In vivo pharmacodynamics of lefamulin, the first systemic pleuromutilin for human use, in a neutropenic murine thigh infection model.

OBJECTIVES: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of lefamulin in the neutropenic murine thigh infection model to ascertain (i) which PK/PD index best correlates with efficacy and (ii) whether the magnitude of the index that drives efficacy varies for different pathogens. METHODS: We evaluated the in vivo PK/PD of lefamulin against five Streptococcus pneumoniae and five Staphylococcus aureus strains using a neutropenic murine thigh infection model. The relationships between bacterial burden in the thigh of normal and neutropenic mice after 24 h of lefamulin treatment and various PK/PD indices were determined. RESULTS: The kinetics of the three doses was linear by AUC. Rate of killing was maximal at concentrations near the MIC; suppression of regrowth was dose dependent, with a post-antibiotic effect of 3.0-3.5 and 1.0-1.5 h against S. pneumoniae and S. aureus, respectively. The efficacy of lefamulin correlated most strongly with the AUC0-24/MIC ratio; coefficient of determination was 79.9% for S. pneumoniae and 78.3% for S. aureus. The magnitude of the 24 h AUC/MIC of total drug required ranged from 9.92 to 32.1 for S. pneumoniae and 40.2 to 82.5 for S. aureus, corresponding to free drug values (∼20% free fraction) of 1.98-6.42 and 8.04-16.5, respectively. CONCLUSIONS: Lefamulin, the first systemically available pleuromutilin in humans, exhibits time- and concentration-dependent killing. The presence of white blood cells had only a slight effect in enhancing the activity of the drug, indicating a leucocyte-independent effect. The identified driver of efficacy, the AUC0-24/MIC ratio and the ratios determined against various S. aureus and S. pneumoniae strains, will inform further non-clinical and clinical trials.

In vivo pharmacokinetics and pharmacodynamics of the lantibiotic NAI-107 in a neutropenic murine thigh infection model.

NAI-107 is a novel lantibiotic compound with potent in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this study was to examine the activity of NAI-107 against S. aureus strains, including MRSA, in the neutropenic murine thigh infection model. Serum pharmacokinetics were determined and time-kill studies were performed following administration of single subcutaneous doses of 5, 20, and 80 mg/kg body weight. The dose fractionation included total doses ranging from 1.56 to 400 mg/kg/72 h, divided into 1, 2, 3, or 6 doses. Studies of treatment effects against 9 S. aureus strains (4 methicillin-susceptible Staphylococcus aureus [MSSA] and 5 MRSA) using a 12-h dosing interval and total dose range of 1.56 to 400 mg/kg/72 h were also performed. A maximum effect (Emax) model was used to determine the pharmacokinetic/pharmacodynamic (PK/PD) index that best described the dose-response data and to estimate the doses required to achieve a net bacteriostatic dose (SD) and a 1-log reduction in CFU/thigh. The pharmacokinetic studies demonstrated an area under the concentration-time curve (AUC) range of 26.8 to 276 mg·h/liter and half-lives of 4.2 to 8.2 h. MICs ranged from 0.125 to 0.5 µg/ml. The 2 highest single doses produced more than a 2-log kill and prolonged postantibiotic effects (PAEs) ranging from 36 to >72 h. The dose fractionation-response curves were similar, and the AUC/MIC ratio was the most predictive PD index (AUC/MIC, coefficient of determination [R2]=0.89; maximum concentration of drug in serum [Cmax]/MIC, R2=0.79; time [T]>MIC, R2=0.63). A ≥2-log kill was observed against all 9 S. aureus strains. The total drug 24-h AUC/MIC values associated with stasis and a 1-log kill for the 9 S. aureus strains were 371±130 and 510±227, respectively. NAI-107 demonstrated concentration-dependent killing and prolonged PAEs. The AUC/MIC ratio was the predictive PD index. Extensive killing was observed for S. aureus organisms, independent of the MRSA status. The AUC/MIC target should be useful for the design of clinical dosing regimens.

Failure of clindamycin to eradicate infection with beta-hemolytic streptococci inducibly resistant to clindamycin in an animal model and in human infections.

