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Piperacillin/tazobactam (PTZ) is a broad-spectrum antibiotic, typically dosed every six hours (q6h). Guidelines recommend dosing PTZ every 2 hours (q2h) intra-operatively for complex abdominal surgery, including liver transplant. The data supporting the guidelines for intra-operative dosing are sparse and the pharmacokinetics/pharmacodynamics (PK/PD) of q2h dosing has not been studied by simulation or in humans. In this study, PK/PD parameters of high-frequency intra-operative dosing and q6h post-operative dosing were compared in critically ill children. Paediatric patients who received PTZ during complex abdominal surgery or transplant and who had intra-operative and post-operative opportunistic samples were included. Using a published PK model and observed concentrations, individual piperacillin PK/PD parameters were estimated using Bayesian estimation. Alternative post-operative dosing strategies were simulated using the patients with the highest and lowest estimated piperacillin clearance. Thirteen patients were included (median age: 3.1 years, 85% liver transplant recipients). PK parameters in the intra-operative and post-operative phases were not significantly different (clearance: 15.8 ± 7.2 vs. 12.6 ± 6.3 L/h/70 kg, P =0.070; central volume: 13.4 [13.1, 13.8] vs. 15.2 [12.2, 16.0] L/70 kg, P =0.22). At an individual level, intra-operative clearance values were -35% to 139% of the post-operative values, whereas central volume intra-operative values were -40% to 77% of the post-operative values. Intra-operative piperacillin exposure was higher during high-frequency dosing compared with the post-operative period (AUC/h: 109 [93.4, 127] vs. 62.8 [41.6, 78.3] mg/L, P =0.002). Simulations showed great variation in optimal dosing strategies that would minimise toxicity and maximise efficacy, indicating a role for individualised dosing in paediatric surgical populations. [ABSTRACT FROM AUTHOR]

• Meropenem-vaborbactam combination could be repurposed to restore the efficacy of first-line anti-tuberculosis drugs isoniazid and rifampin. • Meropenem-vaborbactam restores the rifampin effect in a dose-dependent fashion. • In the hollow fibre model, meropenem-vaborbactam in combination with moxifloxacin was non-inferior to the bedaquiline-pretomanid-linezolid combination regimen used for multidrug-resistant tuberculosis. Meropenem in combination with β-lactamase inhibitors (BLIs) and other drugs was tested to identify alternative treatment regimens for multidrug-resistant tuberculosis (MDR-TB). The following were performed: (1) MIC experiments; (2) static time-kill studies (STKs) with different BLIs; and (3) a hollow fibre model system of TB (HFS-TB) studies with meropenem-vaborbactam combined with human equivalent daily doses of 20 mg/kg or 35 mg/kg rifampin, or moxifloxacin 400 mg, or linezolid 600 mg vs. bedaquiline-pretonamid-linezolid (BPaL) for MDR-TB. The studies were performed using Mycobacterium tuberculosis (M. tuberculosis) H37Rv and an MDR-TB clinical strain (named M. tuberculosis 16D) that underwent whole genome sequencing. Exponential decline models were used to calculate the kill rate constant (K) of different HFS-TB regimens. Whole genome sequencing revealed mutations associated with resistance to rifampin, isoniazid, and cephalosporins. The meropenem-vaborbactam MIC of M. tuberculosis was H37Rv 2 mg/L and > 128 mg/L for M. tuberculosis 16D. Relebactam and vaborbactam improved both the potency and efficacy of meropenem in STKs. Meropenem-vaborbactam alone failed to kill M. tuberculosis 16D but killed below day 0 burden when combined with isoniazid and rifampin, with the moxifloxacin combination being the most effective and outranking bedaquiline and pretomanid. In the HFS-TB, meropenem-vaborbactam-moxifloxacin and BPaL had the highest K (log 10 cfu/mL/day) of 0.31 (95% CI 0.17–0.58) and 0.34 (95% CI 0.21–0.56), while meropenem-vaborbactam-rifampin (35 mg/kg) had a K of 0.18 (95% CI 0.12–0.25). The K for meropenem-vaborbactam-moxifloxacin-linezolid demonstrated antagonism. Adding meropenem-vaborbactam could potentially restore the efficacy of isoniazid and rifampin against MDR-TB. The meropenem-vaborbactam-moxifloxacin backbone regimen has implications for creating a new effective MDR-TB regimen. [ABSTRACT FROM AUTHOR]

• Adequate dosing resulting in effective exposure is crucial for therapeutic success. • Renal function is a vital determinant for achieving effective antibiotic exposure. • Standard dosing is ineffective for high renal function and less-susceptible pathogens. • We propose an intuitive 3-level meropenem dosing algorithm in critically ill patients. • The 3-level algorithm considers renal function and level of knowledge about the pathogen. Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharmacokinetic (PK) modelling was performed in NONMEM®7.3 based on densely sampled meropenem serum samples (n patients = 48; n samples = 1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000–6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft–Gault creatinine clearance (CLCR CG) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCR CG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3 (–MIC) , pathogen and susceptibility known; L3 (+MIC) , MIC known). Whereas patients with higher CLCR CG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information. [ABSTRACT FROM AUTHOR]

