In vivo efficacy of human simulated regimens of carbapenems and comparator agents against NDM-1-producing Enterobacteriaceae.

Doripenem and ertapenem have demonstrated efficacy against several NDM-1-producing isolates in vivo, despite having high MICs. In this study, we sought to further characterize the efficacy profiles of humanized regimens of standard (500 mg given every 8 h) and high-dose, prolonged infusion of doripenem (2 g given every 8 h, 4-h infusion) and 1 g of ertapenem given intravenously every 24 h and the comparator regimens of ceftazidime at 2 g given every 8 h (2-h infusion), levofloxacin at 500 mg every 24 h, and aztreonam at 2 g every 6 h (1-h infusion) against a wider range of isolates in a murine thigh infection model. An isogenic wild-type strain and NDM-1-producing Klebsiella pneumoniae and eight clinical NDM-1-producing members of the family Enterobacteriaceae were tested in immunocompetent- and neutropenic-mouse models. The wild-type strain was susceptible to all of the agents, while the isogenic NDM-1-producing strain was resistant to ceftazidime, doripenem, and ertapenem. Clinical NDM-1-producing strains were resistant to nearly all five of the agents (two were susceptible to levofloxacin). In immunocompetent mice, all of the agents produced ≥1-log10 CFU reductions of the isogenic wild-type and NDM-1-producing strains after 24 h. Minimal efficacy of ceftazidime, aztreonam, and levofloxacin against the clinical NDM-1-producing strains was observed. However, despite in vitro resistance, ≥1-log10 CFU reductions of six of eight clinical strains were achieved with high-dose, prolonged infusion of doripenem and ertapenem. Slight enhancements of doripenem activity over the standard doses were obtained with high-dose, prolonged infusion for three of the four isolates tested. Similar efficacy observations were noted in neutropenic mice. These data suggest that carbapenems are a viable treatment option for infections caused by NDM-1-producing Enterobacteriaceae.

Efficacy of humanized carbapenem and ceftazidime regimens against Enterobacteriaceae producing OXA-48 carbapenemase in a murine infection model.

Enterobacteriaceae producing the OXA-48 carbapenemase are emerging worldwide, leaving few treatment options. Efficacy has been demonstrated in vivo with ceftazidime against a ceftazidime-susceptible OXA-48 isolate but not with imipenem despite maintaining susceptibility. The relationship between phenotype and in vivo efficacy was assessed for OXA-48 producers using humanized regimens of 2 g doripenem every 8 h (q8h; 4 h infusion), 1 g ertapenem q24h, 2 g ceftazidime q8h (2 h inf), and 500 mg levofloxacin q24h. Each regimen was evaluated over 24 h against an isogenic pair (wild-type and OXA-48 Klebsiella pneumoniae strains) and six clinical OXA-48 isolates with and without other extended-spectrum ß-lactamases in immunocompetent and neutropenic murine thigh infection models. Efficacy was determined using the change in bacterial density versus 24-h growth controls in immunocompetent studies and 0-h controls in neutropenic studies. Bacterial reductions of ≥1 log CFU were observed with all agents for the wild-type strain. Consistent with low MICs, ceftazidime and levofloxacin exhibited efficacy against the isogenic OXA-48 strain, whereas doripenem did not, despite having a susceptible MIC; no activity was observed with ertapenem, consistent with a resistant MIC. Similar trends were observed for the clinical isolates evaluated. Ceftazidime, levofloxacin, and ertapenem efficacy against isogenic and clinical OXA-48-producing strains correlated well with phenotypic profiles and pharmacodynamic targets, whereas efficacy with doripenem was variable over the MIC range studied. These data suggest that carbapenems may not be a reliable treatment for treating OXA-48 producers and add to previous observations with KPC and NDM-1 suggesting that genotype may better predict activity of the carbapenems than the phenotypic profile.

Efficacy of humanized carbapenem exposures against New Delhi metallo-ß-lactamase (NDM-1)-producing enterobacteriaceae in a murine infection model.

Enterobacteriaceae producing the novel carbapenemase New Delhi metallo-ß-lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels of in vitro resistance to multiple antibiotics, in vivo efficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-type K. pneumoniae and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24-h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed the in vitro maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was ≤ 8 µg/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producing Enterobacteriaceae under certain conditions, and this warrants further in vivo exploration.

In vitro pharmacodynamics of vancomycin and cefazolin alone and in combination against methicillin-resistant Staphylococcus aureus.

