Evaluation of the pharmacokinetic-pharmacodynamic integration of marbofloxacin in combination with methyl gallate against Salmonella Typhimurium in rats.

Fluoroquinolone resistance in Salmonella Typhimurium is becoming a major concern. Hence, an intervention to limit the growth in resistance is inevitable. One way to combat this challenge is through combination therapy. The combination of antibiotics with phytochemicals has become an ideal means of preventing antimicrobial resistance. Recently, in an in vitro study, the combination of methyl gallate (MG) with marbofloxacin (MAR) has shown to prevent Salmonella Typhimurium invasion. It is also worth to study the effects of plant extracts on the pharmacokinetics of antibiotics. Hence, the objective of this study was to determine the effect of MG on the pharmacokinetics of MAR and pharmacokinetics/pharmacodynamics integration of MG and MAR. The micro-broth dilution method was used to obtain the minimum inhibitory concentration (MIC), and fractional inhibitory concentration (FIC) of MAR and MG. Whereas, the pharmacokinetic was conducted in rats by administering either MAR alone or combined with MG through oral and/or intravenous routes. The results indicated that the MIC of MAR and MG against standard strain Salmonella Typhimurium (ATCC 14028) was 0.031 and 500 µg/mL, respectively. The FICindex of the combination of MAR and MG was 0.5. For orally administered drugs, the Cmax and AUC24h of MAR were 1.04 and 0.78 µg/mL and 5.98 and 6.11 h.µg/mL when MAR was given alone and in combination with MG, respectively. The intravenous administration of MAR showed a half-life of 3.8 and 3.9 h; a clearance rate of 1.1 and 0.73 L/h/kg and a volume of distribution of 5.98 and 4.13 L/kg for MAR alone and in combination with MG, respectively. The AUC24/MIC for MAR alone and in combination with MG was 192.8 and 381.9 h, respectively. In conclusion, MG has shown to increase the antimicrobial activity of MAR in vitro and ex vivo experiments without affecting the pharmacokinetics of MAR in rats.

Susceptibility breakpoint for Danofloxacin against swine Escherichia coli.

BACKGROUND: Improper use of antimicrobials results in poor treatment and severe bacterial resistance. Breakpoints are routinely used in the clinical laboratory setting to guide clinical decision making. Therefore, the objective of this study was to establish antimicrobial susceptibility breakpoints for danofloxacin against Escherichia coli (E.coli), which is an important pathogen of digestive tract infections. RESULTS: The minimum inhibitory concentrations (MICs) of 1233 E. coli isolates were determined by the microdilution broth method in accordance with the guidelines in Clinical and Laboratory Standards Institute (CLSI) document M07-A9. The wild type (WT) distribution or epidemiologic cutoff value (ECV) was set at 8 µg/mL with statistical analysis. Plasma drug concentration data were used to establish pharmacokinetic (PK) model in swine. The in vitro time kill test in our study demonstrated that danofloxacin have concentration dependent activity against E.coli. The PK data indicated that danofloxacin concentration in plasma was rapidly increased to peak levels at 0.97 h and remained detectable until 48 h after drug administration. The pharmacodynamic cutoff (COPD) was determined as 0.03 µg/mL using Monte Carlo simulation. To the best of our knowledge, this is the first study to establish the ECV and COPD of danofloxacin against E.coli with statistical method. CONCLUSIONS: Compared to the COPD of danofloxacin against E.coli (0.03 µg/mL), the ECV for E.coli seemed reasonable to be used as the final breakpoint of danofloxacin against E.coli in pigs. Therefore, the ECV (MIC ≤8 µg/mL) was finally selected as the optimum danofloxacin susceptibility breakpoint for swine E.coli. In summary, this study provides a criterion for susceptibility testing and improves prudent use of danofloxacin for protecting public health.

Individualising Therapy to Minimize Bacterial Multidrug Resistance.