Highlights • Moxifloxacin 800 mg/day is the dose that most likely leads to resistance suppression while exerting maximum bacterial kill. • Linezolid 600 mg once-daily in a robust drug regimen may have similar potential. • Linezolid was shown to have very good activity against Mycobacterium tuberculosis even at decreased pH. • Linezolid is a vital option for kill of bacilli in the acidic phase, particularly if the isolate is resistant to pyrazinamide. Abstract Introduction There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance. Methods Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis was studied in the hollow-fiber infection model system in log-phase growth under neutral pH and slow growth in an acidic environment. Doses that achieved maximum bacterial kill while suppressing the emergence of drug resistance were determined. Through Monte Carlo simulations the quantitative output of this in vitro study was bridged to the human patient population to inform optimal dosage regimens while accounting for clinical minimum inhibitory concentration (MIC) distributions. Results and Discussion Moxifloxacin activity was significantly decreased in an acidified environment. The loss of activity was compensated by accumulation of the drug in TB lung lesions; therefore, moderate efficacy can be expected. Moxifloxacin 800 mg/day is the dose that most likely leads to resistance suppression while exerting maximum bacterial kill. Linezolid demonstrated very good activity even at a reduced pH. Linezolid 900 mg once-daily (QD) is likely to achieve a maximum killing effect and prevent the emergence of drug resistance; 600 mg QD in a robust drug regimen may have similar potential. [ABSTRACT FROM AUTHOR]

• Polymyxin B and rifampicin can synergistically kill Acinetobacter baumannii. • The semi-mechanistic pharmacokinetic/pharmacodynamic model aids dose optimisation. • Simulations with clinically utilised regimens confirmed its therapeutic potential. Antimicrobial resistance is a major global threat. Because of the stagnant antibiotic pipeline, synergistic antibiotic combination therapy has been proposed to treat rapidly emerging multidrug-resistant (MDR) pathogens. We investigated antimicrobial synergy of polymyxin/rifampicin combination against MDR Acinetobacter baumannii. In vitro static time-kill studies were performed over 48 h at an initial inoculum of ∼107 CFU/mL against three polymyxin-susceptible but MDR A. baumannii isolates. Membrane integrity was examined at 1 and 4 h post-treatment to elucidate the mechanism of synergy. Finally, a semi-mechanistic PK/PD model was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by mono- and combination therapies. Polymyxin B and rifampicin alone produced initial killing against MDR A. baumannii but were associated with extensive regrowth. Notably, the combination showed synergistic killing across all three A. baumannii isolates with bacterial loads below the limit of quantification for up to 48 h. Membrane integrity assays confirmed the role of polymyxin-driven outer membrane remodelling in the observed synergy. Subsequently, the mechanism of synergy was incorporated into a PK/PD model to describe the enhanced uptake of rifampicin due to polymyxin-induced membrane permeabilisation. Simulations with clinically utilised dosing regimens confirmed the therapeutic potential of this combination, particularly in the prevention of bacterial regrowth. Finally, results from a neutropenic mouse thigh infection model confirmed the in vivo synergistic killing of the combination against A. baumannii AB5075. Our results showed that polymyxin B combined with rifampicin is a promising option to treat bloodstream and tissue infection caused by MDR A. baumannii and warrants clinical evaluations. [ABSTRACT FROM AUTHOR]

• Linezolid is an oxazolidinone antibiotic used to treat Gram-positive bacterial infections. • The most serious adverse drug reaction (ADR) is linezolid-induced thrombocytopenia (LIT). • Assessment of the value of pharmacist-led interventions on LIT incidence. • Population pharmacokinetic model can optimise the dosage regimen of linezolid. • Interventions by clinical pharmacists reduced the incidence of LIT and other ADRs. This study evaluated the intervention effect of clinical pharmacist-mediated optimisation of a linezolid regimen using a population pharmacokinetic (PPK) model. Patients treated with linezolid in two medical centres from January 2020 to June 2021 were retrospectively included in the control group; those treated from July 2021 to June 2022 were prospectively enrolled in the intervention group. Clinical pharmacists optimised the dosage regimen according to a published linezolid PPK model in the intervention group. An interrupted times series approach was used to analyse the data. The incidence of linezolid-induced thrombocytopenia (LIT), target attainment of pharmacokinetic/pharmacodynamic parameters and other adverse drug reactions (ADRs) were compared between the two groups. In total, 77 and 103 patients were enrolled in the control and intervention groups, respectively. The intervention group had a lower incidence of LIT and other ADRs than the control group (10.7% vs. 23.4%, P = 0.002; 1.0% vs. 7.8%, P = 0.027). The intervention group exhibited a considerably lower trough concentration (C min) and area under the concentration–time curve/MIC ratio (AUC 24 /MIC) (P = 0.001 and P < 0.001). C min and AUC 24 /MIC rates within the target range were substantially higher in the intervention group (49.6% vs. 20.0%, adjusted P < 0.05; 48.1% vs. 25.6%, adjusted P < 0.05). Interventions by clinical pharmacists reduced the incidence of LIT and other ADRs. Implementation of model-informed precision dosing (MIPD) for linezolid markedly increased the C min and AUC 24 /MIC rates within the target range. We recommend MIPD-guided linezolid dose reduction for patients with renal impairment. [Display omitted] [ABSTRACT FROM AUTHOR]