Inducible clindamycin resistance in beta-hemolytic streptococci remains an underrecognized phenomenon of unknown clinical significance. We performed an evaluation of inducible clindamycin resistance using an animal model as well as retrospectively reviewing the charts of patients treated with clindamycin monotherapy who were infected with beta-hemolytic streptococci inducibly resistant to clindamycin. The neutropenic mouse thigh model of infection was used to evaluate the in vivo activity of clindamycin against beta-hemolytic streptococci, including isolates susceptible, inducibly resistant, or constitutively resistant to clindamycin. The clinical microbiology laboratory information system and pharmacy databases were cross-referenced to identify patients with infections due to inducibly clindamycin-resistant beta-hemolytic streptococci who were treated with clindamycin monotherapy. Medical records of these patients were reviewed to evaluate microbiologic and clinical outcomes. Inducible clindamycin resistance resulted in impaired killing of beta-hemolytic streptococci in the animal model. Though suppressed initially, compared to those with constitutive resistance (P=0.0429), by 48 h, colony counts of inducibly clindamycin-resistant organisms were similar to those of constitutively resistant isolates (P=0.1142). In addition, we identified 8 patients infected with inducibly clindamycin-resistant beta-hemolytic streptococci who experienced clinical and microbiologic failure when treated with clindamycin monotherapy. These patients either improved initially and subsequently failed or never responded to clindamycin therapy. We have demonstrated in a murine model of infection and from human cases that inducible clindamycin resistance in beta-hemolytic streptococci is clinically significant. Routine testing and reporting by clinical laboratories should be encouraged and alternative antimicrobial agents considered when these organisms are encountered in clinical care.

Exercise heart rate monitors for anxiety treatment in a rural primary care setting: a pilot study.

BACKGROUND AND OBJECTIVES: Rural patients with anxiety often lack access to traditional biofeedback modalities. Exercise heart rate monitors (HRMs) are tools used in the fitness industry to provide athletes with feedback on heart rate and regulatory breathing strategies. HRMs are inexpensive, discrete, and publicly accessible. This randomized controlled pilot study explored whether use of HRMs for biofeedback during guided mindfulness, diaphragmatic breathing, and progressive muscle relaxation techniques could facilitate anxiety reduction as compared to these techniques alone. METHODS: Fifty-three rural anxiety patients were randomized to HRM or control groups for four weekly 20-minute, scripted sessions with a non-behaviorist wherein they practiced these techniques; the HRM group received feedback on their heart rate response. RESULTS: The HRM group had significantly greater improvement in state anxiety (State-Trait Anxiety Inventory) and self-efficacy (General Self Efficacy Scale), and a greater percentage of the group indicated that they "felt in control of their anxiety." CONCLUSIONS: This pilot study demonstrates that this novel, inexpensive, and accessible tool may be a useful clinical intervention for anxiety and can be easily incorporated by both behaviorists and non-behaviorist primary care clinicians into individual or group biofeedback treatment for patients with anxiety. This tool has additional potential for patients to use for anxiety self-management. Further study with a larger sample and blinded design is warranted.

Inoculum effects of ceftobiprole, daptomycin, linezolid, and vancomycin with Staphylococcus aureus and Streptococcus pneumoniae at inocula of 10(5) and 10(7) CFU injected into opposite thighs of neutropenic mice.

Reduced bactericidal efficacy at a high inoculum is known as the inoculum effect (IE). We used neutropenic mice to compare the IEs of ceftobiprole (CFB), daptomycin (DAP), linezolid (LZD), and vancomycin (VAN) against 6 to 9 strains of Staphylococcus aureus and 4 strains of Streptococcus pneumoniae at 2 inocula in opposite thighs of the same mice. Neutropenic mice had 10(4.5) to 10(5.7) CFU/thigh (low inoculum [LI]) in one thigh and 10(6.4) to 10(7.2) CFU/thigh (high inoculum [HI]) in the opposite thigh when treated for 24 h with subcutaneous (s.c.) doses every 12 h of DAP at 0.024 to 100 mg/kg of body weight and LZD at 0.313 to 320 mg/kg and s.c. doses every 6 h of CFB at 0.003 to 160 mg/kg and VAN at 0.049 to 800 mg/kg. Dose-response data were analyzed by a maximum effect (E(max)) model using nonlinear regression. Static doses for each drug and at each inoculum were calculated, and the difference between HI and LI (IE index) gave the magnitude of IE for each drug-organism combination. Mean (range) IE indexes of S. aureus were 2.9 (1.7 to 4.6) for CFB, 4.1 (2.6 to 9.3) for DAP, 4.6 (1.7 to 7.1) for LZD, and 10.1 (6.3 to 20.3) for VAN. In S. pneumoniae, the IE indexes were 2.5 (1.3 to 3.3) for CFB, 2.0 (1.6 to 2.8) for DAP, 1.9 (1.7 to 2.2) for LZD, and 1.5 (0.8 to 3.2) for VAN; these values were similar for all drugs. In S. aureus, the IE was much larger with VAN than with CFB, DAM, and LZD (P < 0.05). An in vivo time course of vancomycin activity showed initiation of killing at 4- to 16-fold-higher doses at HI than at LI despite similar initial growth of controls.