The scourge of antibiotic resistance threatens modern healthcare delivery. A contributing factor to this significant issue may be antibiotic dosing, whereby standard antibiotic regimens are unable to suppress the emergence of antibiotic resistance. This article aims to review the role of pharmacokinetic and pharmacodynamic (PK/PD) measures for optimising antibiotic therapy to minimise resistance emergence. It also seeks to describe the utility of combination antibiotic therapy for suppression of resistance and summarise the role of biomarkers in individualising antibiotic therapy. Scientific journals indexed in PubMed and Web of Science were searched to identify relevant articles and summarise existing evidence. Studies suggest that optimising antibiotic dosing to attain defined PK/PD ratios may limit the emergence of resistance. A maximum aminoglycoside concentration to minimum inhibitory concentration (MIC) ratio of > 20, a fluoroquinolone area under the concentration-time curve to MIC ratio of > 285 and a ß-lactam trough concentration of > 6 × MIC are likely required for resistance suppression. In vitro studies demonstrate a clear advantage for some antibiotic combinations. However, clinical evidence is limited, suggesting that the use of combination regimens should be assessed on an individual patient basis. Biomarkers, such as procalcitonin, may help to individualise and reduce the duration of antibiotic treatment, which may minimise antibiotic resistance emergence during therapy. Future studies should translate laboratory-based studies into clinical trials and validate the appropriate clinical PK/PD predictors required for resistance suppression in vivo. Other adjunct strategies, such as biomarker-guided therapy or the use of antibiotic combinations require further investigation.

Clinical and pharmacokinetic drug evaluation of delafloxacin for the treatment of acute bacterial skin and skin structure infections.

INTRODUCTION: In the era of multi-drug resistant pathogens, the adequate treatment of skin and skin structure infections remains a challenge for clinicians. Delafloxacin, with its broad spectrum against Gram-positive, Gram-negative and anaerobic organisms, represents a new therapeutic option in this setting, especially when coverage of methicillin-resistant Staphylococcus aureus is required in the empirical or targeted approach. Areas covered: In this drug evaluation, the Authors have reviewed the pharmacokinetic and pharmacodynamic characteristics of delafloxacin. In addition, recent data on clinical efficacy and safety from clinical trials have been included. Expert opinion: Delafloxacin represents an attractive therapeutic option due to a broad antimicrobial and favorable pharmacokinetic and pharmacodynamic profile. Several in vitro studies have demonstrated the low potential for resistance selection if used in empirical regimens. Delafloxacin is a promising candidate for the treatment of Gram-positive infections, especially if co-infection with other pathogens is suspected. This is because of the very low MIC of the agent for Gram-positive (including MRSA) and anaerobic bacteria and because of the wide spectrum of activity against Gram-negative organisms. For these interesting microbiological and PK/PD characteristics we expect future uses of this drug in other indications such as diabetic foot infection, osteomyelitis, prosthetic joint infections, abdominal infections and central nervous system infections.

Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.

Pharmacokinetic/Pharmacodynamics-Optimized Antimicrobial Therapy in Patients with Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia.

Hospital-acquired pneumonia and ventilator-associated pneumonia continue to cause significant morbidity and mortality. With increasing rates of antimicrobial resistance, the importance of optimizing antibiotic treatment is key to maximize treatment outcomes. This is especially important in critically ill patients in intensive care units, in whom the infection is usually caused by less susceptible organisms. In addition, the marked physiological changes that can occur in these patients can cause serious changes in antibiotic pharmacokinetics which in turn alter the attainment of therapeutic drug exposures. This article reviews the various aspects of the pharmacokinetic changes that can occur in the critically ill patients, the barriers to achieving therapeutic drug exposures in pneumonia for systemically delivered antibiotics, the optimization for commonly used antibiotics in hospital- and ventilator-associated pneumonia, the agents that should be avoided in the treatment regimen, as well as the use of adjunctive therapy in the form of nebulized antibiotics.

