therapeutic drug monitoring. Voriconazole is available in both parenteral and oral formulations. Systemic absorption of oral voriconazole is rapid and complete (bioavailability achieving 96%), but is reduced in the fed state. Because its intravenous vehicle (sulfobutylether-cyclodextrin, SBECD) accumulates in patients with moderate renal impairment, those with a creatinine clearance of < 50mL/min should receive only oral voriconazole. Voriconazole is generally well tolerated, and the most common adverse events were visual disturbance (20.6%, such as blurriness, color changes, and enhanced vision) and elevated transaminase levels (13%).
Clinical Studies In this 9-year retrospective study, patients with invasive aspergillosis receiving voriconazole had better survivals than those receiving polyenes, although advances in medicine might have certain contributions. Several predictors of increased overall mortality were identified for designing better treatment strategies.
A study supported prior clinical observations that levels of voriconazole were related to its efficacy and safety. The study also demonstrated clinical improvement by level adjustments.
Universal voriconazole prophylaxis significantly decreased the rate of invasive aspergillosis from 23.5% in lung transplant recipients receiving targeted prophylaxis to 1.5%. Of note, voriconazole was discontinued due to side effects in 14% of the cases.
Combination therapy with voriconazole and caspofungin as primary therapy significantly improved survival of invasive aspergillosis in solid organ transplant recipients with renal failure and disease caused by A. fumigatus.
Review Articles In the article, publications of drug-drug interactions of azole with other agents were comprehensively reviewed, and managements for specific interactions were suggested.
The article reviewed available publications that supported therapeutic monitoring voriconazole concentrations. Despite unstandardized therapeutic range for voriconazole, trough concentrations of approximately 1-6 µg/mL were recommended in most studies.
Voriconazole is recommended as the first-line choice for aspergillosis in this updated and comprehensive guideline.
Adverse Drug Reactions and Warnings
Manufacturer/Distributor Product Information
AmBisome (liposomal amphotericin B)Comments Liposomal amphotericin B comprises spherical unilamellar liposomes which are composed of hydrogenated soy phosphatidylcholine, cholesterol, distearoyl-phophatidylglycerol and amphoterin B. Its FDA indications include 1) empirical therapy for presumed fungal infection in febrile, neutropenic patients; 2) treatment of cryptococcal meningitis in HIV-infected patients; 3) treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate; 4) treatment of visceral leishmaniasis. Liposomal amphotericin B is active against Aspergillus spp. except for some isolates of Aspergillus terreus, Candida spp. except for Candida lusitaniae, Cryptococcus neoformans, Blastomyces dermatitidis, Pseudallescheria boydii, Malassezia furfur, Fusarium spp., and zygomycetes. Liposomal amphotericin B is not active against Trichosporon beigelii. Compared with other lipid formulations of amphotericin B, liposomal amphotericin B has significantly less nephrotoxicity, fewer infusion-related side effects, and better brain penetration than other lipid formulations. Thus, it can be used safely and repeatedly at high doses to treat brain and other difficult-to-treat infections, such as zygomycosis. However, it is also the most expensive agent among all the lipid formulations of amphotericin B. Anaphylaxis has been reported in all amphotericin B preparations, including liposomal amphotericin B. Nevertheless, liposomal amphotericin B has a lower incidence of infusion-related reactions, hypokalemia, and various events related to decreased renal function than amphotericin B deoxycholate. liposomal amphotericin B has the potential to increase digitalis toxicity and enhance curariform effect of skeletal muscle relaxants due to amphotericin-induced hypokalemia, results in additive nephrotoxicity when other nephrotoxic agents are co-administered, and leads to additive hypokalemia with concurrent diuretic use.
Clinical Trials Invasive Fungal Infection Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Löwenberg B, Vulto A, Lugtenburg PJ, de Marie S. Clin Infect Dis. 2008 May 1;46(9):1401-8.
Prophylactic inhalation of liposomal amphotericin B significantly reduced the incidence of invasive pulmonary aspergillosis in patients with prolonged neutropenia.
Raad II, Hanna HA, Boktour M, Jiang Y, Torres HA, Afif C, Kontoyiannis DP, Hachem RY. Leukemia. 2008 Mar;22(3):496-503. Epub 2007 Dec 20. Salvage therapy of invasive aspergillosis with posaconazole demonstrated greater efficacy and safety than that with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, Heussel CP, Lortholary O, Rieger C, Boehme A, Aoun M, Horst HA, Thiebaut A, Ruhnke M, Reichert D, Vianelli N, Krause SW, Olavarria E, Herbrecht R; AmBiLoad Trial Study Group. Clin Infect Dis. 2007 May 15;44(10):1289-97. Favorable responses and survival rates at 12 weeks were similar between patients with invasive mold infection receiving high-loading dose regimen and standard dosing while higher rates of nephrotoxicity in those receiving high-loading dose regimen.
Caillot D, Thiébaut A, Herbrecht R, de Botton S, Pigneux A, Bernard F, Larché J, Monchecourt F, Alfandari S, Mahi L. Cancer. 2007 Dec 15;110(12):2740-6.
Patients with invasive aspergillosis receiving combination therapy with liposomal amphotericin B and caspofunging at the standard dose have significantly more favorable overall responses of than those treated with monotherapy with high-dose liposomal amphotericin B.
Visceral leishmaniasis New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine.Sundar S, Rai M, Chakravarty J, Agarwal D, Agrawal N, Vaillant M, Olliaro P, Murray HW. Clin Infect Dis. 2008 Oct 15;47(8):1000-6. The cure rates of visceral leishmaniasis at 9 months post-treatment were similar in patients receiving liposomal amphotericin B for 15 days and those receiving single-dose liposomal amphotericin B (5 mg/kg or 3.75 mg/kg) followed by miltefosine for 10 or 14 days.
Review Immunocompromised hosts: immunopharmacology of modern antifungals. Ben-Ami R, Lewis RE, Kontoyiannis DP. Clin Infect Dis. 2008 Jul 15;47(2):226-35. An intriguing discussion of the anti-inflammatory properties of the liposomes of liposomal amphotericin B
Liposomal amphotericin B: what is its role in 2008? Lanternier F, Lortholary O. Clin Microbiol Infect. 2008 May;14 Suppl 4:71-83. Detailed description of the unique properties of liposomal amphotericin B in the modern antifungal era.
Amphotericin B lipid preparations: what are the differences? Adler-Moore JP, Proffitt RT. Clin Microbiol Infect. 2008 May;14 Suppl 4:25-36. Comprehensive comparisons among different lipid formulations of amphotericin B, primarily liposomal amphotercin B and amphotericin B lipid complex
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