Patterns of executive functions and theory of mind in adults with a family history of alcohol use disorder: Combined group and single-case analyses.

BACKGROUND: Impairments in executive function and social cognition are highly prevalent in individuals with an alcohol use disorder (AUD). Some studies show that similar difficulties are displayed by individuals with a positive family history of AUD (FH+) compared with individuals with a negative family history (FH-). Yet, no studies have jointly investigated cognitive and affective theory of mind at the behavioral level. Moreover, some studies show preserved executive and socioemotional functioning in FH+ participants. One possible explanation for these divergent results is that FH+ individuals are cognitively heterogeneous. In this study, we examined the frequency and co-occurrence of difficulties in executive function and social cognition among FH+ individuals at the individual level. METHODS: Sixty FH+ and 60 FH- participants matched on age, sex, and education level were included. They completed tasks assessing executive functions (Stroop, Trail Making Test) and affective and cognitive theory of mind (Movie for the Assessment of Social Cognition). They also completed self-report questionnaires measuring impulsivity, alexithymia, and empathy. Single-case analyses assessed the proportion of FH+ participants with difficulties in executive function and/or theory of mind. RESULTS: FH+ individuals exhibited difficulties in response inhibition and made more errors during theory of mind processing, indicating an absence of mental state representation, compared with FH- individuals. In the FH+ sample, 53.33% had executive function and/or theory of mind difficulties. Those with lower theory of mind scores reported higher alexithymia and lower empathy on self-report measures. CONCLUSIONS: FH+ individuals display heterogeneous executive function and theory of mind abilities. Given that they mostly occur independently of one another, executive function and theory of mind difficulties may be distinct vulnerability markers in AUD.

Neural activations during cognitive and affective theory of mind processing in healthy adults with a family history of alcohol use disorder.

BACKGROUND: Social cognition impairments are a common feature of alcohol use disorders (AUD). However, it remains unclear whether these impairments are solely the consequence of chronic alcohol consumption or whether they could be a marker of vulnerability. METHODS: The present study implemented a family history approach to address this question for a key process of social cognition: theory of mind (ToM). Thirty healthy adults with a family history of AUD (FH+) and 30 healthy adults with a negative family history of AUD (FH-), matched for age, sex, and education level, underwent an fMRI cartoon-vignette paradigm assessing cognitive and affective ToM. Participants also completed questionnaires evaluating anxiety, depressive symptoms, childhood trauma, and alexithymia. RESULTS: Results indicated that FH+ individuals differed from FH- individuals on affective but not cognitive ToM processing, at both the behavioral and neural levels. At the behavioral level, the FH+ group had lower response accuracy for affective ToM compared with the FH- group. At the neural level, the FH+ group had higher brain activations in the left insula and inferior frontal cortex during affective ToM processing. These activations remained significant when controlling for depressive symptoms, anxiety, and childhood trauma. CONCLUSIONS: These findings highlight difficulties during affective ToM processing among first-degree relatives of AUD patients, supporting the idea that some of the impairments exhibited by these patients may already be present before the onset of AUD and may be considered a marker of vulnerability.

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).

Pharmacokinetics, serum inhibitory and bactericidal activity, and safety of telavancin in healthy subjects.

The pharmacokinetics, tolerability, and serum inhibitory and bactericidal titers of telavancin, a new rapidly bactericidal lipoglycopeptide with multiple mechanisms of action against gram-positive pathogens, were assessed in a two-part, randomized, double-blind, placebo-controlled, ascending-dose study with 54 healthy men. In part 1, single ascending intravenous doses of 0.25 to 15 mg/kg of body weight were studied. In part 2, multiple ascending doses (30-min infusions of 7.5 to 15 mg/kg/day) were studied over 7 days. Following the administration of multiple doses, steady state was achieved by days 3 to 4. At day 7 after the administration of telavancin at 7.5, 12.5, and 15 mg/kg/day, peak concentrations in plasma were 96.7, 151.3, and 202.5 microg/ml, respectively, and steady-state area-under-the-curve values were 700, 1,033, and 1,165 microg x h/ml, respectively. The elimination half-life ranged from 6.9 to 9.1 h following the administration of doses > or =5 mg/kg. Most adverse events were mild in severity. At 24 h postinfusion, serum from subjects given telavancin demonstrated potent bactericidal activity against methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae strains. The results suggest that telavancin may be an effective once-daily therapy for serious bacterial infections caused by these pathogens.