Previous studies employing time-kill methods have observed synergistic effects against methicillin-resistant Staphylococcus aureus (MRSA) when a ß-lactam is combined with vancomycin. However, these time-kill studies have neglected the importance of human-simulated exposures. We evaluated the effect of human simulated exposures of vancomycin at 1 g every 8 h (q8h) in combination with cefazolin at 1 g q8h against various MRSA isolates. Four clinical isolates (two MRSA isolates [vancomycin MICs, 0.5 and 2.0 µg/ml], a heterogeneous vancomycin-intermediate S. aureus [hVISA] isolate [MIC, 2.0 µg/ml], and a vancomycin-intermediate S. aureus [VISA] isolate [MIC, 8.0 µg/ml]) were evaluated in an in vitro pharmacodynamic model with a starting inoculum of 10(6) or 10(8) CFU/ml. Bacterial density was measured over 48 to 72 h. Time-kill curves were constructed, and the area under the bacterial killing and regrowth curve (AUBC) was calculated. During 10(6) CFU/ml studies, combination therapy achieved greater log(10) CFU/ml changes than vancomycin alone at 12 h (-4.31 ± 0.58 versus -2.80 ± 0.59, P < 0.001), but not at 48 h. Combination therapy significantly reduced the AUBC from 0 to 48 h (122 ± 14) compared with vancomycin alone (148 ± 22, P = 0.017). Similar results were observed during 10(8) CFU/ml studies, where combination therapy achieved greater log(10) CFU/ml changes at 12 h than vancomycin alone (-4.00 ± 0.20 versus -1.10 ± 0.04, P < 0.001) and significantly reduced the AUBC (275 ± 30 versus 429 ± 37, P < 0.001) after 72 h of incubation. In this study, the combination of vancomycin and cefazolin at human-simulated exposures improved the rate of kill against these MRSA isolates and resulted in greater overall antibacterial effect, but no differences in bacterial density were observed by the end of the experiments.

Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infections using in vivo microdialysis.

Staphylococcus aureus and other Gram-positive organisms, including methicillin-resistant S. aureus, continue to be the predominant pathogens associated with diabetic foot infections. Consequently, linezolid is often used to treat these infections. The purpose of the current study was to describe the pharmacokinetic profile and determine the level of penetration of linezolid into healthy thigh tissue and infected wound tissue of the same extremity in 9 diabetic patients with chronic lower limb infections by use of in vivo microdialysis. Hourly plasma and dialysate samples were obtained over a 12-h dosing interval following 3 to 4 doses of linezolid (600 mg intravenously every 12 h). Plasma protein binding was also assessed at 1, 6, and 12 h postdose. The means ± standard deviations (SD) for the maximum concentration in serum (C(max)), the volume of distribution at terminal phase (V(z)), and the half-life (t(1/2)) for linezolid in plasma were 11.99 ± 3.67 µg/ml, 0.71 ± 0.25 liters/kg of body weight, and 4.71 ± 1.23 h, respectively. Mean protein binding was 14.78% (range, 3.85 to 32.03%). The mean areas under the concentration-time curves from 0 to 12 h for the free, unbound fraction of linezolid (fAUC(0-12) values) ± SD for plasma, wound tissue, and thigh tissue were 51.24 ± 12.72, 82.76 ± 59.01, and 92.52 ± 60.44 µg · h/ml, respectively. Tissue penetration ratios (tissue fAUC to plasma fAUC) were similar for thigh (1.42; range, 1.08 to 2.23) and wound (1.27; range, 0.86 to 2.26) tissues (P = 0.648). With the currently approved dosing regimen, linezolid penetrated well into both healthy thigh tissue and infected wound tissue in these diabetic patients.

In vitro pharmacodynamics of simulated pulmonary exposures of tigecycline alone and in combination against Klebsiella pneumoniae isolates producing a KPC carbapenemase.