Integrated pharmacokinetic-Pharmacodynamic (PK/PD) model to evaluate the in vivo antimicrobial activity of Marbofloxacin against Pasteurella multocida in piglets.

BACKGROUND: Marbofloxacin is a veterinary fluoroquinolone with high activity against Pasteurella multocida. We evaluated it's in vivo activity against P. multocida based on in vivo time-kill data in swine using a tissue-cage model. A series of dosages ranging from 0.15 to 2.5 mg/kg were administered intramuscularly after challenge with P. multocida type B, serotype 2. RESULTS: The ratio of the 24 h area under the concentration-time curve divided by the minimum inhibitory concentration (AUC24TCF/MIC) was the best PK/PD index correlated with the in vivo antibacterial effectiveness of marbofloxacin (R2 = 0.9279). The AUC24TCF/MIC necessary to achieve a 1-log10 CFU/ml reduction and a 3-log10 CFU/ml (90% of the maximum response) reduction as calculated by an inhibitory sigmoid Emax model were 13.48 h and 57.70 h, respectively. CONCLUSIONS: Marbofloxacin is adequate for the treatment of swine infected with P. multocida. The tissue-cage model played a significant role in achieving these PK/PD results.

Efficacy of intramuscular moxifloxacin in the treatment of experimental osteomyelitis caused by methicillin-resistant Staphylococcus aureus.

Fluoroquinolones have been well studied in the treatment of chronic osteomyelitis due to their beneficial pharmacokinetic (PK) and pharmacodynamic profiles. The purpose of this study was to determine the efficacy of intramuscular (IM) moxifloxacin administration in the treatment of experimental osteomyelitis by methicillin-resistant Staphylococcus aureus. Following an experimental osteomyelitis animal model described previously, three groups of rabbits (A = control; B = IM moxifloxacin administration; C = PK study of moxifloxacin penetration into bone) were evaluated. Three weeks after bacterial inoculation, surgical debridement was performed in all animals and IM treatment commenced for Groups B and C. Sacrifice was performed in an A:B group animal ratio of 1:2 at weekly intervals from 7th to 42nd day post debridement and from 21st to 56th day post debridement for Groups A and B, respectively (including 2-week interval without antibiotics for Group B). Cancellous bone was harvested for microbiological and histopathological analyses at re-operation and sacrifice for Groups A and B. Cortical bone moxifloxacin levels were measured in Group C following 7, 14, 35 and 42 days of treatment. In Group A, bacterial growth after surgical debridement was significant, whereas high eradication rates were observed in Group B. Radiological abnormalities and histopathological findings were evaluated. Moxifloxacin bone levels, observed in Group C, were approximately 43 times higher than the minimum inhibitory concentration, with no difference found between infected and healthy tibial bone. The therapeutic protocol was very effective in this model of experimental osteomyelitis. However, further evaluation of these results in clinical studies is crucial.

Pharmacodynamics of Finafloxacin, Ciprofloxacin, and Levofloxacin in Serum and Urine against TEM- and SHV-Type Extended-Spectrum-ß-Lactamase-Producing Enterobacteriaceae Isolates from Patients with Urinary Tract Infections.