Treatment of hospitalized patients with complicated gram-positive skin and skin structure infections: two randomized, multicentre studies of quinupristin/dalfopristin versus cefazolin, oxacillin or vancomycin. Synercid Skin and Skin Structure Infection Group.

Quinupristin/dalfopristin (Synercid), the first injectable streptogramin antibiotic available for the treatment of complicated gram-positive skin and skin structure infections, was compared with standard comparators (cefazolin, oxacillin or vancomycin) in one USA and one international trial. These two randomized, open-label trials of virtually identical design enrolled a total of 893 patients (450 quinupristin/dalfopristin, 443 comparator). The majority of patients had erysipelas, traumatic wound infection or clean surgical wound infection. Staphylococcus aureus was the most frequently isolated pathogen in both treatment groups and polymicrobial infection was more common in the quinupristin/dalfopristin group than in the comparator group. The clinical success rate (cure plus improvement) in the clinically evaluable population was equivalent between the two treatment groups (68.2% quinupristin/dalfopristin, 70.7% comparator; 95% CI, -10.1, 5.1) despite a shorter mean duration of treatment for quinupristin/dalfopristin patients. In the bacteriologically evaluable population, by-patient and by-pathogen bacteriological eradication rates were somewhat lower for quinupristin/dalfopristin (65.8% and 66.6%, respectively) than for the comparator regimens (72.7% and 77.7%, respectively). The lower bacteriological response rates in the quinupristin/dalfopristin group were, in part, due to a higher rate of polymicrobial infections and a higher incidence of patients classified as clinical failure, a category which included premature discontinuation of treatment because of local venous adverse events. The bacteriological eradication rate for quinupristin/dalfopristin was higher in monomicrobial infections than in polymicrobial infections (72.6% versus 63.3%, respectively), whereas the corresponding rate for the comparator regimens was lower for monomicrobial infections than polymicrobial infections (70.8% versus 83.1%). This finding was not unexpected, since the spectrum of quinupristin/dalfopristin is focused on gram-positive pathogens and additional antibiotics to treat gram-negative bacteria were not required per protocol. The systemic tolerability of both treatment regimens was qualitatively similar. A higher rate of drug-related venous adverse events was reported for quinupristin/dalfopristin (66.2%) than for the comparator regimen (28.4%). Premature discontinuation of study drug was primarily due to adverse clinical events for quinupristin/dalfopristin (19.1%), whereas the most common reason for discontinuation among those receiving the comparator regimens was treatment failure (11.5%). Quinupristin/dalfopristin is an effective alternative for the treatment of hospitalized patients with complicated skin and skin structure infections due to quinupristin/ dalfopristin-susceptible gram-positive organisms, including methicillin- and erythromycin-resistant S. aureus.

An overview of mortality risk prediction in sepsis.

