Antimicrobial Pharmacodynamics Research Articles

Pharmacokinetics and pharmacodynamics of antimicrobials in sepsis

Pharmacokinetics and pharmacodynamics of antimicrobials in sepsis

Should Airway Interstitial Fluid Be Used to Evaluate the Pharmacokinetics of Macrolide Antibiotics for Dose Regimen Determination in Respiratory Infection?

Macrolide antibiotics are important drugs to combat infections. The pharmacokinetics (PK) of these drugs are essential for the determination of their optimal dose regimens, which affect antimicrobial pharmacodynamics and treatment success. For most drugs, the measurement of their concentrations in plasma/serum is the surrogate for drug concentrations in target tissues for therapy. However, for macrolides, simple reliance on total or free drug concentrations in serum/plasma might be misleading. The macrolide antibiotic concentrations of serum/plasma, interstitial fluid (ISF), and target tissue itself usually yield very different PK results. In fact, the PK of a macrolide antibiotic based on serum/plasma concentrations alone is not an ideal predictor for the in vivo efficacy against respiratory pathogens. Instead, the PK based on drug concentrations at the site of infection or ISF provide much more clinically relevant information than serum/plasma concentrations. This review aims to summarize and compare/discuss the use of drug concentrations of serum/plasma, airway ISF, and tissues for computing the PK of macrolides. A better understanding of the PK of macrolide antibiotics based on airway ISF concentrations will help optimize the antibacterial dose regimen as well as minimizing toxicity and the emergence of drug resistance in clinical practice.

Antimicrobial pharmacodynamics of vancomycin and disulfiram (Antabuse®) in Staphylococcus aureus.

Intravenous vancomycin (VAN) is the primary treatment for systemic infections due to methicillin-resistant Staphylococcus aureus (MRSA). Pharmacokinetic/pharmacodynamic target (PK/PD) indices for VAN therapies are more difficult to achieve for MRSA isolates with a minimum inhibitory concentration (MIC) greater than 1 µg mL-1. This research investigated the in vitro antimicrobial PD interaction of disulfiram (DSF) with VAN as a potential adjuvant therapy for infections due to these bacteria. The antimicrobial interaction was assessed by differential analysis using checkerboard titration testing, time-kill studies, flow cytometry, and the post-antibiotic effect (PAE) experiment. Ten MRSA strains with MICs ranging from 1 to >256 µg mL-1 for VAN were evaluated. A comprehensive PD assessment of the VAN/DSF interaction was performed using the VAN-intermediate (VISA) strain Mu50 (MIC 8 µg mL-1). The addition of DSF lowered the MIC and minimum bactericidal concentration (MBC) of VAN in either a synergistic or additive manner for the MRSA panel. Optimal bactericidal effects and suppression of VISA Mu50 growth were observed with a 4/8 µg mL-1 combination of VAN/DSF, but not the individual drugs. Flow cytometry further confirmed the enhanced killing action on a cellular level; however, the addition of DSF had an overall antagonistic effect on the PAEs for VAN. This research established that DSF exhibits additive to synergistic killing action with VAN for MRSA. Conversely, antagonism was observed on the PAE of VAN with DSF addition for the Mu50 strain. Flow cytometry further confirmed the enhanced bactericidal effect on a cellular level while revealing that DSF may counteract the muropeptide fortification mechanism against VAN in VISA.

Do Different Sutures with Triclosan Have Different Antimicrobial Activities? A Pharmacodynamic Approach.

(1) Background: Three antimicrobial absorbable sutures have different triclosan (TS) loads, triclosan release kinetics and hydrolysis times. This in vitro study aims to analyse and compare their antimicrobial pharmacodynamics. (2) Methods: Time-kill assays were performed with eight triclosan-susceptible microorganisms common in surgical site infections (SSIs) and a segment of each TS. Microbial concentrations were measured at T0, T4, T8 and T24 h. Similar non-triclosan sutures (NTS) were used as controls. Microbial concentrations were plotted and analysed with panel analysis. They were predicted over time with a double-exponential model and four parameters fitted to each TS × microorganism combination. (3) Results: The microbial concentration was associated with the triclosan presence, timeslot and microorganism. It was not associated with the suture material. All combinations shared a common pattern with an early steep concentration reduction from baseline to 4–8 h, followed by a concentration up to a 24-h plateau in most cases with a mild concentration increase. (4) Conclusions: Microorganisms seem to be predominantly killed by contact or near-contact killing with the suture rather than the triclosan concentration in the culture medium. No significant in vitro antimicrobial pharmacodynamic difference between the three TS is identified. Triclosan can reduce the suture microbial colonisation and SSI risk.

