Analysis of Phase 3 telavancin nosocomial pneumonia data excluding patients with severe renal impairment and acute renal failure.

OBJECTIVES: Telavancin is approved in Europe for the treatment of nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus when other alternatives are not suitable. The approved European prescribing information contraindicates the use of telavancin in patients with severe renal impairment (creatinine clearance <30 mL/min, including patients on haemodialysis) and pre-existing acute renal failure owing to the higher observed mortality in these patients. Data from the ATTAIN studies were reanalysed, excluding patients with these contraindicating conditions at baseline. (At the time of submission of this article, the European marketing authorization of telavancin for the treatment of nosocomial pneumonia was suspended pending evidence of a new European Medicines Agency-approved supplier. Clinigen Healthcare Ltd, Theravance's commercialization partner for telavancin in Europe, is in the process of seeking approval of a new manufacturing source.) METHODS: A post hoc analysis of data from two Phase 3 ATTAIN trials of telavancin for the treatment of Gram-positive nosocomial pneumonia assessing clinical outcomes and safety. RESULTS: The all-treated population for this analysis represented 84.2% (1266/1503) of the ATTAIN all-treated population. The cure rates in the clinically evaluable population were similar in the telavancin (82.5%, 231/280) and vancomycin (81.3%, 243/299) groups [treatment difference (95% CI): 1.3% (-5.0% to 7.6%)], and were consistent with the overall ATTAIN study results. The cure rate was higher in the telavancin than the vancomycin treatment group in microbiologically evaluable patients with only Gram-positive pathogens isolated at baseline [85.0% (130/153) versus 75.2% (109/145), respectively; treatment difference (95% CI): 9.7% (0.6%-18.8%)]. The incidences of adverse events were similar between treatment groups and consistent with the overall findings of the ATTAIN study. CONCLUSIONS: This analysis demonstrated that in the subset of patients without severe renal impairment or pre-existing acute renal failure, clinical and safety outcomes were similar in the telavancin and vancomycin treatment groups.

Telavancin pharmacokinetics and pharmacodynamics in patients with complicated skin and skin structure infections and various degrees of renal function.

This study characterized the pharmacokinetic/pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved telavancin renal dose adjustment schemes. A previously published two-compartment open model with first-order elimination and a combined additive and proportional residual error model derived from 749 adult subjects in 11 clinical trials was used to simulate the individual concentration-time profiles for 10,260 subjects (NONMEM). The dosing regimens simulated were 10 mg/kg of body weight once daily for individuals with creatinine clearances (CL(CR)s) of >50 ml/min, 7.5 mg/kg once daily for individuals with CL(CR)s of 30 to 50 ml/min, and 10 mg/kg every 2 days for those with CL(CR)s of <30 ml/min. The area under the concentration-time curve (AUC) under one dosing interval (AUC(τ)) was computed as dose/CL. The probability of achieving an AUC(τ)/MIC ratio of ≥ 219 was evaluated separately for each renal dosing scheme. Evaluation of the dosing regimens demonstrated similar AUC values across the different renal function groups. For all renal dosing strata, >90% of the simulated subjects achieved an AUC(τ)/MIC ratio of ≥ 219 for MIC values as high as 2 mg/liter. For patients with CL(CR)s of <30 ml/min, the probability of target attainment (PTA) exceeded 90% for both the AUC0₋24 (AUC from 0 to 24 h) and AUC24₋48 intervals for MICs of ≤ 1 mg/liter. At a MIC of 2 mg/liter, the PTAs were 89.3% and 23.6% for the AUC0₋24 and AUC24₋48 intervals, respectively. The comparable PTA profiles for the three dosing regimens across their respective dosing intervals indicate that the dose adjustments employed in phase III trials for complicated skin and skin structure infections were appropriate.

Effects of telavancin on coagulation test results.