OBJECTIVE: To review the evolution and development of mortality risk prediction methods as they have been applied to the management of septic patients. DATA SOURCES: Selected relevant articles from the pertinent literature. STUDY SELECTION: Theoretical and clinical data on the mortality risk identification, severity of illness scoring systems, and cytokine levels as they relate to mortality in patients with sepsis. DATA EXTRACTION: All concepts relating to mortality risk prediction, cytokines, severity of illness, and intensive care unit (ICU) mortality were explored and interrelated accordingly. DATA SYNTHESIS: In order to improve the precision of the evaluation of new therapies for the treatment of sepsis, to monitor their utilization and to refine their indications, it has been recommended that mortality risk stratification or severity of illness scoring systems be utilized in clinical trials and in practice. With the increasing influence of managed care on healthcare delivery, there will be an increased demand for techniques to stratify patients for cost-effective allocation of care. Severity of illness scoring systems are widely utilized for patient stratification in the management of cancer and heart disease. However, the use of such systems in patients with sepsis has been limited to application in clinical trial design for assurance of balance among treatment groups. Mortality risk prediction in sepsis has evolved from identification of risk factors, and simple counts of failing organs, to sophisticated techniques that mathematically transform a raw score, comprised of physiologic and/or clinical data, into a predicted risk of death. Most of the developed systems are based on global ICU populations rather than upon sepsis patient databases. A few, newer systems are derived from such databases. However, the overall discriminating ability of the various methods is similar. Mortality prediction has also been carried out from assessments of endotoxin or cytokine (interleukin-1, interleukin-6, tumor necrosis factor) plasma concentrations. While increased levels of these substances have been correlated with increased mortality, difficulties with bioassay and their sporadic appearance in the bloodstream prevent these measurements from being practically applied. The calibration of risk prediction methods comparing predicted with actual mortality across the breadth of risk for a population of patients is excellent, but overall accuracy in individual patient predictions is such that clinical judgment must remain a major part of decision-making. However, as databases of appropriate patient information increase in size and complexity, it may be possible in the future to devise a scoring system that can be relied on to assist in clinical decision-making. CONCLUSIONS: Severity of illness scoring systems are widely used in critically ill patients. However, their use in patients with sepsis has largely been limited to a means of stratification in clinical trials. As newer sepsis therapies become available, it may be possible to use such systems for refining their indications, and monitoring their utilization. Finally, as the databases supporting the systems increase in size and complexity, it may be possible to utilize them in clinical decision-making.

Review of in vitro activity, pharmacokinetic characteristics, safety, and clinical efficacy of cefprozil, a new oral cephalosporin.

OBJECTIVE: To review the pharmacokinetics, microbiology, clinical efficacy, safety, and tolerance of cefprozil, a new, broad-spectrum oral cephalosporin. DATA SOURCES: Published clinical trials and microbiologic, pharmacokinetic, and safety data were identified by MEDLINE; additional references were derived from bibliographies of these articles; microbiologic data on file were provided by Bristol-Myers Squibb. STUDY SELECTION: Only published comparative clinical trial reports are included in the review of clinical efficacy. Noncomparative clinical data pertaining to uses of cefprozil not approved by the Food and Drug Administration are not included. DATA SYNTHESIS: Data are presented on the in vitro microbiologic activity of cefprozil against 10,152 bacterial isolates, including most of the clinically important streptococci (e.g., Streptococcus pyogenes, Streptococcus pneumoniae), beta-lactamase-positive and -negative Staphylococcus aureus and Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, Clostridium difficile, and numerous other gram-negative aerobes and anaerobes. In clinical trials, cefprozil appears to be at least as effective as commonly used comparison agents such as cefaclor, cefixime, and amoxicillin/clavulanic acid. Additionally, cefprozil is better tolerated than the latter two agents, especially with regard to gastrointestinal adverse effects. CONCLUSIONS: Cefprozil is a broad-spectrum cephalosporin that provides coverage against both gram-negative and -positive bacteria that may cause otitis media, pharyngitis/tonsillitis, skin and skin-structure infections, secondary bacterial infection of acute bronchitis, and acute bacterial exacerbations of chronic bronchitis. The beta-lactamase stability of cefprozil appears to exceed that of other oral cephalosporins for some important pathogens. Cefprozil is used primarily for second-line treatment as less-expensive, first-line generic alternatives generally are available. Cefprozil demonstrates clinical advantages over many other orally administered beta-lactam antibiotics in terms of antimicrobial spectrum, a once- or twice-daily dosing regimen, and/or reduced incidence of adverse effects.