Multidrug-resistant Klebsiella pneumoniae strains that produce a serine carbapenemase (KPC) are emerging worldwide, with few therapeutic options that retain consistent susceptibility. The objective of this study was to determine the effect of combination therapy with tigecycline versus tigecycline alone against KPC-producing isolates (KPC isolates). An in vitro pharmacodynamic model was used to simulate adult steady-state epithelial lining fluid concentrations of tigecycline (50 mg every 12 h) given alone and in combination with either meropenem (2 g by 3-hour infusion every 8 h) or rifampin (600 mg every 12 h). Five KPC isolates with various phenotypic profiles were exposed over 48 h. Time-kill curves were constructed, and the areas under the bacterial killing and regrowth curves (AUBCs) were calculated. No regimens tested were able to maintain bactericidal reductions in CFU over 48 h. The AUBCs for tigecycline and meropenem monotherapies at 48 h ranged from 375.37 to 388.11 and from 348.62 to 383.83 (CFU-h/ml), respectively. The combination of tigecycline plus meropenem significantly reduced the AUBCs at 24 and 48 h for isolates with tigecycline MICs of ≤ 2 µg/ml and meropenem MICs of ≤ 16 µg/ml (P < 0.001) but added no additional activity when the meropenem MIC was 64 µg/ml (P = 0.5). Rifampin provided no additional reduction in CFU or AUBC over tigecycline alone (P = 0.837). The combination of tigecycline with high-dose, prolonged-infusion meropenem warrants further study as a potential treatment option for these multidrug-resistant organisms.

In vivo efficacy of a human-simulated regimen of ceftaroline combined with NXL104 against extended-spectrum-beta-lactamase (ESBL)-producing and non-ESBL-producing Enterobacteriaceae.

Ceftaroline exhibits in vitro activity against extended-spectrum ß-lactamase (ESBL)-, AmpC-, and KPC-producing Enterobacteriaceae when combined with the novel ß-lactamase inhibitor NXL104. The purpose of this study was to evaluate the efficacy of a human-simulated regimen of ceftaroline plus NXL104 against Enterobacteriaceae in a murine thigh infection model. Twelve Enterobacteriaceae isolates were tested with neutropenic ICR mice. Seven of these isolates were also tested with immunocompetent mice. Doses were given to simulate human free-drug exposures of ceftaroline (600 mg) plus NXL104 (600 mg) every 8 h over 24 h by targeting the percentage of time that free drug concentrations remain above the MIC, ƒT>MIC. The change in log(10) CFU/ml compared with 0 h controls was observed after 24 h. Human-simulated exposures were achieved against all isolates (MICs of ≤0.015 to 1 µg/ml) in both the neutropenic and the immunocompetent host models, which was equivalent to a ƒT>MIC of 100%. A 0.5 to ≥ 2 log CFU reduction was observed in the neutropenic thigh infection model. Furthermore, significantly greater reductions in bacterial density were observed for five of seven isolates studied in an immunocompetent model than in the neutropenic-host model. Regardless of immune status, ceftaroline (600 mg) combined with NXL104 (600 mg) every 8 h provided predictable efficacy against ESBL-, non-ESBL-, and KPC-producing isolates with an MIC of ≤ 1 µg/ml and could be useful in combating the growing threat of resistant Enterobacteriaceae.

Tissue penetration and pharmacokinetics of tigecycline in diabetic patients with chronic wound infections described by using in vivo microdialysis.

Tissue penetration of systemic antibiotics is an important consideration for positive outcomes in diabetic patients. Herein we describe the exposure profile and penetration of tigecycline in the interstitial fluid of wound margins versus that of uninfected thigh tissue in 8 adult diabetic patients intravenously (IV) administered 100 mg and then 50 mg of tigecycline twice daily for 3 to 5 doses. Prior to administration of the first dose, 2 microdialysis catheters were inserted into the subcutaneous tissue, the first within 10 cm of the wound margin and the second in the thigh of the same extremity. Samples for determination of plasma and tissue concentrations were simultaneously collected over 12 h under steady-state conditions. Tissue concentrations were corrected for percent in vivo recovery by the retrodialysis technique. Plasma samples were also collected for determination of protein binding at 1, 6, and 12 h postdose for each patient. Protein binding data were corrected using a fitted polynomial equation. The mean patient weight was 95.1 kg (range, 63.6 to 149.2 kg), the mean patient age was 63.5 ± 9.4 years, and 75% of the patients were males. The mean values for the plasma, thigh, and wound free area under the concentration-time curve from 0 to 24 h (fAUC(0-24)) were 2.65 ± 0.33, 2.52 ± 1.15, and 2.60 ± 1.02 µg·h/ml, respectively. Protein binding was nonlinear, with the percentage of free drug increasing with decreasing serum concentrations. Exposure values for thigh tissue and wound tissue were similar (P = 0.986). Mean steady-state tissue concentrations for the thigh and wound were similar at 0.12 ± 0.02 µg/ml, and clearance from the tissues appeared similar to that from plasma. Tissue penetration ratios (tissue fAUC/plasma fAUC) were 99% in the thigh and 100% in the wound (P = 0.964). Tigecycline penetrated equally well into wound and uninfected tissue of the same extremity.

