Gary E. Stein

Tigecycline: A Critical Analysis

Tigecycline (GAR-936) is the first glycylcycline antibiotic to be approved by the US Food and Drug Administration (FDA). The drug overcomes the 2 major resistance mechansisms of tetracycline: drug-specific efflux pump acquisition and ribosomal protection. Tigecycline is active against many gram-positive and -negative organisms, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and -resistant enterococci, and extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. It is also active against many anaerobic bacteria, as well as atypical pathogens, including rapidly growing, nontuberculous mycobacteria. Tigecycline is concentrated in cells and is eliminated primarily via biliary excretion. Diminished renal function does not significantly alter its systemic clearance. Furthermore, tigecycline does not interfere with common cytochrome P450 enzymes, making pharmacokinetic drug interactions uncommon. It provides parenteral therapy for complicated skin/skin-structure and intra-abdominal infections. The only prominent adverse effects are associated with tolerability, most notably nausea and vomiting. Tigecycline will be most useful as empirical therapy for polymicrobial infections, especially in cases in which deep tissue penetration is needed or in which multidrug-resistant pathogens are suspected.

Ceftaroline: A Novel Cephalosporin with Activity against Methicillin-resistant Staphylococcus aureus

Ceftaroline (PPI 0903, formerly TAK-599), the active metabolite of a N-phosphono prodrug, ceftaroline fosamil, has been approved by the US Food and Drug Administration for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. This antimicrobial agent binds to penicillin binding proteins (PBP) inhibiting cell wall synthesis and has a high affinity for PBP2a, which is associated with methicillin resistance. Ceftaroline is consistently active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus, including methicillin-resistant, vancomycin-intermediate, linezolid-resistant, and daptomycin-nonsusceptible strains. It possesses variable activity against Enterobacteriaceae and good activity against oral anaerobes. The drug is usually administrated intravenously at 600 mg every 12 h. Ceftaroline has low protein binding and is excreted by the kidneys and thus requires dose adjustments in individuals with renal failure. Clinical trials have demonstrated noninferiority when compared with vancomycin in the treatment of acute bacterial skin and skin structure infections and noninferiority when compared with ceftriaxone in the treatment of community-acquired bacterial pneumonia. Ceftaroline demonstrated a safety profile similar to that of comparator drugs in clinical trials.

Single oral dose fluconazole compared with conventional clotrimazole topical therapy of Candida vaginitis

OBJECTIVES Candida vaginitis is currently treated with a wide range of intravaginal preparations usually prescribed over several days. Fluconazole with its marked activity against Candida species and favorable pharmacokinetics offered a safe, effective, and convenient alternative to topical therapy in a single-dose regimen. STUDY DESIGN We conducted a multicenter, randomized, prospective, single-blinded study of 429 patients with acute Candida vaginitis, comparing the efficacy and safety of a single oral 150 mg dose of fluconazole with 7-day clotrimazole 100 mg vaginal treatment. Posttherapy evaluations and mycologic eradication rates were conducted. RESULTS No statistically significant differences were seen between fluconazole and clotrimazole in the clinical, mycologic, or therapeutic responses. At the 14-day evaluation clinical cure or improvement was seen in 94% of fluconazole-treated patients and 97% of clotrimazole-treated patients. Mycologic and therapeutic cures were seen in 77% and 76% of the fluconazole and 72% of the clotrimazole groups, respectively. At the 35-day evaluation 75% of both groups remained clinically cured, and 56% of the fluconazole and 52% of the clotrimazole group were considered therapeutic cures. In both treatment groups patients with a history of recurrent vaginitis (33/84) compared with those without a history of recurrent vaginitis (177/266) were significantly less likely to respond clinically and mycologically (p < 0.001). Twenty-seven percent of the fluconazole-treated patients and 17% of the clotrimazole-treated patients reported mild side effects only. CONCLUSION Fluconazole administered as a single 150 mg oral dose proved to be as safe and effective as 7 days of intravaginal clotrimazole therapy for Candida vaginitis. Therapy of vaginitis should be individualized, taking into consideration severity of disease, history of recurrent vaginitis, and patient preference.

Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection

This multicenter clinical trial compared single-dose fosfomycin tromethamine with a 7-day course of nitrofurantoin for the treatment of acute uncomplicated lower urinary tract infection (UTI) in female patients. Healthy females with symptoms of acute uncomplicated UTI were enrolled in a double-masked, randomized clinical trial. Assessable patients had >10(5) colony-forming units per milliliter of a uropathogen in a clean-voided midstream urine sample. Patients received a single 3-g dose of fosfomycin tromethamine plus 7 days of placebo capsules or a single 3-g dose of placebo plus 7 days of nitrofurantoin monohydrate/macrocrystal 100-mg capsules. Treatment efficacy was assessed by both bacteriologic and clinical response 5 to 11 days after the initial treatment dose (visit 2) and 5 to 11 days (visit 3) and 4 to 6 weeks (visit 4) after the last day of medication. Of the 749 patients initially enrolled in the study, 375 received fosfomycin and 374 received nitrofurantoin. There were no clinical differences in patient characteristics between the 2 groups at study entry. Overall, 94% of pretreatment isolates were susceptible to fosfomycin and 83% were susceptible to nitrofurantoin. Bacteriologic cure rates at the first follow-up visit (5 to 11 days after initiation of treatment) were 78% and 86% for fosfomycin and nitrofurantoin, respectively (P = 0.02). At visit 3 (1 week posttreatment), they were 87% and 81% for fosfomycin and nitrofurantoin, respectively (P = 0.17). Both treatment groups had an 80% overall clinical success rate (cure and improvement). Twenty patients (5.3%) who received fosfomycin and 21 patients (5.6%) who received nitrofurantoin reported an adverse effect related to study medication. The most common side effects related to fosfomycin treatment were diarrhea (2.4%), vaginitis (1.8%), and nausea (0.8%). Both bacteriologic and clinical cure rates observed with a single 3-g dose of fosfomycin were comparable to those achieved with a 7-day course of nitrofurantoin in female patients with acute uncomplicated UTI.

Telavancin: A Novel Lipoglycopeptide

Telavancin, a derivative of vancomycin, is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of complicated skin and skin-structure infections. It has also been effective in the treatment of gram-positive pneumonia. This antibiotic has a dual mechanism of action by inhibiting peptidoglycan synthesis and causing membrane depolarization. Telavancin is consistently active against Staphylococcus aureus, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus, linezolid-resistant S. aureus, and daptomycin-nonsusceptible strains. The drug is usually administrated intravenously at 10 mg/kg every 24 h. Telavancin is excreted by the kidneys, and thus, dosage adjustments are required in cases of renal failure. Clinical trials have demonstrated non-inferiority, compared with vancomycin, in the treatment of complicated skin and skin-structure infections and pneumonia. Telavancin is associated with higher rates of renal events, altered taste, nausea, and vomiting but lesser rates of pruritus and infusion-related events, compared with vancomycin.