Ciprofloxacin-resistant Haemophilus influenzae infection in a patient with chronic lung disease.

OBJECTIVE: To report a case of ciprofloxacin-resistant Haemophilus influenzae infection in a patient with chronic lung disease who was exposed to multiple courses of antimicrobial therapy. CASE SUMMARY: The patient suffered recurrent pulmonary infections and developed bronchiectasis as a consequence of longstanding, severe, combined immunodeficiency disease. He had received ciprofloxacin on several occasions for treatment and prophylaxis of recurrent pulmonary infections. On a recent admission his usual H. influenzae isolate, which had been highly susceptible to ciprofloxacin (minimum inhibitory concentration [MIC] < or = 0.06 mg/L) on previous admissions, was resistant to ciprofloxacin and ofloxacin (MIC 8 and 16 mg/L, respectively). The patient responded to treatment with ceftizoxime and was discharged with oral cefixime, which was to be taken for a total of two weeks. DISCUSSION: Rare isolates of H. influenzae resistant to ofloxacin and lomefloxacin have been noted in Europe and Asia; however, none resistant to the fluoroquinolones have been previously reported in the US, and no resistance has been reported to ciprofloxacin. We believe that repetitive, cycling exposure to ciprofloxacin may have induced the resistance that developed in this patient's flora. CONCLUSIONS: Fluoroquinolones may be added to the list of drugs to which H. influenzae have become resistant. Only judicious use of these drugs will preserve their activity against important pathogens in community-acquired infections.

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.

Serum and blister fluid pharmacokinetics and bactericidal activities of ampicillin-sulbactam, cefotetan, cefoxitin, ceftizoxime, and ticarcillin-clavulanate.

Ampicillin-sulbactam, ticarcillin-clavulanate, cefoxitin, cefotetan, and ceftizoxime are promoted for the treatment of mixed aerobic-anaerobic bacterial infections. Their activities have been compared in vitro but not in vivo. In order to assess the in vivo activities of these agents in serum and interstitial fluid, we administered single, intravenous doses of these antimicrobial agents to healthy subjects. Concentrations of the antimicrobial agents in serum and suction-induced blister fluid and bactericidal activity were measured by high-pressure liquid chromatography and the standard methodology of the National Committee for Clinical Laboratory Standards, respectively. The organisms used for bactericidal activity tests were one isolate each of Staphylococcus aureus, Klebsiella pneumoniae, and Bacteroides fragilis. Pharmacokinetic parameters in serum and blister fluid were similar to those derived in other investigations. Of note were the high and prolonged concentrations of ticarcillin and cefotetan in blister fluid, despite high-level serum protein binding. The bactericidal activities in serum and blister fluid reflected the relative in vitro activities and kinetic dispositions of the various antimicrobial agents except for the bactericidal activity of cefotetan, which was substantially lower in blister fluid than serum, despite a blister fluid:serum area under the concentration-time curve ratio of 1.5. Similarly, the activity of ticarcillin-clavulanate in blister fluid was also substantially less than would have been predicted by the blister fluid:serum ratio of the area under the concentration-time curve of 1.1, possibly because of the low concentrations of clavulanate in blister fluid. The rankings of the in vivo bactericidal activities of the five drugs were as follows: for S. aureus, ampicillin-sulbactam > ticarcillin-clavulanate > ceftizoxime > cefoxitin > cefotetan; for K. pneumoniae, ceftizoxime > cefotetan > ampicillin-sulbactam = ticarcillin-clavulanate > cefoxitin; and for B.fragilis, ticarcillin-clavulanate > cefotetan > ceftizoxime > ampicillin-sulbactam = cefoxitin.

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.

Pharmacology and pharmacokinetics of cefprozil.