Current Aspects of Pediatric Pharmacokinetics and Pharmacodynamics of Antimicrobials in Japan: Importance of the Promotion of Population PK/PD Analysis.

Pharmacologic knowledge is important for pediatricians conducting feasible pharmacokinetic or pharmacodynamic (PK/PD) studies or applying effective antimicrobial therapies in children. Because of the difficulties in conducting PK/PD studies in children, antimicrobial PK/PD data in children are still limited. To fill in the lack of knowledge, promotion of population PK/PD analysis, which allows us to handle sparse sampling data from individual patients, is important because it is considered a suitable methodology to conduct PK/PD studies in children with limited blood drug concentration data for PK/PD analysis. Population PK/PD analysis is also useful in the clinical setting to provide individualized optimal dosage for each patient with various conditions. Here we summarized the current aspects of pediatric PK/PD studies of antimicrobials in Japan from clinical and research perspectives, specifically focusing on the importance of population PK/PD analysis.

Modelling the antimicrobial pharmacodynamics for bacterial strains with versus without acquired resistance to fluoroquinolones or cephalosporins

Antimicrobial resistance threatens therapeutic options for human and animal bacterial diseases worldwide. Current antimicrobial treatment regimens were designed against bacterial strains that were fully susceptible to them. To expand the useable lifetime of existing antimicrobial drug classes by modifying treatment regimens, data are needed on the antimicrobial pharmacodynamics (PD) against strains with reduced susceptibility. In this study, we generated and mathematically modelled the PD of the fluoroquinolone ciprofloxacin and the cephalosporin ceftriaxone against non-typhoidal Salmonella enterica subsp. enterica strains with varying levels of acquired resistance. We included Salmonella strains across categories of reduced susceptibility to fluoroquinolones or cephalosporins reported to date, including isolates from human infections, food-animal products sold in retail, and food-animal production. We generated PD data for each drug and strain via time-kill assay. Mathematical models were compared in their fit to represent the PD. The best-fit model's parameter values across the strain susceptibility categories were compared. The inhibitory baseline sigmoid Imax (or Emax) model was best fit for the PD of each antimicrobial against a majority of the strains. There were statistically significant differences in the PD parameter values across the strain susceptibility categories for each antimicrobial. The results demonstrate predictable multiparameter changes in the PD of these first-line antimicrobials depending on the Salmonella strain's susceptibility phenotype and specific genes conferring reduced susceptibility. The generated PD parameter estimates could be used to optimise treatment regimens against infections by strains with reduced susceptibility.

Optimizing antimicrobial use: challenges, advances and opportunities.

An optimal antimicrobial dose provides enough drug to achieve a clinical response while minimizing toxicity and development of drug resistance. There can be considerable variability in pharmacokinetics, for example, owing to comorbidities or other medications, which affects antimicrobial pharmacodynamics and, thus, treatment success. Although current approaches to antimicrobial dose optimization address fixed variability, better methods to monitor and rapidly adjust antimicrobial dosing are required to understand and react to residual variability that occurs within and between individuals. We review current challenges to the wider implementation of antimicrobial dose optimization and highlight novel solutions, including biosensor-based, real-time therapeutic drug monitoring and computer-controlled, closed-loop control systems. Precision antimicrobial dosing promises to improve patient outcome and is important for antimicrobial stewardship and the prevention of antimicrobial resistance.

Hypoalbuminemia as Surrogate and Culprit of Infections.