BACKGROUND: The lipoglycopeptide antibiotic, telavancin, may interfere with some laboratory coagulation tests including prothrombin time (PT) and activated partial thromboplastin time (aPTT). OBJECTIVE: To evaluate the effects of telavancin on PT and aPTT assays in common use. METHODS: Pooled normal human plasma was spiked with telavancin 10, 20, 100 or 200 µg/ml (equivalent to trough, 2 × trough, peak and 2 × peak clinical plasma concentrations, respectively) or diluent control (0.9% sodium chloride). Samples were analysed using 16 PT reagents and seven aPTT reagents. RESULTS: Telavancin 200 µg/ml (corresponding to 2 × peak clinical plasma concentration), produced significant PT prolongation (> 9% difference vs. diluent control) with all the 16 PT reagents (range 12% to > 600%). At lower telavancin concentrations, PT prolongation was dose-dependent and varied among reagents, but appeared greatest with preparations containing recombinant tissue factor. With telavancin 10 µg/ml (equivalent to trough), PT prolongation was 10% with HemosIL(®) PT-Fibrinogen Recombinant, while ranging from 5% to -1% with all other reagents. Significant (> 34% difference vs. baseline) and dose-dependent aPTT prolongation was observed with all the seven reagents in samples spiked with telavancin 100 or 200 µg/ml (range 65-142% at 200 µg/ml). aPTT reagents containing a silica activator appeared to be more sensitive to telavancin interference. Telavancin 10 µg/ml was not associated with increased aPTT with any of the reagents tested. CONCLUSIONS: Telavancin has the potential to prolong both PT and aPTT in vitro. It is recommended that samples for PT or aPTT be obtained just prior to a telavancin dose (trough).

Influence of coadministration on the pharmacokinetics of mezlocillin and cefotaxime in healthy volunteers and in patients with renal failure.

The pharmacokinetic disposition of cefotaxime, desacetyl cefotaxime, and mezlocillin after the administration of each drug singly and in combination was examined in eight healthy volunteers and in five anuric patients with end-stage renal disease (ESRD). In the presence of ESRD, the total body clearance of cefotaxime decreased from 256.7 +/- 41.5 to 65.4 +/- 42.0 ml/min, and its elimination half-life (t1/2) increased from 1.1 to 3.6 hours as compared with healthy volunteers. Concomitant administration of mezlocillin in healthy volunteers decreased the total body clearance of cefotaxime by 42% and increased its steady-state volume of distribution. This reduction in clearance was reflected by a decrease in both renal and nonrenal clearances. In the presence of ESRD, coadministration of mezlocillin increased the t1/2 of cefotaxime to 5.8 hours. Desacetyl cefotaxime accumulated in ESRD with a prolongation of its elimination t1/2 to 18.7 hours from 1.7 hours in healthy volunteers. Desacetyl cefotaxime peak plasma concentrations occurred later with the combination regimen in the presence of ESRD. The clearance of mezlocillin was reduced and t1/2 prolonged in ESRD from 194.6 +/- 31.9 to 76.4 +/- 38.8 ml/min and 1.4 to 2.3 hours, respectively. Concomitant administration of cefotaxime did not alter the pharmacokinetics of mezlocillin. These data suggest that in the presence of normal renal function, lower doses of cefotaxime may be adequate to maintain similar cefotaxime plasma concentrations when mezlocillin is coadministered compared to when cefotaxime is given alone. Additional pharmacodynamic and clinical studies with this combination are warranted to further elucidate the clinical impact of this pharmacokinetic interaction.

Vancomycin treatment for enterococcal meningitis.

Although clinical disease due to enterococcus is common, there has been only limited experience in the treatment of central nervous system infections by this pathogen. In particular, there have been few reports regarding the treatment of such infections in the penicillin-allergic individual. We present two cases of meningitis due to enterococci, including one case with a brain abscess, in patients with strong histories of penicillin sensitivity. We treated these patients with vancomycin hydrochloride and an aminoglycoside. Vancomycin with an aminoglycoside seems to be a reasonable treatment for enterococcal central nervous system infections.