Background and rationale for revised clinical and laboratory standards institute interpretive criteria (Breakpoints) for Enterobacteriaceae and Pseudomonas aeruginosa: I. Cephalosporins and Aztreonam.

Widespread resistance in Enterobacteriaceae and Pseudomonas aeruginosa to cephalosporin and monobactam antibiotics due to extended-spectrum ß-lactamases (ESBLs) has resulted in the need for reassessment of the interpretative criteria (breakpoints) established for these agents more than 2 decades ago. Following extensive evaluation, the Clinical and Laboratory Standards Institute recently adopted and published new breakpoints for these agents for use in clinical laboratories and provided updated recommendations for use of the ESBL screening test. This paper summarizes the background and supportive rationale for new interpretative criteria for cephalosporins and aztreonam for testing Enterobacteriaceae.

Comparative pharmacodynamics of the new oxazolidinone tedizolid phosphate and linezolid in a neutropenic murine Staphylococcus aureus pneumonia model.

Tedizolid phosphate (TR-701) is a novel oxazolidinone prodrug (converted to the active form tedizolid [TR-700]) with potent Staphylococcus aureus activity. The current studies characterized and compared the in vivo pharmacokinetic/pharmacodynamic (PD) characteristics of TR-701/TR-700 and linezolid against methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in the neutropenic murine pneumonia model. The pharmacokinetic properties of both drugs were linear over a dose range of 0.625 to 40 mg/kg of body weight. Protein binding was 30% for linezolid and 85% for TR-700. Mice were infected with one of 11 isolates of S. aureus, including MSSA and community- and hospital-acquired MRSA strains. Each drug was administered by oral-gastric gavage every 12 h (q12h). The dosing regimens ranged from 1.25 to 80 mg/kg/12 h for linezolid and 0.625 to 160 mg/kg/12 h for TR-701. At the start of therapy, mice had 6.24 ± 0.40 log(10) CFU/lungs, which increased to 7.92 ± 1.02 log(10) CFU/lungs in untreated animals over a 24-h period. A sigmoid maximum-effect (E(max)) model was used to determine the antimicrobial exposure associated with net stasis (static dose [SD]) and 1-log-unit reduction in organism relative to the burden at the start of therapy. The static dose pharmacodynamic targets for linezolid and TR-700 were nearly identical, at a free drug (non-protein-bound) area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) of 19 and 20, respectively. The 1-log-unit kill endpoints were also similar, at 46.1 for linezolid and 34.6 for TR-700. The exposure targets were also comparable for both MSSA and MRSA isolates. These dosing goals support further clinical trial examination of TR-701 in MSSA and MRSA pneumonia.

In vivo activity of oritavancin in animal infection models and rationale for a new dosing regimen in humans.

Oritavancin is a novel glycopeptide antibiotic with concentration-dependent killing of Gram-positive cocci and pharmacokinetics characterized by extensive tissue distribution and a long terminal half-life. Its development was hindered by a 16- to 32-fold underestimation of activity against staphylococci and enterococci because of oritavancin's sticking to vials and tubes. Dose-fractionation studies in animal models suggested the peak concentration was the major index for efficacy. Once-daily intravenous administration of oritavancin was effective in methicillin-resistant Staphylococcus aureus (MRSA) endocarditis, penicillin-susceptible and cephalosporin-resistant pneumococcal meningitis in rabbits, staphylococcal and enterococcal central venous catheter infections in rats, and 24-hour postprophylaxis of inhaled anthrax in mice. Orally administered oritavancin was more effective than vancomycin in Clostridium difficile infection in hamsters. Pharmacodynamics suggested that a single dose of oritavancin at 1200 mg would be efficacious in humans. Simulation of this dose in neutropenic mice was highly effective in methicillin-sensitive S. aureus and MRSA thigh and bacteremia infections and pneumococcal lung infections.

Forgotten antibiotics: an inventory in Europe, the United States, Canada, and Australia.