The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid

Abstract Background: The rising prevalence of nosocomial methicillin-resistant Staphylococcus aureus (MRSA) and the recent emergence of community-associated MRSA are major clinical, public health, and economic challenges. MRSA is a leading cause of nosocomial pneumonia and complicated skin and soft-tissue infections (cSSTI). Vancomycin and linezolid are two commonly used antimicrobial agents with activity against Gram-positive pathogens, particularly MRSA, that are used to treat both nosocomial pneumonia and cSSTI. Recently, the therapeutic efficacy of vancomycin in the treatment of hospitalized patients with MRSA infections has been questioned due to the emergence of MRSA strains with reduced susceptibility to vancomycin together with concerns related to inadequate dosing and poor tissue penetration of the drug. Scope: A literature review was conducted to investigate the pharmacokinetics and pulmonary and tissue penetration of vancomycin and linezolid. Using MEDLINE and EMBASE, the most relevant articles in English published over the past 25 years (up to October 2008) were identified and summarized. Studies in human volunteers and adult patients that measured concentrations of antibiotic in serum, epithelial lining fluid (ELF), and tissue were selected for further review. Findings: For both drugs, pharmacokinetic studies were conducted in diverse patient populations and employed varying techniques to measure tissue concentrations. Vancomycin concentrations in ELF ranged from 5 to 25% of simultaneous plasma levels, while concentrations in whole homogenized lung tissue were slightly higher (24–41%). Distribution of vancomycin into soft tissue was variable. For linezolid, overall mean concentrations in ELF and in soft tissue were generally similar or higher than simultaneous plasma levels, although variability in tissue penetration across studies in healthy volunteers and patients was seen. Limitations: The studies included in this review vary greatly in their designs and patient populations; this, together with methodologic difficulties, limits the interpretation of the data. Conclusions: In the absence of clinical data correlating ELF concentrations and clinical outcome, the clinical significance of differences in pulmonary penetration of vancomycin and linezolid is unknown. Higher vancomycin serum concentrations may be necessary to achieve appropriate lung concentrations to optimize treatment outcomes. Linezolid demonstrates adequate penetration into lung and other soft issues with sustained concentrations above the minimum inhibitory concentrations for susceptible pathogens, including MRSA, for the majority of the dosing interval. Examination of the pharmacokinetic data adds insights not provided by the clinical trial data and together provides clinicians with a more comprehensive basis for selecting appropriate antimicrobial therapy for the treatment of serious MRSA infections.

Pharmacokinetics and Pharmacodynamics of Linezolid in Obese Patients with Cellulitis

BACKGROUND: Linezolid is an oxazolidinone antimicrobial with excellent oral bioavailability and tissue penetration and is active against multidrug-resistant skin/soft tissue pathogens. OBJECTIVE: To study the pharmacokinetics and antibacterial activity of linezolid against selective skin/soft tissue pathogens in obese patients. METHODS: We obtained multiple serum samples from 7 obese patients (>50% over their calculated ideal body weight) receiving oral linezolid 600 mg every 12 hours for treatment of cellulitis. Following a minimum of 3 doses, serum concentrations of linezolid were measured in each subject prior to (trough) and 1 and 6 hours after a dose. These samples were then tested against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (linezolid minimum inhibitory concentrations [MICs] 1.0, 2.0, 4.0 μg/mL) and one strain each of vancomycin-resistant Enterococcus faecium (VRE) (MIC 2.0 μg/mL), Bacteroides fragilis (MIC 2.0 μg/mL), and Peptostreptococcus magnus (MIC 1.0 μg/mL). Serum inhibitory titers (SITs) and bactericidal titers (SBTs) were measured at each time point, and the median activity for these 7 patients was calculated. RESULTS: Mean linezolid serum concentrations were 4.2, 12.3, and 7.2 μg/mL at these respective time points. Median SITs for 12 hours (100% of the dosing interval) were observed against each organism with the exception of the least susceptible strain of MRSA (MIC 4.0 μg/mL); serum inhibitory activity was observed only at the one-hour time point against this isolate. Furthermore, prolonged (⩾6 h) median SBTs were observed against one isolate of MRSA (MIC 1.0 μg/mL) as well as the strain of VRE and P. magnus. CONCLUSIONS: Serum concentrations of oral linezolid in this patient population were diminished compared with those of healthy volunteers, but still provided prolonged serum inhibitory activity against common pathogens associated with skin/soft tissue infections. One treatment concern would be an obese patient receiving oral linezolid who was infected with a less susceptible (MIC ⩾4.0 μg/mL) strain of S. aureus. Bactericidal activity was also observed against selective pathogens.