Economic impact of oral ciprofloxacin. A pharmacist's perspective.

With increasing numbers of patients covered under diagnostic-related group or prospective payment systems, there is mounting pressure to reduce the costs associated with caring for patients while maintaining the quality of care. New, broad-spectrum, parenteral antimicrobial agents are a prime target for cost control. The availability of an orally administered drug that is effective in a variety of serious infections would have a significant impact on cost reduction in hospitals. A significant proportion of the cost of parenteral drug therapy is associated with labor, supplies, and equipment. An orally administered drug would obviate these costs. Additionally, iatrogenic problems associated with parenteral therapy (e.g., phlebitis) would be avoided, the quantities of expensive parenteral drugs purchased might be reduced, and the duration of hospitalization for selected diseases such as osteomyelitis would probably decrease. Finally, the ease of oral administration may allow longer courses of therapy for resistant infections than have heretofore been possible. Oral ciprofloxacin and similar compounds present both opportunities and challenges for pharmacists. The fiscal impact may be beneficial for the hospital in terms of cost reductions for drug purchases and in expediting discharge for prolonged courses of outpatient therapy. The magnitude of cost reductions will vary substantially depending upon the types of patients and infections managed in a given institution. The challenge for pharmacists is to assure that these valuable compounds, as well as all antimicrobial agents, are appropriately utilized to avoid the offsetting costs of adverse effects, superinfection, unnecessary use, and the development of resistance.

Amdinocillin pharmacokinetics. Simultaneous administration with cephalothin and cerebrospinal fluid penetration.

In the treatment of serious infections, combinations of beta-lactam antibiotics are being utilized in order to avoid aminoglycoside toxicity and to achieve antibacterial synergy. The pharmacokinetic disposition of amdinocillin and cephalothin was determined, when administered alone or in combination to healthy volunteers, as well as the penetration of amdinocillin into human cerebrospinal fluid. Six subjects received, on separate occasions, single intravenous doses of amdinocillin 10 mg/kg, cephalothin 15 mg/kg, or a combination of the two in the same doses. The elimination half-lives of amdinocillin and cephalothin are increased when these drugs are given simultaneously, compared with when they are administered alone. However, no significant differences were observed. When they were given in combination, no significant changes in plasma clearance, renal clearance, or steady-state volume of distribution were found. Eight patients undergoing lumbar puncture for various neurologic disorders without inflamed meninges received a single dose of 10 mg/kg amdinocillin intravenously. One to two hours later, simultaneous plasma and cerebrospinal fluid samples were obtained. The concentration of amdinocillin in the cerebrospinal fluid ranged from approximately 1 to 10 percent of concomitant plasma concentrations. Thus, amdinocillin penetrates in the cerebrospinal fluid in marginal amounts in the absence of meningeal inflammation.

Serum bactericidal activity from intravenous ciprofloxacin and azlocillin given alone and in combination to healthy subjects.

Ciprofloxacin plus azlocillin have been shown to exhibit in vitro synergy versus a variety of organisms, including Pseudomonas aeruginosa. This study examined this interaction in vivo, testing serum bactericidal activity (SBA) in six healthy male subjects after intravenous administration of ciprofloxacin 4 mg/kg (C), azlocillin 60 mg/kg (A), and the two simultaneously (C/A). Eight different organisms were tested: four isolates of P. aeruginosa with varying susceptibilities to C and A, and one isolate each of Escherichia coli (EC), Staphylococcus aureus (SA) Serratia marcescens (SM), and Klebsiella pneumoniae (KP), all of which were susceptible to both drugs. Blood samples were collected at the end of 30-min infusions and at 4 and 8 hr. Reciprocal titers were plotted versus time and area under the bactericidal titer curve (AUBC) calculated to assess antibacterial interactions. Results indicated that P. aeruginosa-1 (PA-1), EC, and KP were synergistically killed by C/A. AUBC for PA-1 were C = 36, A = 11, C/A = 144, p less than 0.05. AUBC for EC were C = 1059, A = 180, C/A = 1504, p = 0.05. AUBC for KP were C = 327, A = 97, C/A = 584, p = 005. Additive effects were demonstrated versus all of the other organisms except Serratia marcescens, where an indifferent effect was observed. Ciprofloxacin plus azlocillin may be a useful combination of the treatment of selected Gram-negative bacillary infections.