In view of the alarming spread of antimicrobial resistance in the absence of new antibiotics, this study aimed at assessing the availability of potentially useful older antibiotics. A survey was performed in 38 countries among experts including hospital pharmacists, microbiologists, and infectious disease specialists in Europe, the United States, Canada, and Australia. An international expert panel selected systemic antibacterial drugs for their potential to treat infections caused by resistant bacteria or their unique value for specific criteria. Twenty-two of the 33 selected antibiotics were available in fewer than 20 of 38 countries. Economic motives were the major cause for discontinuation of marketing of these antibiotics. Fourteen of 33 antibiotics are potentially active against either resistant Gram-positive or Gram-negative bacteria. Urgent measures are then needed to ensure better availability of these antibiotics on a global scale.

Protein binding: do we ever learn?

Although the influence of protein binding (PB) on antibacterial activity has been reported for many antibiotics and over many years, there is currently no standardization for pharmacodynamic models that account for the impact of protein binding of antimicrobial agents in vitro. This might explain the somewhat contradictory results obtained from different studies. Simple in vitro models which compare the MIC obtained in protein-free standard medium versus a protein-rich medium are prone to methodological pitfalls and may lead to flawed conclusions. Within in vitro test systems, a range of test conditions, including source of protein, concentration of the tested antibiotic, temperature, pH, electrolytes, and supplements may influence the impact of protein binding. As new antibiotics with a high degree of protein binding are in clinical development, attention and action directed toward the optimization and standardization of testing the impact of protein binding on the activity of antibiotics in vitro become even more urgent. In addition, the quantitative relationship between the effects of protein binding in vitro and in vivo needs to be established, since the physiological conditions differ. General recommendations for testing the impact of protein binding in vitro are suggested.

Optimizing aminoglycoside use.

The appearance of new third- and fourth-generation cephalosporins, carbapenems, and fluoroquinolones have decreased the use of aminoglycosides as monotherapy for most gram-negative infections. Historically, aminoglycosides were used in combination with other antibiotics to enhance bacterial killing and improve overall efficacy. However, most studies have failed to demonstrate improved outcomes in patients treated with antibiotic combinations over those receiving monotherapy. Only recently has early combination therapy been associated with reduced mortality in septic shock. This article reviews the pharmacokinetics, pharmacodynamics, and toxicodynamics of aminoglycosides, describing dosing strategies and other effects to improve outcomes in critically ill patients with serious infections.

Therapeutic monitoring of vancomycin in adults summary of consensus recommendations from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.

Vancomycin is a commonly used antibiotic due to its effectiveness in treating serious gram-positive infections caused by methicillin-resistant Staphylococcus aureus. As commercial drug assays and a multitude of pharmacokinetic data from a variety of patient populations are widely available, therapeutic monitoring of serum vancomycin concentrations is frequently performed by clinicians, with the expectation that targeting the concentrations within a relatively narrow range can minimize toxicity yet still achieve therapeutic success. Much debate exists, however, over the value of routine therapeutic monitoring of vancomycin levels because of conflicting evidence regarding the ability of serum concentrations to predict effectiveness or prevent toxicity. In addition, studies have suggested that the potential for nephrotoxicity or ototoxicity with vancomycin monotherapy is minimal at conventional dosages of 1 g (15 mg/kg) every 12 hours. However, increased rates of nephrotoxicity have recently been reported with doses of 4 g/day or higher. The American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists published a consensus statement on therapeutic monitoring of serum vancomycin levels in adults. These organizations established an expert panel to review the scientific data and controversies associated with vancomycin monitoring and to make recommendations based on the available evidence. As the members of this panel, we summarize the conclusions and highlight the recommendations from the consensus statement. We determined that the area under the concentration-time curve (AUC): minimum inhibitory concentration (MIC) ratio is the most useful pharmacodynamic parameter to predict vancomycin effectiveness and suggested a target ratio of 400 or greater to eradicate S. aureus. In addition, trough serum concentration monitoring is the most accurate and practical method to monitor vancomycin serum levels. Increasing trough concentrations to 15-20 mg/L to attain the target AUC:MIC ratio may be desirable but is currently not supported by clinical trials. Alternative therapies should be considered in patients with S. aureus infections that demonstrate a vancomycin MIC of 2 mg/L or greater because the target AUC:MIC ratio ( 400) is unlikely to be achieved in this setting. Increasing the dosage to result in higher trough concentrations may increase the potential for toxicity; however additional clinical experience is required to determine the extent.