The pharmacodynamics of finafloxacin, ciprofloxacin, and levofloxacin against extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae isolates were compared. Since quinolones lose activity in acidic media, and particularly in urine, their activities were tested in parallel under conventional conditions and in acidic artificial urine. For this purpose, TEM- and SHV-type ESBL-producing Escherichia coli and Klebsiella pneumoniae strains and their wild-type counterparts were exposed in a modified Grasso model to simulated concentrations of drugs in serum and urine following oral doses of either finafloxacin at 800 mg once a day (q.d.), immediate-release ciprofloxacin at 500 mg twice a day (b.i.d.), extended-release ciprofloxacin at 1,000 mg q.d., or levofloxacin at 500 or 750 mg q.d. The concentrations of the drugs in urine were fitted by compartmental modeling. Bacteria were cultivated in Mueller-Hinton broth (MHB) at pH 7.2 or 5.8 or in artificial urine at pH 5.8. Bacteria were counted every 2 h until 10 h and at 24 h; the areas under the bacterial-count-versus-time curves were calculated. It was found that finafloxacin eliminated all strains within 2 h under all the conditions studied. At all doses studied, ciprofloxacin and levofloxacin were highly active against wild-type strains in MHB at pH 7.2 but lost activity in MHB, and particularly in urine, at pH 5.8. Viable counts of ESBL producers were reduced for 6 to 8 h by 3 log10 titers, but the bacteria regrew thereafter. Ciprofloxacin and levofloxacin were almost inactive against the SHV producer grown in artificial urine. We conclude that pharmacodynamic models using artificial urine may mirror the physiology of urinary tract infections more closely than those using conventional media. In contrast to ciprofloxacin and levofloxacin, finafloxacin gained activity in this model at an acidic pH, maintained activity in artificial urine, and was active against TEM and SHV producers.

Effect of rifampicin and efavirenz on moxifloxacin concentrations when co-administered in patients with drug-susceptible TB.

Objectives: We compared the pharmacokinetics of moxifloxacin during rifampicin co-treatment or when dosed alone in African patients with drug-susceptible recurrent TB. Methods: Patients in the intervention arm of the Improving Retreatment Success (IMPRESS) randomized controlled TB trial received 400 mg of moxifloxacin, with rifampicin, isoniazid and pyrazinamide in the treatment regimen. Moxifloxacin concentrations were measured in plasma during rifampicin-based TB treatment and again 4 weeks after treatment completion, when given alone as a single dose. Moxifloxacin concentration-time data were analysed using non-linear mixed-effects models. Results: We included 58 patients; 42 (72.4%) were HIV co-infected and 40 (95%) of these were on efavirenz-based ART. Moxifloxacin pharmacokinetics was best described using a two-compartment disposition model with first-order lagged absorption and elimination using a semi-mechanistic model describing hepatic extraction. Oral clearance (CL/F) of moxifloxacin during rifampicin-based TB treatment was 24.3 L/h for a typical patient (fat-free mass of 47 kg), resulting in an AUC of 16.5 mg·h/L. This exposure was 7.8% lower than the AUC following the single dose of moxifloxacin given alone after TB treatment completion. In HIV-co-infected patients taking efavirenz-based ART, CL/F of moxifloxacin was increased by 42.4%, resulting in a further 30% reduction in moxifloxacin AUC. Conclusions: Moxifloxacin clearance was high and plasma concentrations low in our patients overall. Moxifloxacin AUC was further decreased by co-administration of efavirenz-based ART and, to a lesser extent, rifampicin. The clinical relevance of the low moxifloxacin concentrations for TB treatment outcomes and the need for moxifloxacin dose adjustment in the presence of rifampicin and efavirenz co-treatment need further investigation.

Zabofloxacin for chronic bronchitis.

Treatment of lower respiratory tract infection poses as an ongoing challenge among respiratory tract diseases. Bacterial infections are causes of acute exacerbations in chronic bronchitis and indications for antibacterial therapy. Several antibiotics were applied to treat bacterial infections in chronic bronchitis, among them fluoroquinolones are considered potent, broad-spectrum agents with excellent tissue penetration. This monograph focuses on zabofloxacin, a novel fluoroquinolone agent recently approved and launched in South Korea, and summarizes the drug's antibacterial efficacy, pharmacokinetic properties and toxicity. Recent advances concerning fluoroquinolones in chronic bronchitis will be discussed, along with a comparison between zabofloxacin and moxifloxacin. Zabofloxacin has proved to be noninferior to moxifloxacin against major community-acquired Gram-positive and Gram-negative respiratory tract pathogens and found to be well tolerated in both oral and parenteral administrations. These features can make it a potential antimicrobial agent in therapy of chronic bronchitis and other lower respiratory tract infections.

Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo.

BACKGROUND: No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. METHODS: We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. RESULTS: The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. CONCLUSIONS: We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.

Neonate with Mycoplasma hominis meningoencephalitis given moxifloxacin.

Mycoplasma hominis is a commensal organism in the genitourinary tract that can cause life-threatening CNS infections in neonates after intrauterine infection or through vertical transmission during birth. We present a case of an 11-day-old neonate presenting with fever and supporting laboratory evidence of a CNS infection. No systemic maternal infection or maternal genitourinary tract infection occurred at the time of delivery. Empirical treatment was initiated, consisting of amoxicillin, cefotaxime, and aciclovir. After clinical deterioration, 16S ribosomal DNA PCR in cerebrospinal fluid detected M hominis, antibiotic treatment was switched to moxifloxacin, and pharmacokinetic data were obtained. This Grand Round illustrates the challenges that exist in the diagnosis and treatment of M hominis meningoencephalitis: bacterial cultures are often negative and recommended empirical antimicrobials do not provide adequate antimicrobial coverage. Optimal antimicrobial treatment regimens for M hominis meningoencephalitis are unknown. Although we describe successful treatment of a neonate with a complicated M hominis meningoencephalitis with moxifloxacin, caution with fluoroquinolone monotherapy (including moxifloxacin) has to be taken into account because resistance to fluoroquinolones has previously been described.

The role of moxifloxacin in tuberculosis therapy.

Tuberculosis (TB) remains a global threat with more than 9 million new infections. Treatment remains difficult and there has been no change in the duration of the standard regimen since the early 1980s. Moreover, many patients are unable to tolerate this treatment and discontinue therapy, increasing the risk of resistance. There is a growing tide of multidrug resistance and few effective antibiotics to tackle the problem. Since the turn of the millennium there has been a surge in interest in developing new therapies for TB and a number of new drugs have been developed. In this review the repurposing of moxifloxacin, an 8-methoxy-fluoroquinolone, for TB treatment is discussed. The evidence that underpins the development of this agent is reviewed. The results of the recently completed phase III trials are summarised and the reasons for the unexpected outcome are explored. Finally, the design of new trials that incorporate moxifloxacin, and that address both susceptible disease and multidrug resistance, is described.

Shortening Tuberculosis Treatment With Fluoroquinolones: Lost in Translation?

The disappointing recent failure of fluoroquinolone-containing regimens to shorten the duration of tuberculosis treatment in costly phase 3 trials has raised serious questions about the reliability of preclinical tuberculosis models, especially mice, and the current paradigm of regimen development. Therefore we re-examined data from murine models and early-stage clinical trials on which the pivotal trials were based, concluding that phase 3 trial results were in line with preceding studies. Finally, we offer suggestions for a more efficient and integrated preclinical and clinical regimen development program where quantitative pharmacokinetic and pharmacodynamic models more predictive of curative treatment durations are set forth.

Rifampicin-moxifloxacin interaction in tuberculosis treatment: a real-life study.

SETTING: Rifampicin (RMP) has been reported to reduce moxifloxacin (MFX) levels, which may interfere with the effectiveness of MFX in treating tuberculosis (TB). OBJECTIVE: To study the MFX-RMP interaction in patients receiving MFX with or without RMP as part of their anti-tuberculosis treatment regimen. DESIGN: Patients with pulmonary TB followed up by the Tuberculosis Out-patient Clinic of the Pulmonary Department, Aristotle University of Thessaloniki, Greece, who underwent treatment with MFX during the periods 1 May 2012-30 April 2014 and 1 January-31 March 2015, were included in the study. MFX levels were compared between 12 patients who were receiving RMP (Group 1) and 10 who were not (Group 2). RESULTS: The participants did not significantly differ in body mass index, days of MFX treatment or MFX dose/kg. Neither the peak concentration (Cmax) nor the 24 h area under the curve (AUC24) differed significantly between the two groups (Group 1, Cmax median 3.9 [range 1.9-4.5] mg/l; AUC24 29.1 [10-47.4] mg·h/l and Group 2, Cmax 4.1 [2-6.4] mg/l; AUC24 36.5 [14.6-54.2] mg·h/l). CONCLUSION: Although a decrease in MFX exposure was observed in the RMP-treated group, the effect was lower than previously reported in a real-life setting. The large variability observed in MFX pharmacokinetics in both groups may suggest the need for dose readjustment in some patients, regardless of RMP co-administration.