Inpatient antibiotic resistance: Everyone's problem.

Greater efforts aimed at using antimicrobials sparingly and appropriately, as well as developing new antimicrobials with activity against multidrug-resistant pathogens, are ultimately needed to address the threat of antimicrobial resistance. This article describes the evidence-based management of inpatient infections caused by resistant bacteria and the role family physicians can play in reducing further development of resistance through antimicrobial stewardship practices.

Iontophoretic drug delivery across human nail.

Topical trans-nail delivery of antifungal drugs is limited by several physicochemical and physiological factors. Use of chemical permeation enhancers has been a common approach for enhancing trans-nail delivery of drugs. The potential of physical permeation enhancement techniques has been found to be higher than the potential of chemical permeation enhancers in transdermal delivery of hydrophilic drugs and macromolecular therapeutic agents. However, application of physical permeation enhancement techniques has not been explored for trans-nail drug delivery. In the current work, iontophoresis was applied across human nail in vitro to assess its efficiency in enhancing drug delivery. Salicylic acid (SA) was used as test diffusant. The influence of pH, ionic strength, and current density was studied. Obviously, increase in current density increased the trans-nail transport flux. It appears that about 50-100 mM ionic strength is required for optimal conduction of electric current across nail. The flux enhancement factor (iontophoretic flux/passive flux) also increased with increase in pH due to increased ionization of SA. This study demonstrates the efficacy of iontophoresis in enhancing the trans-nail delivery of drugs.

Antibiotic stewardship: The FP's role.

Drug resistance is an expanding problem in outpatient settings. The text and tables that follow can help you fight it by adhering to optimal prescribing guidelines.

Antibiotic Tissue Penetration in Diabetic Foot Infections A Review of the Microdialysis Literature and Needs for Future Research.

Although many antimicrobial agents display good in vitro activity against the pathogens frequently implicated in diabetic foot infections, effective treatment can be complicated by reduced tissue penetration in this population secondary to peripheral arterial disease and emerging antimicrobial resistance, which can result in clinical failure. Improved characterization of antibiotic tissue pharmacokinetics and penetration ratios in diabetic foot infections is needed. Microdialysis offers advantages over the skin blister and tissue homogenate studies historically used to define antibiotic penetration in skin and soft-tissue infections by defining antibiotic penetration into the interstitial fluid over the entire concentration versus time profile. However, only a select number of agents currently recommended for treating diabetic foot infections have been evaluated using these methods, which are described herein. Better characterization of the tissue penetration of antibiotic agents is needed for the development of methods for maximizing the pharmacodynamic profile of these agents to ultimately improve treatment outcomes for patients with diabetic foot infections.

Impact of various conditions on the efficacy of dual carbapenem therapy against KPC-producing Klebsiella pneumoniae.

The efficacy of dual carbapenem therapy under various conditions, including increased MIC, different immune status and treatment duration and use of a higher ertapenem dose, was evaluated in a murine thigh model. Three KPC-producing Klebsiella pneumoniae isolates with different phenotypic profiles were used. Human-simulated doripenem and ertapenem doses were given alone or in combination. Three isolates were tested over 24 h in immunocompetent and immunocompromised ICR mice. Two of the isolates were also evaluated over 72 h in neutropenic mice. High-dose ertapenem regimens were also evaluated. The efficacy of combination therapy was enhanced in the immunocompetent model over the neutropenic model (P<0.05 for all three isolates). In the immunocompetent model, bacterial density was further reduced with use of combination therapy over doripenem monotherapy for two isolates with doripenem MICs≤16 mg/L (statistically greater for one isolate; P<0.05). Whilst not statistically different at 24 h in neutropenic mice, combination therapy demonstrated significantly greater efficacy over doripenem alone for one of two isolates at 72 h (P<0.05). Use of ertapenem 2g did not enhance efficacy over ertapenem 1 g (P>0.05). The beneficial effects of dual carbapenem therapy and potential difference in efficacy based on doripenem MICs are evident at 24 h in an immunocompetent setting. Within a neutropenic setting, enhanced efficacy with combination therapy may only be evident with continued therapy. Dual carbapenem regimens may represent a promising option for infections caused by KPC-producing isolates, particularly when the MIC is low.