Hypoalbuminemia is associated with the acquisition and severity of infectious diseases, and intact innate and adaptive immune responses depend on albumin. Albumin oxidation and breakdown affect interactions with bioactive lipid mediators that play important roles in antimicrobial defense and repair. There is bio-mechanistic plausibility for a causal link between hypoalbuminemia and increased risks of primary and secondary infections. Serum albumin levels have prognostic value for complications in viral, bacterial and fungal infections, and for infectious complications of non-infective chronic conditions. Hypoalbuminemia predicts the development of healthcare-associated infections, particularly with Clostridium difficile. In coronavirus disease 2019, hypoalbuminemia correlates with viral load and degree of acute lung injury and organ dysfunction. Non-oncotic properties of albumin affect the pharmacokinetics and pharmacodynamics of antimicrobials. Low serum albumin is associated with inadequate antimicrobial treatment. Infusion of human albumin solution (HAS) supplements endogenous albumin in patients with cirrhosis of the liver and effectively supported antimicrobial therapy in randomized controlled trials (RCTs). Evidence of the beneficial effects of HAS on infections in hypoalbuminemic patients without cirrhosis is largely observational. Prospective RCTs are underway and, if hypotheses are confirmed, could lead to changes in clinical practice for the management of hypoalbuminemic patients with infections or at risk of infectious complications.

Association between antimicrobial drug class selection for treatment and retreatment of bovine respiratory disease and health, performance, and carcass quality outcomes in feedlot cattle.

Treatment and control of bovine respiratory disease (BRD) is predicated on the use of two categories of antimicrobials, namely bacteriostatic drugs that inhibit bacterial growth and replication (STATIC), and bactericidal drugs that kill bacteria in in vitro culture systems (CIDAL). Recently, we reported that initial BRD treatment with a STATIC antimicrobial followed by retreatment with a CIDAL antimicrobial was associated with a higher frequency of multidrug-resistant bacteria isolated from field cases of BRD submitted to a veterinary diagnostic laboratory. The present study was conducted to test the hypothesis that calves administered the same class of antimicrobial for first and second BRD treatment (i.e., CIDAL-CIDAL or STATIC-STATIC) would have improved health and performance outcomes at the feedlot compared to calves that received a different antimicrobial class for retreatment (i.e., STATIC-CIDAL or CIDAL-STATIC). The association between antimicrobial treatments and health, performance, and carcass quality outcomes were determined by a retrospective analysis of 4,252 BRD treatment records from a commercial feedlot operation collected from 2001 to 2005. Data were compared using generalized linear mixed statistical models that included gender, season, and arrival weight as covariates. The mean (±SE) probability of BRD cases identified as requiring four or more treatments compared to three treatments was greater in calves that received STATIC-CIDAL (73.58 ± 2.38%) or STATIC-STATIC (71.32 ± 2.52%) first and second antimicrobial treatments compared to calves receiving CIDAL-CIDAL (50.35 ± 3.46%) first and second treatments (P < 0.001). Calves receiving CIDAL-CIDAL first and second treatments also had an increased average daily gain (1.11 ± 0.03 kg/d) compared to calves receiving STATIC-CIDAL (0.95 ± 0.03 kg/d) and STATIC-STATIC (0.84 ± 0.02 kg/d) treatments (P < 0.001). Furthermore, CIDAL-CIDAL-treated calves had a higher probability of a choice quality grade at slaughter (36.44 ± 4.80%) compared to STATIC-CIDAL calves (28.09 ± 3.88%) (P = 0.037). There was no effect of antimicrobial treatment combination on BRD mortality (P = 0.855) or yield grade (P = 0.240) outcomes. These observations suggest that consideration should be given to antimicrobial pharmacodynamics when selecting drugs for retreatment of BRD. These findings have implications for developing BRD treatment protocols that address both post-treatment production and antimicrobial stewardship concerns.

Association between antimicrobial drug class for treatment and retreatment of bovine respiratory disease (BRD) and frequency of resistant BRD pathogen isolation from veterinary diagnostic laboratory samples.