Activities of clindamycin, daptomycin, doxycycline, linezolid, trimethoprim-sulfamethoxazole, and vancomycin against community-associated methicillin-resistant Staphylococcus aureus with inducible clindamycin resistance in murine thigh infection and in vitro pharmacodynamic models.

Controversy exists about the most effective treatment options for community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and about the ability of these strains to develop inducible resistance to clindamycin during therapy. Using both in vitro pharmacodynamic and murine thigh infection models, we evaluated and compared several antimicrobial compounds against CA-MRSA. Strains with inducible macrolide lincosamide-streptogramin type B (iMLS(B)) resistance and strains in which resistance was noninducible were evaluated. Two levels of inocula (10(5) and 10(7)) were evaluated for clindamycin activity in the in vivo model. In both models, the antimicrobial evaluation was performed in triplicate, and bacterial quantification occurred over 72 h, with drug doses that were designed to simulate the free drug area-under-the-concentration-time curve values (fAUCs) obtained from human samples. When the activity of clindamycin against the iMLS(B) strains was evaluated, constitutive resistance was noted at 24 h (MIC of >256), and failure was noted at an inoculum of > or =10(6) in the in vivo models. However, at a low inoculum (10(5)) in the murine thigh-infection model, clindamycin demonstrated modest activity, reducing the CFU/thigh count for clindamycin resistance-inducible strains at 72 h (0.45 to 1.3 logs). Overall, administration of daptomycin followed by vancomycin demonstrated the most significant kill against all strains in both models. Against the clindamycin noninducible strain, clindamycin and doxycycline demonstrated significant kill. Doxycycline, linezolid, and trimethoprim-sulfamethoxazide (not run in the murine model) demonstrated bacteriostatic activity against clindamycin resistance-inducible isolates. This study demonstrates that clindamycin's activity against the iMLS(B) strains tested is partially impacted by inoculum size. At present, there are several alternatives that appear promising for treating clindamycin resistance-inducible strains of CA-MRSA.

Tissue concentrations: do we ever learn?

Over the last decades, numerous papers have appeared--and still are appearing--that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms. A common method is to use measurements of concentrations in tissue homogenates, comparing these with values derived from the corresponding blood samples and on that basis draw conclusions with respect to the potential clinical use of the drug. This approach is not justifiable for a number of reasons that includes both pharmacokinetic as well as pharmacodynamic causes. This way of presenting data with the derived conclusions is often misleading and may ultimately be harmful in patient care.

Pharmacokinetics-pharmacodynamics of gatifloxacin in a lethal murine Bacillus anthracis inhalation infection model.

We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC of the drug for the organism (AUC(0-24)/MIC ratio) was the PK-PD measure most predictive of survival (R(2) = 0.96). The 50% effective dose (ED(50)) and the ED(90) and ED(99) corresponded to AUC(0-24)/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED(99)). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.

In vivo pharmacodynamic activity of the glycopeptide dalbavancin.

Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either Streptococcus pneumoniae or Staphylococcus aureus by using the thigh infection model. The burden of organisms for S. pneumoniae was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of S. aureus but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [C(max)]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the C(max)/MIC parameters correlated well with the in vivo efficacy of treatment against S. pneumoniae and S. aureus (for 24-h AUC/MIC, R(2) = 78 and 77%, respectively; for C(max)/MIC, R(2) = 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 +/- 7 for five S. pneumoniae isolates. A similar treatment endpoint for the treatment against five strains of S. aureus required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 +/- 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log(10) in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC(90) for the target gram-positive organisms would fall within this value.

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.

Outcomes evaluation of patients with ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species as defined by CLSI reference methods: report from the SENTRY Antimicrobial Surveillance Program.

As extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae continue to emerge worldwide, selection of empiric treatment modalities is an increasing challenge. Data describing the clinical outcomes associated with different treatment regimens have been limited. Using data from centers with confirmed ESBL- and non-ESBL-producing Escherichia coli and Klebsiella species isolates in North America, Latin America, and Europe, potential risk factors for the occurrence of invasive ESBL- and non-ESBL-producing Enterobacteriaceae infections and factors associated with clinical outcome were evaluated. Of the 175 cases considered evaluable, 77% were ESBL-producing organisms. Underlying comorbidities and potential risk factors were generally similar between ESBL and non-ESBL cases with a statistically greater proportion of ESBL cases requiring gastrostomy or jejunostomy tubes, ventilatory assistance, or care in the intensive care unit before culture (P