Impact of aflatoxin B1 on the pharmacokinetic disposition of enrofloxacin in broiler chickens.

The potential impact of subchronic exposure of aflatoxin B1 was investigated on the pharmacokinetic disposition of enrofloxacin in broiler chickens. Broiler chickens given either normal or aflatoxin B1 (750µg/kg diet) supplemented diet for 6 weeks received a single oral dose of enrofloxacin (10mg/kg body wt). Blood samples were drawn from the brachial vein at predetermined time intervals after drug administration. Enrofloxacin plasma concentrations analyzed by RP-HPLC were significantly lower in aflatoxin B1-exposed broiler chickens at 0.167, 0.5 and 1.0h after drug administration. In aflatoxin B1-exposed broiler chickens, the absorption rate constant (ka) of enrofloxacin (0.20±0.05h(-1)) was significantly decreased as compared to the unexposed birds (0.98±0.31h(-1)). The values of [Formula: see text] , tmax and AUC0-∞ of enrofloxacin were nonsignificantly increased by 17%, 26% and 17% in aflatoxin-exposed broiler chickens, respectively. Subchronic aflatoxin B1 exposure markedly decreased the initial absorption of enrofloxacin without significantly influencing other pharmacokinetic parameters in broiler chickens.

A Monte Carlo pharmacokinetic/pharmacodynamic simulation to evaluate the efficacy of minocycline, tigecycline, moxifloxacin, and levofloxacin in the treatment of hospital-acquired pneumonia caused by Stenotrophomonas maltophilia.

BACKGROUND: Stenotrophomonas maltophilia has emerged as an important opportunistic pathogen in recent years. Increasing antimicrobial resistance and other contraindications have greatly compromised trimethoprim/sulfamethoxazole (SXT) as the first-line therapeutic option. The objective of this study was to explore other options for treating hospital-acquired pneumonia (HAP) caused by S. maltophilia. METHODS: A total of 102 strains of S. maltophilia were isolated from sputum and bronchoalveolar lavage (BAL) specimens of patients with HAP in our institution. The minimum inhibitory concentration (MIC) values of minocycline, tigecycline, moxifloxacin, and levofloxacin were determined by the agar dilution method. Based on the MICs and the population pharmacokinetic parameters of the investigated antimicrobials, a Monte Carlo simulation was performed to simulate the pharmacokinetic/pharmacodynamic (PK/PD) indices of different regimens. The probability of target attainment (PTA) was estimated at each MIC value and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. RESULTS: The susceptibility rates to minocycline, tigecycline, moxifloxacin, and levofloxacin were 96.1%, 80.4%, 74.5%, and 69.6%, respectively. The estimated CFRs were 96.2% for minocycline 100 mg twice daily; 50.8%/67.1%/75.4% for tigecycline 50/75/100 mg twice daily; 34.3%/48.0%/56.6% for levofloxacin 500/750/1000 mg once daily; and 45.7% for moxifloxacin 400 mg once daily. CONCLUSIONS: The simulation results suggest that minocycline may be a proper choice for treatment of HAP caused by S. maltophilia, while tigecycline, moxifloxacin, and levofloxacin may not be optimal as monotherapy.

A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization.

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.