Although 90% of BRD relapses are reported to receive retreatment with a different class of antimicrobial, studies examining the impact of antimicrobial selection (i.e. bactericidal or bacteriostatic) on retreatment outcomes and the emergence of antimicrobial resistance (AMR) are deficient in the published literature. This survey was conducted to determine the association between antimicrobial class selection for treatment and retreatment of BRD relapses on antimicrobial susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Pathogens were isolated from samples submitted to the Iowa State University Veterinary Diagnostic Laboratory from January 2013 to December 2015. A total of 781 isolates with corresponding animal case histories, including treatment protocols, were included in the analysis. Original susceptibility testing of these isolates for ceftiofur, danofloxacin, enrofloxacin, florfenicol, oxytetracycline, spectinomycin, tilmicosin, and tulathromycin was performed using Clinical and Laboratory Standards Institute guidelines. Data were analyzed using a Bayesian approach to evaluate whether retreatment with antimicrobials of different mechanistic classes (bactericidal or bacteriostatic) increased the probability of resistant BRD pathogen isolation in calves. The posterior distribution we calculated suggests that an increased number of treatments is associated with a greater probability of isolates resistant to at least one antimicrobial. Furthermore, the frequency of resistant BRD bacterial isolates was greater with retreatment using antimicrobials of different mechanistic classes than retreatment with the same class. Specifically, treatment protocols using a bacteriostatic drug first followed by retreatment with a bactericidal drug were associated with a higher frequency of resistant BRD pathogen isolation. In particular, first treatment with tulathromycin (bacteriostatic) followed by ceftiofur (bactericidal) was associated with the highest probability of resistant M. haemolytica among all antimicrobial combinations. These observations suggest that consideration should be given to antimicrobial pharmacodynamics when selecting drugs for retreatment of BRD. However, prospective studies are needed to determine the clinical relevance to antimicrobial stewardship programs in livestock production systems.

1559. Ertapenem Plus Ceftriaxone or Ceftaroline Dual Β-Lactam Combination for Enterococcus faecalis

BackgroundAmpicillin-ceftriaxone β-lactam therapy has become the standard of care for treating serious Enterococcus faecalis infections. Alternative regimens are of interest due to ceftriaxone’s association with C. difficile infections and VRE colonization, and ampicillin’s instability and inconvenient dosing schedule.Methods E. faecalis wild-type strain JH2-2 was utilized in a 48-hour in vitro pharmacodynamic model with a starting inoculum of 106 colony-forming units (CFU)/mL. Models were performed in duplicate to triplicate. Simulated doses of ertapenem 1g every 24 hours (fCmax 12.2 μg/mL; half-life 4 hours; MIC 4 μg/mL), ceftriaxone 2 g every 12 hours (fCmax 28.5 μg/mL; half-life 6.5 hours; MIC 512 μg/mL), and ceftaroline 600 mg every 8 hours (fCmax 27.1 μg/mL; half-life 2.7 hours; MIC 2 μg/mL) were tested. Ertapenem was also combined with ceftriaxone or ceftaroline. Bacterial counts were obtained at 0, 4, 8, 24, 32, and 48 hours. Bactericidal activity was defined as ≥ 3-log10 CFU/mL reduction from the initial inoculum. MICs were assessed at 0, 24, and 48 hours using E-tests in accordance with CLSI.ResultsErtapenem plus ceftriaxone, and ertapenem plus ceftaroline demonstrated bactericidal activity at 24 hours, but bacterial regrowth was observed at 48 hours (Table 1). An ertapenem MIC increase was only noted in one set of the ertapenem plus ceftriaxone models to 16mcg/mL at 48 hours, from 4mcg/mL at 0 hours. All other models did not have an increase in MIC.ConclusionBactericidal activity of ertapenem-based dual β-lactam combinations may prove to be an alternative treatment for severe E. faecalis infections. Mechanistic understanding of penicillin-binding protein (PBP) saturation and optimization of antimicrobial pharmacodynamics must be explored. Disclosures All authors: No reported disclosures.

Bacterial brothers in arms: cooperation of Staphylococcus aureus and Pseudomonas aeruginosa during antimicrobial exposure.