Comparative pharmacokinetics, pharmacodynamics, and tolerability of ertapenem 1 gram/day administered as a rapid 5-minute infusion versus the standard 30-minute infusion in healthy adult volunteers.

STUDY OBJECTIVE: To compare ertapenem pharmacokinetics, pharmacodynamics, and tolerability when administered as a rapid 5-minute infusion to the standard 30-minute infusion. DESIGN: Prospective, randomized, crossover pharmacokinetic study. SETTING: Clinical research center. SUBJECTS: Twelve healthy adult volunteers. INTERVENTION: Each subject received ertapenem 1 g intravenously, administered either as a rapid 5-minute infusion or the standard 30-minute infusion, every 24 hours for 3 days (first phase); after a 4-day washout period, each subject then received the other infusion every 24 hours for 3 days (second phase). MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected after the first and third (steady-state) doses of each study phase, and protein binding was assessed by use of ultrafiltration. Pharmacokinetic analyses were conducted using noncompartmental and compartmental methods. A 5000-subject Monte Carlo simulation was used to assess the probability of target attainment for free drug concentration remaining above the minimum inhibitory concentration (MIC) for 40% or greater of the dosing interval (40% fT > MIC) over an MIC range. Ertapenem was well tolerated and adverse events were similar for both infusions. The ertapenem steady-state mean ± SD maximum concentrations were 193.3 ± 43.3 and 165.7 ± 20.4 mg/L for the 5- and 30-minute infusions, respectively; the mean ± SD areas under the concentration-time curves from 0-24 hours were 561.2 ± 77.0 and 531.3 ± 56.9 µg · hr/ml (geometric mean ratio 1.008, 90% confidence interval 0.999-1.017), respectively. Protein binding was concentration dependent (range 87.9-98.9%). A two-compartment model best described ertapenem pharmacokinetics with the following parameter estimates: clearance 1.89 ± 0.19 L/hr, volume of central compartment 5.04 ± 0.56 L, and transfer constants k12 0.43 ± 0.08/hr and k21 0.44 ± 0.07/hr. The probabilities of target attainment for 5- and 30-minute infusions were 97.0% and 97.9% at an MIC of 0.25 mg/L and 1.7% and 2.8% at an MIC of 0.5 mg/L, respectively. CONCLUSION: Ertapenem administered as a rapid 5-minute infusion provides a well tolerated, bioequivalent, and pharmacodynamically equivalent regimen to the 30-minute infusion at clinically relevant MICs.

Acute physiology and chronic health evaluation II score is a better predictor of mortality than IBMP-10 in patients with ventilator-associated pneumonia.

BACKGROUND: The (Immunodeficiency, Blood pressure [<90 mm Hg], Multilobular intiltrates [chest x-ray], Platelets [<100×109/L], hospitalization [<10 days] before the onset of ventilator-associated pneumonia [VAP]) IBMP-10 is a new scoring system proposed as an easy-to-use alternative to the Acute Physiology and Chronic Health Evaluation II (APACHE II) score for predicting mortality in patients with ventilator-associated pneumonia (VAP). The objective of this study was to determine the validity of the IBMP-10 score compared with APACHE II in predicting mortality for an independent population consisting predominantly of surgical and neurotrauma patients. METHODS: The IBMP-10 and APACHE II scores on the day of VAP diagnosis were calculated, and areas under the receiver-operating characteristic curves (AUROCs) were compared to determine the tests' abilities to predict 14- and 28-day mortality. RESULTS: A total of 168 patients meeting the radiologic and clinical criteria for VAP for a single hospitalization between 2004 and 2007 were included; 80% of these were from the surgical or neurotrauma intensive care unit. Overall mortality rates were 15% and 23% at 14 and 28 days, respectively. The AUROC for the IMBP-10 score for predicting 14-day mortality was 0.609 (p=0.084) compared with 0.648 (p=0.017) for the APACHE II score. Both IBMP-10 and APACHE II AUROCs for predicting 14-day mortality were lower than observed in the original score validation (0.808 and 0.743, respectively). The AUROCs for predicting 28-day mortality were 0.602 (p=0.056) and 0.705 (p<0.001) for IBMP10 and APACHE II, respectively. CONCLUSIONS: The IBMP-10 score was less reliable than the APACHE II score in predicting 14-day mortality in this independent population of VAP patients. This finding highlights the need for additional validation of new disease severity scoring systems in a study population independent of the population used to derive score criteria, as well as in more specific populations of critically ill patients.