Cefprozil is a new orally administered cephalosporin with a spectrum of in vitro activity similar to that of cefuroxime. The pharmacokinetics of cefprozil are linear relative to dose size. Gastrointestinal absorption produces maximal plasma concentrations of approximately 10 mg/L 1-2 hours after administration of an oral dose of 500 mg. Approximately 94% of the dose is absorbed, and 60%-70% is excreted in the urine as unchanged drug. The renal clearance exceeds the glomerular filtration rate, thus suggesting active tubular secretion. Administration with food or antacids produces negligible effects on the rate or extent of absorption. Kinetic disposition in the elderly is similar to that in young healthy individuals, but elimination is slightly slower in infants and children. Because renal impairment, but not hepatic dysfunction, significantly reduces the elimination of cefprozil, it is recommended that the dosage be reduced by 50% in patients whose creatinine clearance is less than 30 mL/min. Penetration of the interstitial fluid by cefprozil is excellent, with concentrations approaching those observed in the plasma. The pharmacokinetic disposition of cefprozil, coupled with its in vitro activity, supports the use of once- or twice-daily dosage regimens.

Gram-negative sepsis, the sepsis syndrome, and the role of antiendotoxin monoclonal antibodies.

The incidence and mortality, pathogenesis, clinical manifestations, and management of sepsis and the sepsis syndrome are reviewed, and the use of antiendotoxin monoclonal antibodies to treat patients with sepsis is discussed. The sepsis syndrome and septic shock are induced by the presence of endotoxin, a lipopolysaccharide found in the outer membrane of gram-negative bacteria. Proper management of gram-negative sepsis includes appropriate antimicrobial therapy, fluids and electrolytes, nutritional support, administration of vasopressors, and mechanical ventilation if necessary. To date, two antiendotoxin monoclonal antibodies have been produced and subjected to extensive clinical testing. HA-1A, a human cell line-derived monoclonal immunoglobulin M (IgM) antibody that contains only a small fragment of murine protein, was tested in one trial. HA-1A significantly reduced mortality in patients with sepsis and gram-negative bacteremia and produced better resolution of major morbidities than placebo in those patients. E5, an IgM antibody produced entirely via murine monoclonal antibody technology, was evaluated in two trials. Results from the first trial showed that E5 significantly reduced mortality in patients with gram-negative infection who were not in refractory shock. In contrast, results from the second trial did not show any significant reduction in mortality among patients with gram-negative infection who received E5. However, resolution of major morbidities occurred more frequently among E5 recipients in both trials. HA-1A and E5 were both well tolerated in the trials. The cost of therapy is expected to be $3000-$4000 per treatment course. The antiendotoxin monoclonal antibodies represent the next step along the path toward important reductions in morbidity and mortality from gram-negative infection. However, the financial implications of the use of HA-1A and E5 are enormous, and stringent patient selection criteria for administration of these products will have to be developed.

Pharmacokinetic disposition and bactericidal activities of cefepime, ceftazidime, and cefoperazone in serum and blister fluid.

Cefepime is a new broad-spectrum cephalosporin with excellent gram-positive and gram-negative activity including activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter cloacae. The pharmacokinetic disposition of cefepime is similar to that of ceftazidime. We compared the pharmacokinetic characteristics and the extent and duration of bactericidal activity in serum and suction-induced blister fluid after single 2-g intravenous doses of cefepime, ceftazidime, and cefoperazone given to healthy subjects. One clinical isolate each of E. cloacae, P. aeruginosa, and S. aureus was used to assess bactericidal activity. Results of the pharmacokinetic analysis were similar to previously reported data for these drugs. The high serum protein binding of cefoperazone (approximately 90%) contributed to poor blister fluid penetration. The other drugs penetrated well into this fluid compartment. Cefepime showed significantly greater bactericidal activity in serum and blister fluid against E. cloacae than the other study drugs, ceftazidime was significantly better in serum and blister fluid against P. aeruginosa, and cefoperazone was significantly better against S. aureus only in serum. None of the study drugs had significant bactericidal activity in blister fluid against S. aureus. Cefepime is a promising antimicrobial agent for the treatment of infections due to E. cloacae.

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.