The optimal selection of antibacterials during polymicrobial infections is poorly defined. The objective of the current investigation was to quantify the pharmacodynamics of relevant antimicrobials during co-culture of Pseudomonas aeruginosa with two separate Staphylococcus aureus phenotypes. Time-kill experiments were conducted against co-cultures of the P. aeruginosa strain PA01 paired with either the normal phenotype (NP) MRSA isolate COL or the small colony variant phenotype (SCVP) MRSA isolate Ia48. The killing by levofloxacin, gentamicin, clindamycin, vancomycin and polymyxin B was evaluated to investigate drugs with activity against one or both pathogens. A Hill-type function and a mechanism-based model were used to describe bacterial killing. P. aeruginosa attenuated the activity of clindamycin against NP MRSA, with a reduction in the Emax (maximal killing) from 3.67 (95% CI 2.79-4.56) in monoculture to 1.86 (95% CI 1.35-2.37) during co-culture, whereas a significant protective effect was not observed for other antibacterials. The reduction in NP MRSA killing by clindamycin was described well by a mechanism-based model that generated a maximal killing rate constant of clindamycin against the susceptible NP MRSA subpopulation of 0.267 h-1 in monoculture and 0.0395 h-1 in the presence of P. aeruginosa. During exposure to gentamicin, P. aeruginosa was the dominant organism in co-culture experiments regardless of the drug concentration or S. aureus phenotype; however, the SCVP MRSA was able to dominate the joint population beginning at a levofloxacin concentration of 1.5 mg/L. The anti-staphylococcal activity of clindamycin was attenuated by the presence of P. aeruginosa.

World Health Organization Global Gonococcal Antimicrobial Surveillance Program (WHO GASP): review of new data and evidence to inform international collaborative actions and research efforts.

Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a serious public health problem, compromising the management and control of gonorrhoea globally. Resistance in N. gonorrhoeae to ceftriaxone, the last option for first-line empirical monotherapy of gonorrhoea, has been reported from many countries globally, and sporadic failures to cure especially pharyngeal gonorrhoea with ceftriaxone monotherapy and dual antimicrobial therapies (ceftriaxone plus azithromycin or doxycycline) have been confirmed in several countries. In 2018, the first gonococcal isolates with ceftriaxone resistance plus high-level azithromycin resistance were identified in England and Australia. The World Health Organization (WHO) Global Gonococcal Antimicrobial Surveillance Program (GASP) is essential to monitor AMR trends, identify emerging AMR and provide evidence for refinements of treatment guidelines and public health policy globally. Herein we describe the WHO GASP data from 67 countries in 2015-16, confirmed gonorrhoea treatment failures with ceftriaxone with or without azithromycin or doxycycline, and international collaborative actions and research efforts essential for the effective management and control of gonorrhoea. In most countries, resistance to ciprofloxacin is exceedingly high, azithromycin resistance is present and decreased susceptibility or resistance to ceftriaxone has emerged. Enhanced global collaborative actions are crucial for the control of gonorrhoea, including improved prevention, early diagnosis, treatment of index patient and partner (including test-of-cure), improved and expanded AMR surveillance (including surveillance of antimicrobial use and treatment failures), increased knowledge of correct antimicrobial use and the pharmacokinetics and pharmacodynamics of antimicrobials and effective drug regulations and prescription policies (including antimicrobial stewardship). Ultimately, rapid, accurate and affordable point-of-care diagnostic tests (ideally also predicting AMR and/or susceptibility), new therapeutic antimicrobials and, the only sustainable solution, gonococcal vaccine(s) are imperative.

Новое в фармакодинамике противобактериальных средств на 28-м конгрессе ECCMID

Новое в фармакодинамике противобактериальных средств на 28-м конгрессе ECCMID

Review of the international consensus guidelines for the optimal use of the polymyxins

Polymyxins are often the only agents that remain in vitro active against extensively resistant bacterial pathogens. However, the use of polymyxins is compromised by the number of unresolved issues, including the technical aspects of antimicrobial susceptibility testing, pharmacokinetic and pharmacodynamics parameters, optimal dosing regimens, and combined use with other antibiotics. All of the aspects of polymyxin use are discussed in detail in recently published «International consensus guidelines for the optimal use of the polymyxins», that was endorsed by the following professional societies: American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Antiinfective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP).