• Omadacycline showed excellent efficacy in HFS- Mab at exposures that could be achieved in >99% of patients on 300 mg/day. • Sustained sputum culture conversion (SSCC) in 8/10 patients on omadacycline 300 mg/day-based combinations vs. 1/9 on guideline-based regimens. • No toxicity was observed in any of the cases vs. 9/9 patients treated with guideline-based regimens. • Omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months in one patient. Guideline-based therapy (GBT) for pulmonary Mycobacterium abscessus (Mab) disease achieves sustained sputum culture conversion (SSCC) rates of 30%; this is reflected by poor efficacy of GBT in the hollow fiber system model of Mab (HFS- Mab), which killed ∼1.22 log 10 CFU/mL. This study was performed to determine which clinical dose of omadacycline, a tetracycline antibiotic, should be used in combination therapy to treat pulmonary Mab disease for relapse-free cure. First, omadacycline intrapulmonary concentration-time profiles of seven daily doses were mimicked in the HFS- Mab model and exposures associated with optimal efficacy were identified. Second, 10,000 subject Monte-Carlo simulations were performed to determine whether oral omadacycline 300 mg/day achieved these optimal exposures. Third, a retrospective clinical study on omadacycline vs. primarily tigecycline-based salvage therapy was conducted to assess rates of SSCC and toxicity. Fourth, a single patient was recruited to validate the findings. Omadacycline efficacy in the HFS- Mab was 2.09 log 10 CFU/mL at exposures achieved in >99% of patients on 300 mg/day omadacycline. In the retrospective study of omadacycline 300 mg/day-based combinations vs. comparators, SSCC was achieved in 8/10 vs. 1/9 (P =0.006), symptom improvement in 8/8 vs. 5/9 (P =0.033), toxicity in 0 vs. 9/9 (P <0.001), and therapy discontinuation due to toxicity in 0 vs. 3/9 (P <0.001) cases, respectively. In one prospectively recruited patient, omadacycline 300 mg/day salvage therapy achieved SSCC and symptom-resolution in 3 months. Based on the preclinical and clinical data, omadacycline 300 mg/day in combination regimens could be appropriate for testing in Phase III trials in patients with Mab pulmonary disease. [ABSTRACT FROM AUTHOR]

Polymyxin B (PMB) and fosfomycin are two ‘old’ antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, the use of each antibiotic in monotherapy has been associated with high rates of treatment failure. Therefore, the objective of this study was to investigate the combinatorial pharmacodynamics of PMB and fosfomycin against KPC-producing K. pneumoniae (KPC-Kp) . PMB front-loading (3.33 mg/kg for one dose, followed by 1.43 mg/kg every 12 h starting 12 h later) and burst (5.53 mg/kg for one dose, with no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4 g every 8 h) against KPC-2-producing K. pneumoniae ST258 in a hollow-fibre infection model over 120 h. Population analysis profiles were used to track the temporal PMB and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (PMB MIC = 0.5 mg/L; fosfomycin MIC ≤ 8 mg/L), monotherapies resulted in >3 log 10 CFU/mL killing within 3 h but re-growth and proliferation of resistant subpopulations within 48 h. PMB combinations with fosfomycin demonstrated rapid bacterial killing (>6 log 10 CFU/mL reductions) while preventing propagation of PMB and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC = 0.5 mg/L; fosfomycin MIC = 32 mg/L), a PMB burst and fosfomycin combination caused a >6 log 10 CFU/mL reduction within 1 h, although bacterial re-growth occurred with the amplification of fosfomycin-resistant subpopulations. PMB in combination with fosfomycin may provide a practicable treatment strategy against KPC-Kp and warrants further investigation . [ABSTRACT FROM AUTHOR]

Purpose The purpose of this study was to identify the optimum dosing regimen of linezolid in sepsis patients with and without renal dysfunction and sepsis patients on low-dose continuous renal replacement therapy (CRRT) using a pharmacokinetics/pharmacokinetics (PK/PD) approach. Methods Sepsis patients with and without renal dysfunction (creatinine clearance < 50 mL/min), and sepsis patients on low-dose CRRT (dose: 800 mL/h) were studied. The PK data were modeled using a two-compartment model, and then used for simulation. The target PK/PD was the 24-h area under the concentration-time curve to minimum inhibitory concentration ratio of ≥ 80. Dosing regimens were evaluated using cumulative fraction of response (CFR) and safety probability (trough level < 7 µg/mL) by Monte Carlo simulation. Results Twenty-seven patients, including 8 patients with preserved renal function, 9 patients with renal dysfunction, and 10 patients on CRRT, were studied. The proposed regimen to attain CFR ≥ 90% was 800 mg every 12 h (safety probability 82.4%) for patients with preserved renal function. By contrast, the target CFR was attained with a decreased regimen in patients with renal dysfunction and those on CRRT [600 mg every 24h (safety probability 68.6%) and 800 mg every 24h (42.1%)]. Conclusions We identified different dosage strategies to achieve target linezolid concentrations according to renal function and use of CRRT in sepsis patients. Because of unassured safety probability in patients without preserved renal function, dosing regimens should be adjusted based on the therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection. [ABSTRACT FROM AUTHOR]