Monotherapy versus combination antimicrobial therapy: a review.

In view of the newer antibiotics that can cover the spectrum of organisms in mixed infections, single agents are now a viable option for antimicrobial therapy. In addition, monotherapy is relatively nontoxic and possibly less costly than combination therapy. Combinations may be more effective in preventing the emergence of resistance, however, and can also provide synergistic effects. They are a necessity in mycobacterial infections, enterococcal endocarditis, and deep-seated pseudomonal infections, as well as in patients with gram-negative bacillary infection with profound granulocytopenia.

Antimicrobial cost and quality control: challenges in the 1990s.

Increasing constraints on health care reimbursement, competition among hospitals, and new high-cost technologies all contribute to escalation of costs in hospitals. The goal in the 1990s is to provide optimum, cost-effective care for patients without compromising quality. Among many proved methods is an effective formulary system with explicit criteria for use of medications, guidelines for use in specialized circumstances, and suggestions for therapeutic alternatives. This last method of cost control received endorsement from several organizations and offers an important function for hospital pharmacists. Hospital pharmacies can play a major role in minimizing antimicrobial costs and promoting optimum patient care.

Bacterial resistance to beta-lactams, and its prevention with combination antimicrobial therapy.

The clinical and economic impacts of bacterial resistance are substantial. The development of bacterial resistance during a course of therapy often leads to clinical failure, prolonged hospitalization, increased morbidity, mortality, and increased health care costs. Resistance has been reported to occur most frequently with aminoglycosides, quinolones, and beta-lactam antimicrobials, and often occurs during the course of treatment of gram-negative bacillary infection. Resistance is most commonly due to enzymatic inactivation, permeability changes, or receptor mutation. Strategies for the prevention of resistance include appropriate infection-control practices, judicious use of antimicrobials, enhancement of host defenses, and the use of antimicrobial combinations. Despite success in vitro and in experimental animal models of infection, clinical trials in humans of antimicrobial combinations for the prevention of resistance have yielded mixed results. Use of the most potent agents available, preferably in bactericidal synergistic combinations, may be effective in preventing in vivo emergence of bacterial resistance.

Therapeutic decisions: assessing clinical fit.

Quality health care has been defined as the maximization of desired outcomes while minimizing undesirable consequences. Therefore, the optimal antimicrobial agent for a given clinical condition will be one that is the most rapidly effective, produces the least patient discomfort, results in minimal disruption of the patient's or hospital flora, and causes minimal dissatisfaction with the treatment program and its attendant costs. The clinical utility of antimicrobials is generally judged on the basis of in vitro activity, kinetic disposition, resistance trends, safety, and cost. Fluoroquinolones possess characteristics in each of these areas; for example, broad, potent gram-negative spectrum coupled with excellent oral absorption and tissue penetration, and relative safety and reduced cost compared with parenteral therapy. Drawbacks include the emergence of resistance among certain bacteria, particularly staphylococci and Pseudomonas aeruginosa, drug interactions that may compromise efficacy, and greater cost than other potentially useful oral antimicrobial agents. Indications for the agents' use can be categorized as appropriate (gram-negative osteomyelitis, complicated urinary tract infection, prostatitis, certain sexually transmitted diseases, bacterial gastroenteritis), potential (gastrointestinal tract decontamination in granulocytopenic patients, exacerbations of chronic obstructive pulmonary disease, nosocomial pneumonia and bacteremia, eradication of certain bacterial carrier states), or inappropriate (community-acquired pulmonary infections, especially aspiration pneumonitis, serious gram-positive infections, uncomplicated urinary tract infection, surgical prophylaxis except prostatic surgery). Gram-negative osteomyelitis serves as a model to demonstrate the fluoroquinolones as agents for quality health care. Current and future investigations should focus on the cost effectiveness and cost utility of the agents.