Summary of Ceftaroline Fosamil Clinical Trial Studies and Clinical Safety

In October 2010, the new cephalosporin, ceftaroline fosamil, was approved by the US Food and Drug Administration for therapy of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSIs). The active metabolite, ceftaroline, demonstrates in vitro activity against typical bacterial pathogens most often associated with CABP or ABSSSIs, including resistant Gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus. The efficacy and safety of ceftaroline fosamil was assessed in 2 large phase 3 programs of randomized, double-blind, clinical trials for CABP and ABSSSIs. For both indications, therapy with ceftaroline fosamil was observed to be noninferior to the comparator agents (ceftriaxone for CABP and vancomycin plus aztreonam for ABSSSIs) at both a standard test of cure assessment time (8-15 days after discontinuation of study drug) and an early assessment time point (day 3 or 4 of study). In the integrated analysis of the trials for CABP (FOCUS 1 and 2), clinical cure rates for the ceftaroline group were numerically higher than those for the ceftriaxone group (for the clinically evaluable population 84.3% vs 77.7%; difference: 6.6%; 95% confidence interval, 1.6%-11.8%). Among patients with CABP caused by S. pneumoniae, clinical cure rates were markedly higher in the ceftaroline treatment group than in the ceftriaxone treatment group (59 of 69 [85.5%] vs 48 of 70 [68.6%], respectively). For the ABSSSI studies (CANVAS 1 and 2), microbiologically evaluable (ME) success rates were similar between the treatment groups. Notably, the clinical cure rates in ME patients with methicillin-resistant S. aureus ABSSSIs were 142 of 152 (93.4%) and 115 of 122 (94.3%), for ceftaroline and vancomycin plus aztreonam, respectively, and did not differ from those achieved in infections due to methicillin-susceptible S. aureus (93.0%-94.5%). Ceftaroline fosamil was well tolerated, with a safety profile similar to the comparator agents used in these phase 3 trials.

Development of a standardized susceptibility test for Campylobacter with quality-control ranges for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem

A standardized agar dilution susceptibility testing method was developed for Campylobacter that consisted of testing on Mueller-Hinton medium supplemented with 5% defibrinated sheep blood in an atmosphere of 10% CO2, 5% O2, and 85% N2. Campylobacter jejuni ATCC 33560 was identified as a quality-control (QC) strain. Minimal inhibitory concentration (MIC) QC ranges were determined for two incubation time/temperature combinations: 36 degrees C for 48 hr and 42 degrees C for 24 hr. Quality-control ranges were determined for ciprofloxacin, doxycycline, erythromycin, gentamicin, and meropenem. For all antimicrobial agents tested at both temperatures, 95-100% of the QC MIC results fell within recommended QC ranges. Twenty-one Campylobacter clinical isolates, encompassing five species of Campylobacter (C. jejuni, C. coli, C. jejuni, subsp. doylei, C. fetus, and C. lari) were tested in conjunction with the C. jejuni QC strain. While C. jejuni and C. coli could be reliably tested under both test conditions, growth of C. jejuni subsp. doylei, C. fetus, and C. lari isolates was inconsistent when incubated at 42 degrees C. Therefore, it is recommended that these species only be tested at 36 degrees C.

Tigecycline: an update

Tigecycline is a broad-spectrum antibiotic with activity against difficult-to-treat pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., Acinetobacter baumannii, and Gram-negative bacterial strains that produce extended-spectrum β-lactamases. Minimal organ toxicity and lack of dosage adjustment in most patients are important considerations for tigecycline use. Tigecycline has been shown to be as effective and safe as standard antimicrobial therapy for treatment of adults with complicated intra-abdominal infections, complicated skin and skin structure infections, and community-acquired bacterial pneumonia. The clearest applications of tigecycline are for on-label indications. Whether tigecycline should be utilized as therapy for other infections including hospital-acquired infections with a high likelihood of multidrug-resistant pathogens is a complex issue that requires ongoing assessment. This article offers an updated overview of tigecycline clinical studies, current microbial resistance patterns, pharmacokinetic/pharmacodynamic investigations, and safety analyses.