The effect of real-time pharmacokinetic/pharmacodynamic (PK/PD) optimisation of high-dose continuous-infusion meropenem on the clinical outcome of patients receiving combination antimicrobial therapy for treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections was retrospectively assessed. Data for all patients with KPC-Kp-related infections who received antimicrobial combination therapy containing high-dose continuous-infusion meropenem optimised by means of therapeutic drug monitoring (TDM) were retrieved. Optimal PK/PD exposure was considered a steady-state concentration to minimum inhibitory concentration ratio ( C ss /MIC) of 1–4. Univariate binary logistic regression analysis was performed to identify independent predictors of clinical outcome. Among the 30 eligible patients, 53.3% had infections caused by meropenem-resistant KPC-Kp (MIC ≥ 16 mg/L). Tigecycline and colistin were the two antimicrobials most frequently combined with meropenem. Mean doses of continuous-infusion meropenem ranged from 1.7 to 13.2 g/daily. The C ss /MIC ratio was ≥1 in 73.3% of cases and ≥4 in 50.0%. Clinical outcome was successful in 73.3% of cases after a median treatment length of 14.0 days. In univariate analysis, a significant correlation with successful clinical outcome was found for a C ss /MIC ratio ≥1 (OR = 10.556, 95% CI 1.612–69.122; P  = 0.014), a C ss /MIC ratio ≥4 (OR = 12.250, 95% CI 1.268–118.361; P  = 0.030) and a Charlson co-morbidity index of ≥4 (OR = 0.158, 95% CI 0.025–0.999; P  = 0.05). High-dose continuous-infusion meropenem optimised by means of real-time TDM may represent a valuable tool in improving clinical outcome when dealing with the treatment of infections caused by KPC-Kp with a meropenem MIC ≤ 64 mg/L. [ABSTRACT FROM AUTHOR]

• One hundred and thirty-two publications on pharmacokinetic/pharmacodynamic (PKPD) models for time courses of antibiotic effects were reviewed. • Points to consider when developing such PKPD models are discussed. • Models describing bacterial growth, regrowth, drug effects and interactions are shown. • An interactive online table enables the review of PKPD models from 1963 to 2021. Pharmacokinetic/pharmacodynamic (PKPD) models have emerged as valuable tools for the characterization and translation of antibiotic effects, and consequently for drug development and therapy. In contrast to traditional PKPD concepts for antibiotics such as minimum inhibitory concentration and PKPD indices, PKPD models enable description of the continuous, often species- or population-dependent time course of antimicrobial effects, commonly considering mechanistic pathogen- and drug-related knowledge. This review presents a comprehensive overview of previously published PKPD models describing repeated measurements of antibiotic effects. A literature review was conducted to identify PKPD models based on: (i) antibiotic compounds; (ii) Gram-positive or Gram-negative pathogens; and (iii) in-vitro or in-vivo longitudinal colony-forming unit data. In total, 132 publications were identified that were released between 1963 and 2021, including models based on exposure to single antibiotics (n =92) and drug combinations (n =40), as well as different experimental settings (e.g. static/traditional dynamic/hollow-fibre/animal time-kill models, n =90/27/32/11). An interactive, fully searchable table summarizes the details of each model, namely variants and mechanistic elements of PKPD submodels capturing observed bacterial growth, regrowth, drug effects and interactions. Furthermore, the review highlights the main purposes of PKPD model development, including the translation of preclinical PKPD to clinical settings, and the assessment of varied dosing regimens and patient characteristics for their impact on clinical antibiotic effects. In summary, this comprehensive overview of PKPD models will assist in identifying PKPD modelling strategies to describe growth, killing, regrowth and interaction patterns for pathogen–antibiotic combinations over time, and ultimately facilitate model-informed antibiotic translation, dosing and drug development. [ABSTRACT FROM AUTHOR]

Monte Carlo simulations were performed for various vancomycin dosage regimens to evaluate the potential for development of vancomycin resistance in meticillin-resistant Staphylococcus aureus (MRSA). When the target of free AUC 24 /MIC ≥ 200 was considered (where AUC 24 is the area under the drug concentration–time curve in a 24-h interval and MIC is the minimum inhibitory concentration), a standard dose regimen (1000 mg every 12 h) yielded unacceptable simulated outcomes in patients with normal renal function; in particular, the probability of target attainment (PTA) was only 30.5% at an MIC of 1 mg/L. For the same dosage regimens and the mutant prevention concentration (MPC)-based pharmacokinetic target (total AUC 24 /MPC > 15), the cumulative fraction of response exceeded 80% for all renal function strata; low values of PTA (<80%) were obtained only for isolates with MPCs of ≥22.4 mg/L, which consisted of all 21 strains of heterogeneous vancomycin-intermediate S. aureus (hVISA) and a handful of non-hVISA strains with MICs of 2 mg/L (32%; 16/50). Based on the current status of vancomycin resistance, we conclude that total AUC 24 /MPC > 15, derived from in vivo experiments, is more suitable to predict the development of vancomycin resistance. In clinical practice, individualised vancomycin therapy should be considered to minimise selection of resistance mutations. [ABSTRACT FROM AUTHOR]