Imipenem monotherapy versus combination therapy in the management of mixed bacterial infection: a critical appraisal.

There has been a great deal of interest in the use of imipenem monotherapy rather than combinations of antimicrobials for mixed bacterial infections. A review of the published comparative studies of imipenem versus combinations in serious mixed bacterial infections indicated that, overall, imipenem is at least as effective as, and maybe less expensive than, the combinations tested. Several studies suggest that clinical response to imipenem is more rapid than to the comparison regimens; however, other factors may have influenced these values, and the numbers of patients in these reports were small. Imipenem is devoid of the adverse effects associated with aminoglycosides. Other adverse effects, including superinfection and central nervous system toxicity, were similar for imipenem and the comparison regimens. Meta-analysis of the published reports and abstracts revealed that imipenem is as effective as combination regimens for the treatment of serious mixed bacterial infection.

Ceforanide: antibacterial activity, pharmacology, and clinical efficacy.

Ceforanide is a new cephalosporin with a longer elimination half-life than any currently available cephalosporin. Its activity is very similar to that of cefamandole, a second-generation cephalosporin, except that ceforanide is less active against most gram-positive organisms. Many coliforms, including Escherichia coli, Klebsiella, Enterobacter, and Proteus, are susceptible to ceforanide, as are most strains of Salmonella, Shigella, Hemophilus, Citrobacter and Arizona species. However, most strains of Serratia marcescens and all Pseudomonas aeruginosa are resistant to this compound. Peak serum concentrations in excess of 100 micrograms/ml are achieved after a 1 g intravenous dose. The elimination half-life of ceforanide is about 3 hrs in patients with normal renal function; this allows twice daily dosing for the majority of patients. As renal excretion amounts for 85-90% of drug elimination, the serum half-life increases to approximately 20 hours in anuric patients. Tissue penetration studies demonstrate inhibitory concentrations in cardiac tissue, bone, and joint fluid. Minor adverse effects have been reported after large doses of ceforanide. Clinical trials indicate that ceforanide is effective in the treatment of skin and soft tissue, pulmonary and urinary tract infections, bone and joint infections, and endocarditis. Ceforanide also has been shown to be as effective as cephalothin or cephaloridine when given prophylactically for vaginal hysterectomy.

The economic impact of HA-1A (Centoxin) against endotoxin.

Monoclonal antibodies have been shown to reduce morbidity and mortality in selected subsets of patients with Gram-negative sepsis and/or septic shock. However, the acquisition costs of the antibody products are expected to be in the range of $US3500 to $US4000 per course of therapy and precise identification of patients who will benefit may be difficult. Therefore, the economic impact of these antibodies will be significant. We have performed a model cost-effectiveness and cost-benefit analysis specific to our institution based on previously reported mortality figures. Our data suggest that the cost-effectiveness of HA-1A (Centoxin) will be comparable with that of a variety of commonly used medical interventions, but will produce an incremental increase in costs of at least $US7000 per patient because of the acquisition cost of the drug, as well as an increase in numbers of survivors whose hospitalisation will be prolonged.

Emergence of multiple antibiotic resistance during the therapy of Klebsiella pneumoniae meningitis.

A patient is described in whom multiple antibiotic resistance developed during the course of therapy of Klebsiella pneumoniae meningitis. Sequential resistance developed to chloramphenicol, gentamicin and eventually amikacin. As previously reported, the use of the chloramphenicol alone in the therapy of gram-negative bacillary meningitis can result in rapid emergence of resistance and treatment failure. In this patient, the subsequent emergence of gentamicin and amikacin resistance may have been related to the omission of intrathecal aminoglycoside. A short review of the literature is presented and recommendations are made for the therapy of gram-negative bacillary meningitis.