The purpose of this report was to assess the impact of poor compliance on the efficacy of levofloxacin (LFX) and moxifloxacin (MOX), two fluoroquinolones with different pharmacokinetic (PK) and pharmacodynamic (PD) properties, in respiratory infections. The f AUC 0–24 h and f AUC 0–24 h /MIC 90 ratio, a PK/PD index predictive of bacterial eradication, were extracted from previously described population PK models for LFX and MOX. The MIC 90 was according to EUCAST. Monte Carlo simulations were used with LFX 500 mg every 24 h (q24 h) or every 12 h (q12 h), LFX 750 mg q24 h and MOX 400 mg q24 h in non-compliance scenarios to derive the proportion of patients achieving target ratios of f AUC 0–24 h /MIC 90 > 33.8 for Streptococcus pneumoniae and >100 for Haemophilus influenzae and Moraxella catarrhalis (PTA > 90%). In non-adherent dosing scenarios, LFX 500 mg q24 h was not able to reach the PK/PD index guaranteeing clinical efficacy. With LFX 500 mg q12 h or 750 mg q24 h, this probability was maintained although patients can take the dose with delays of up to 12 h and 11 h, respectively, for the three bacterial types. With MOX 400 mg q24 h, the probability of achieving this PK/PD index is maintained with delay in dosing up to 16 h. In conclusion, LFX 500 mg q24 h is the least robust treatment against S. pneumoniae , H. influenzae and M. catarrhalis in a non-adherence situation. A good choice is LFX 500 mg q12 h, but in order to favour patient adherence, LFX 750 mg q24 h or MOX 400 mg q24 h appears as more appropriate. [ABSTRACT FROM AUTHOR]

Despite the use of recommended therapies, invasive infections by Aspergillus terreus show a poor response. For years, investigative studies on the failure of therapy of fungal infections have focused on in vitro susceptibility data. However, it is well known that low minimum inhibitory concentrations (MICs) are not always predictive of response to therapy despite a correct dosage schedule. Many experimental and clinical studies have tried to establish a relationship between MICs and outcome in serious fungal infections but have come to contradictory and even surprising conclusions. The success or failure of treatment is determined by many factors, including the in vitro susceptibility of the causative fungal isolate, the pharmacokinetics/pharmacodynamics of the drug used for treatment, pharmacokinetic variability in the population, and the underlying disease that patients suffer. To try to understand this poor response to treatment, available data on the in vitro susceptibility of A. terreus , the experimental and clinical response to amphotericin B, triazoles and echinocandins, and the pharmacokinetics/pharmacodynamics of these antifungals have been reviewed. Of special interest are the fungistatic activites of these drugs against A. terreus and the high interpatient variability of serum drug levels observed in therapy based on triazoles, which make monitoring of infected patients necessary. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this report was to compare two different methods for dose optimisation of antimicrobials. The probability of target attainment (PTA) was calculated using Monte Carlo simulation to predict the PK/PD target of fT>MIC or modelling and simulation of time–kill curve data. Ceftobiprole, the paradigm compound, activity against two MRSA strains was determined, ATCC 33591 (MIC=2mg/L) and a clinical isolate (MIC=1mg/L). A two-subpopulation model accounting for drug degradation during the experiment adequately fit the time–kill curve data (concentration range 0.25–16× MIC). The PTA was calculated for plasma, skeletal muscle and subcutaneous adipose tissue based on data from a microdialysis study in healthy volunteers. A two-compartment model with distribution factors to account for differences between free serum and tissue interstitial space fluid concentration appropriately fit the pharmacokinetic data. Pharmacodynamic endpoints of fT>MIC of 30% or 40% and 1- or 2-log kill were used. The PTA was >90% in all tissues based on the PK/PD endpoint of fT>MIC >40%. The PTAs based on a 1- or 2-log kill from the time–kill experiments were lower than those calculated based on fT>MIC. The PTA of a 1-log kill was >90% for both MRSA isolates for plasma and skeletal muscle but was slightly below 90% for subcutaneous adipose tissue (both isolates ca. 88%). The results support a dosing regimen of 500mg three times daily as a 2-h intravenous infusion. This dose should be confirmed as additional pharmacokinetic data from various patient populations become available. [Copyright &y& Elsevier]

Abstract: The aims of this study were to investigate the penetration of meropenem (MER) into human prostate tissue and to assess MER regimens for prostatitis by performing a site-specific pharmacokinetic/pharmacodynamic evaluation. Patients with prostatic hypertrophy (n =49) prophylactically received a 0.5-h infusion of MER (250mg or 500mg) before transurethral resection of the prostate. MER concentrations in plasma (0.5–5h) and prostate tissue (0.5–1.5h) were measured chromatographically. Concentration data were analysed pharmacokinetically with a three-compartment model and were used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T >MIC, % of 24h) in prostate tissue, an indicator for antibacterial effects at the site of action. The prostate tissue/plasma ratio was 16.6% for the maximum drug concentration and 17.7% for the area under the drug concentration–time curve, irrespective of the dose. Against MIC distributions for clinical isolates of Escherichia coli, Klebsiella spp. and Proteus spp., 500mg once daily achieved a >90% probability of attaining the bacteriostatic target (20% T >MIC) in prostate tissue, and 500mg twice daily achieved a >90% probability of attaining the bactericidal target (40% T >MIC) in prostate tissue. However, against the Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability of attaining the bacteriostatic or bactericidal targets. [Copyright &y& Elsevier]

Abstract: Several pathophysiological changes in critically ill patients are important in determining the therapeutic success of β-lactam antibiotics. The aim of this study was to assess the population pharmacokinetics and probabilities of target attainment (PTAs) of doripenem in patients with ventilator-associated pneumonia, comparing administration by 1-h and 4-h infusion. Patients were randomised into two groups: Group I received a 1-h infusion of 0.5g every 8h (q8h) for seven doses; and Group II received a 4-h infusion of 0.5g q8h for seven doses. A Monte Carlo simulation was performed to determine the PTAs. PTAs of achieving 40% T >MIC [exposure time during which the free drug concentration remains above the minimum inhibitory concentration (MIC)] and 75% T >MIC are required for effective bactericidal activity of this agent in immunocompetent and immunocompromised hosts, respectively. Values of volume of distribution and total clearance of doripenem in these patients were 17.26±1.83L and 24.89±1.63L/h, respectively. For pathogens with a MIC of 1μg/mL, the PTAs of achieving 40% T >MIC following administration of doripenem by a 1-h and 4-h infusion of 0.5g q8h were 92.95% and 98.32%, respectively. For pathogens with a MIC of 2μg/mL in immunocompromised hosts, the PTAs of achieving 80% T >MIC following administration of doripenem by 1-h and 4-h infusion of 2g q8h were 56.57% and 91.21%, respectively. In conclusion, these findings indicated that higher than recommended doses in this patient population, particularly neutropenic patients, would be necessary to optimise the pharmacokinetics of doripenem. [Copyright &y& Elsevier]

Abstract: This study compared the susceptibility breakpoints based on pharmacokinetic/pharmacodynamic (PK/PD) models and Monte Carlo simulation with those defined by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for antibiotics used for the treatment of infections caused by Gram-positive bacteria. A secondary objective was to evaluate the probability of achieving the PK/PD target associated with the success of antimicrobial therapy. A 10000-subject Monte Carlo simulation was executed to evaluate 13 antimicrobials (47 intravenous dosing regimens). Susceptibility data were extracted from the British Society for Antimicrobial Chemotherapy database for bacteraemia isolates. The probability of target attainment and the cumulative fraction of response (CFR) were calculated. No antibiotic was predicted to be effective (CFR≥90%) against all microorganisms. The PK/PD susceptibility breakpoints were also estimated and were compared with CLSI and EUCAST breakpoints. The percentages of strains affected by breakpoint discrepancies were calculated. In the case of β-lactams, breakpoint discrepancies affected <15% of strains. However, higher differences were detected for low doses of vancomycin, daptomycin and linezolid, with PK/PD breakpoints being lower than those defined by the CLSI and EUCAST. If this occurs, an isolate will be considered susceptible based on CLSI and EUCAST breakpoints although the PK/PD analysis predicts failure, which may explain treatment failures reported in the literature. This study reinforces the idea of considering not only the antimicrobial activity but also the dosing regimen to increase the probability of clinical success of an antimicrobial treatment. [Copyright &y& Elsevier]

Abstract: The in vitro activity and in vivo efficacy of a new ciprofloxacin derivative (UB-8902) were evaluated. In vitro time–kill curves were performed for ciprofloxacin (CIP), moxifloxacin (MXF) and UB-8902 against CIP-susceptible (Ab58) and CIP-resistant (Ab661 and Ab33) Acinetobacter baumannii strains. UB-8902 showed similar bactericidal activity to CIP and MXF against these strains. In the in vivo experiments in mice, the toxicity of UB-8902, its 50% protective dose (PD50) (peritoneal sepsis model), its pharmacokinetic/pharmacodynamic (PK/PD) parameters and its efficacy in a pneumonia model were studied. The maximum tolerated dose of UB-8902 was 512mg/kg. PD50 values were 16, 128 and 32mg/kg for Ab58, Ab661 and Ab33, respectively. Pharmacokinetic parameters of UB-8902 were similar to MXF and were lower than those for CIP, whilst pharmacodynamic parameters were better than CIP. In the pneumonia model, UB-8902 decreased the bacterial lung concentration [4.62 colony-forming units (CFU)/g and 4.15log10 CFU/g] and positive blood cultures (60% and 62.5%) for Ab58 and Ab33, respectively, compared with the control. In conclusion, UB-8902 presents bactericidal activity against A. baumannii strains resistant to CIP. Moreover, it is effective at reducing mortality in a model of peritoneal sepsis with a dose lower than the toxic one, and it is efficacious in a murine pneumonia model. [Copyright &y& Elsevier]

Abstract: The pharmacokinetic/pharmacodynamic (PK/PD) indices useful for predicting antimicrobial clinical efficacy are well established. The most common indices include the time free drug concentration in plasma is above the minimum inhibitory concentration (MIC) (fT>MIC) expressed as a percent of the dosing interval, the ratio of maximum concentration to MIC (C max/MIC), and the ratio of the area under the 24-h concentration–time curve to MIC (AUC0–24/MIC). A single PK/PD index may correlate well with an entire antimicrobial class. For example, the β-lactams correlate well with the fT>MIC. However, other classes may be more complex and a single index cannot be generalised to the class, e.g. the macrolides. The rationale behind which PK/PD index best correlates with efficacy depends on several factors, including the mechanism of action, the microbial kill kinetics, the degree of protein binding and the degree of tissue distribution. Studies have traditionally emphasised the first two factors, whilst the significance of protein binding and tissue distribution is increasingly appreciated. In fact, the latter two factors may partially elucidate why the magnitude of reported target indices are not always as expected. For example, tigecycline and telithromycin are clinically efficacious with average serum concentrations below their MICs over a 24-h period. Therefore, to understand more fully the PK/PD relationship of antibiotics and to better predict the clinical efficacy of antibiotic dosing regimens, assessment of free drug concentrations at the site of action is warranted. [Copyright &y& Elsevier]

Abstract: Improved dosing regimens have been proposed for various antimicrobial agents by application of pharmacokinetic/pharmacodynamic (PK/PD) principles. However, for topical ophthalmic use there are several limitations to changing the dosing regimen, such as drug formulation and bioavailability. In this study, we investigated the relationship between dosing interval and antibacterial efficacy in an in vitro PK model mimicking post-operative endophthalmitis. The in vitro PK model simulated the aqueous humour concentration following topical application of 0.3% gatifloxacin ophthalmic solution to rabbit eyes. A clinical isolate of Enterococcus faecalis was exposed to gatifloxacin three times repeatedly at various intervals from 0h to 8h. The area between the control growth curve and the bacterial killing and re-growth curve for 24h (ABBC) was used to evaluate efficacy. The ABBC showed bell-shaped dependence on the dosing interval with a peak at 3h. Under limited condition of total exposure amount, i.e. area under the concentration–time curve, the antimicrobial efficacy appears to be associated with the cumulative time of a 24-h period such that the concentration exceeds the minimum inhibitory concentration (T >MIC) rather than the peak concentration:MIC ratio. The length of intermission of T >MIC during repeated dosing appears to be proportional to the decrease in efficacy of gatifloxacin against E. faecalis. A longer dosing interval, as long as T >MIC is continuous, would likely be more efficient at preventing post-operative enterococcal endophthalmitis. However, further investigation is necessary to explore whether this model is applicable to a variety of pathogens and drugs. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to assess the clinical efficacy of high-dose levofloxacin plus rifampicin in the empirical treatment of non-tuberculous spondylodiscitis in an epidemiological context of low incidence of staphylococcal fluoroquinolone resistance. All consecutive adult patients with spondylodiscitis (January 2003 to December 2006) were empirically treated with high-dose levofloxacin (500mg every 12h normalised to renal function and optimised by means of therapeutic drug monitoring whenever feasible) plus rifampicin 600mg every 24h. Trough and peak plasma concentrations were targeted at 1–3mg/L and 6–9mg/L, respectively, to maximise the concentration-dependent activity of levofloxacin in bone. Follow-up was performed until 9 months after the end of therapy. Forty-eight patients were included. Eleven patients underwent a surgical approach for spine stabilisation. Among the 29 bacterial isolates, Staphylococcus aureus was the most frequent (65.5%) (all meticillin-susceptible strains). Tailored levofloxacin plasma exposure over time was ensured in most cases. Median treatment duration was 15.1 weeks. Overall response rates were: 77.1% at the intent-to-treat analysis; 84.1% among patients who completed therapy (N =44); and 96.3% among those receiving targeted therapy against documented levofloxacin-susceptible isolates (N =27). No patient had evidence of disease relapse at follow-up. Our findings suggest that high-dose levofloxacin regimens may be highly effective in the treatment of non-tuberculous spondylodiscitis and support its putative role in combination with rifampicin against S. aureus. [Copyright &y& Elsevier]

Abstract: Patients admitted to Intensive Care Units (ICUs) are at very high risk of developing severe nosocomial infections. Consequently, antimicrobials are among the most important and commonly prescribed drugs in the management of these patients. Critically ill patients in ICUs include representatives of all age groups with a range of organ dysfunction related to severe acute illness that may complicate long-term illness. The range of organ dysfunction, together with drug interactions and other therapeutic interventions (e.g. haemodynamically active drugs and continuous renal replacement therapies), may strongly impact on antimicrobial pharmacokinetics in critically ill patients. In the last decade, it has become apparent that the intrinsic pharmacokinetic (PK) and pharmacodynamic (PD) properties are the major determinants of in vivo efficacy of antimicrobial agents. PK/PD parameters are essential in facilitating the translation of microbiological activity into clinical situations, ensuring a successful outcome. In this review, we analyse the typical patterns of antimicrobial activity and the corresponding PK/PD parameters, with a special focus on a PK/PD dosing approach of the antimicrobial agent classes commonly utilised in the ICU setting. [Copyright &y& Elsevier]

• Several factors have led to wide intra-patient and inter-patient variability of pharmacokinetics (PK) in antibiotics • Cystic fibrosis (CF) pathological changes can affect the disposition of antibacterial agents • The present study reviewed the PK/pharmacodynamics (PD) of antibiotics in CF patients • PD/PK indices and therapeutic drug monitoring protocols can provide solid tools to individualise antibiotic therapies in CF patients Cystic fibrosis affects several organs, predisposing patients to severe bacterial respiratory infections, including those caused by methicillin-resistant Staphylococcus aureus. Cystic fibrosis is also associated with a wide spectrum of pathological changes that can significantly affect the absorption, distribution, metabolism, and/or elimination of several drugs, including antibacterial agents. Therefore, awareness of the pharmacokinetic derangements in patients with cystic fibrosis is mandatory for the optimisation of antibiotic therapy. This review discusses the basic principles of pharmacokinetics and the pathophysiology of the pharmacokinetics changes associated with cystic fibrosis; it also provides an update of available data for the most widely used antibiotics. Evidence accumulated in the last few years has clearly shown that a significant number of cystic fibrosis patients treated with conventional dosing schemes have sub-therapeutic antibiotic concentrations, increasing their risk of therapeutic failure and/or the emergence of resistant pathogens. Some proposals to optimise antibiotic therapies in this clinical setting based on therapeutic drug monitoring are also discussed. [ABSTRACT FROM AUTHOR]

• Polymyxins are used as a last resort against multidrug-resistant Gram-negative bacteria. • f AUC/MIC is best correlated with the antimicrobial efficacy of polymyxins against Gram-negative pathogens. • Well-designed randomised clinical are desperately needed. Polymyxins are increasingly used as a last resort for the treatment of infections caused by multidrug-resistant Gram-negative bacteria in patients. Over the last decade, significant progress has been made in understanding the pharmacokinetics/pharmacodynamics/toxicodynamics (PK/PD/TD) of parenteral and inhaled polymyxins. This mini-review provides an overview of polymyxin chemistry, different dose definitions, and the latest research on their clinical use, toxicities, and PK/PD after intravenous and inhalation administration. Optimising the PK/PD/TD of polymyxins in patients is critical to maximise their efficacy while minimising toxicities and the emergence of resistance. [ABSTRACT FROM AUTHOR]

Abstract: The pharmacokinetics of the new oral des-fluoroquinolone antimicrobial garenoxacin (GRNX) was investigated in elderly patients with respiratory tract infections. Patients were treated with GRNX (200mg or 400mg) once daily for 7 days. Plasma GRNX concentrations were determined and pharmacokinetic parameters were estimated by Bayesian predictions using reported population pharmacokinetic parameters. At each dose, the maximum plasma concentration (C max) and the area under the concentration–time curve (AUC) were comparable with those reported in young subjects, except that the estimated C max and AUC values in one patient receiving the 200mg dose whose body weight and creatinine clearance rate (CLCr) were 38kg and 17mL/min, respectively, were higher than those of the other patients given 200mg GRNX and were comparable with those of patients who received the 400mg dose. These results suggest that the recommended dose of GRNX should be 400mg for most elderly and young patients, but only 200mg in patients whose body weight and CLCr are <40kg and <30mL/min, respectively. [Copyright &y& Elsevier]

Abstract: Previously, ertapenem 50mg/kg every 6h given subcutaneously to mice achieved a similar 24-h cumulative free time above the minimum inhibitory concentration (fT>MIC) to 1g every 24h in humans. However, this simplified regimen (SR) does not provide a superimposable concentration–time profile to that observed in humans, thus allowing concentrations to fluctuate above and below the minimum inhibitory concentration (MIC) throughout the 24-h period. Herein, we compared a complex regimen (CR; 9 various mg/kg doses over 24h) providing a near superimposable concentration–time profile with the SR to determine implications on bacterial kill against eight extended-spectrum β-lactamase (ESBL)-producing isolates over a wide MIC range. The CR resulted in a similar (±5%) 24-h cumulative fT>MIC to ertapenem 1g every 24h in humans over an MIC range of 0.032mg/L to 16mg/L. Similar bacterial kill was observed with both regimens against all eight ESBL-producing isolates examined. In mouse models, it appears that the 24-h cumulative fT>MIC and not the distribution of the fT>MIC over 24h drives efficacy. [Copyright &y& Elsevier]

• In vitro studies are essential for the evaluation of new antibiotic treatments. • Animal models are an important link between in vitro data and clinical testing. • Market authorization and dosing guidelines rely on preclinical pharmacokinetic/pharmacodynamic (PK/PD) studies. • Mathematical modeling can optimize study design and translation of preclinical data. • More clinical trials for optimal dosing are warranted but are difficult to perform. Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes. [ABSTRACT FROM AUTHOR]