Antibiotic Dosing in Chronic Kidney Disease and End-Stage Renal Disease: A Focus on Contemporary Challenges.

Infections are an important cause of morbidity and mortality among patients with chronic kidney disease. Therefore, appropriate antibiotic dosing is imperative to achieve positive patient outcomes while minimizing antibiotic dose-related toxicity. Accurately assessing renal function and determining the influence of renal replacement therapy on antibiotic clearance makes drug dosing in this patient population challenging. Furthermore, as technological advances in hemodialysis and peritoneal dialysis occur, research incorporating newer dialysis parameters to guide drug dosing may not be readily available. Currently, there are limited data to guide drug dosing in the setting of automated peritoneal dialysis, short daily hemodialysis, and nocturnal hemodialysis. Antibiotic-dosing recommendations should be carefully evaluated considering the accuracy of the renal function assessment, the similarity of the operating characteristics of the renal replacement therapy studied compared with those being used, and whether the dosing strategy takes advantage of the pharmacodynamic profile of the antibiotic under consideration. After implementing the antibiotic-dosing regimen, therapeutic drug monitoring should occur when possible along with careful monitoring for antibiotic efficacy and safety.

Pharmacokinetics and Pharmacodynamics of Antimicrobials in Critically Ill Patients.

Critically ill patients with severe infections often have altered pharmacokinetic and pharmacodynamic variables that lead to challenging treatment decisions. These altered variables can often lead to inadequate dosing and poor treatment outcomes. The pharmacokinetic parameters include absorption, distribution, metabolism, and excretion. Pharmacodynamics is the relationship between drug serum concentrations and pharmacologic and toxicologic properties of the medication. In addition to these altered parameters, these critically ill patients frequently are receiving organ support in the forms of continuous renal replacement therapy or extra-corporeal membrane oxygenation. Altered pharmacodynamics can lead to decreased end-organ perfusion, which can ultimately lead to treatment failure or exposure-related toxicity. The most common antimicrobials utilized in the intensive care unit are classified by the pharmacodynamic principles of time-dependent, concentration-dependent, and concentration dependent with time-dependence. Thus, the aim of this review is to outline pharmacokinetic and pharmacodynamic changes of critically ill patients with severe infections and provide strategies for optimal antibiotic agent dosing in these patients.

Proline-rich antimicrobial peptides show a long-lasting post-antibiotic effect on Enterobacteriaceae and Pseudomonas aeruginosa

Proline-rich antimicrobial peptides (PrAMPs) represent a promising class of potential therapeutics to treat multiresistant infections. They inhibit bacterial protein translation at the 70S ribosome by either blocking the peptide-exit tunnel (oncocin type) or trapping release factors (apidaecin type). Besides direct concentration-dependent antibacterial effects, the post-antibiotic effect (PAE) is the second most important criterion of antimicrobial pharmacodynamics to be determined in vitro. Here, PAEs of 10 PrAMPs and three antibiotics against three Escherichia coli strains, Klebsiella pneumoniae ATCC 10031 and Pseudomonas aeruginosa ATCC 27853 were studied after 1 h of exposure. A robust high-throughput screening to determine PAEs was established, i.e. liquid handling by a 96-channel pipetting system and continuous incubation and absorbance measurement in a microplate reader. Prolonged PAEs (≥4 h) were detected for all peptides at their MIC values against all strains; PAEs were even >10 h for Api88, Api137, Bac7(1-60) and A3-APO. The PAEs increased further at 4 × MIC. Aminoglycosides gentamicin and kanamycin usually showed lower PAEs (≤4 h) at MIC, but PAEs increased to > 10 h at 4 × MIC. Bacteriostatic chloramphenicol exhibited the shortest PAEs (<4 h). The PAEs of PrAMPs studied against Enterobacteriaceae and P. aeruginosa for the first time were typically 4-fold stronger than for conventional antibiotics. Together with their fast and irreversible uptake by bacteria, the observed prolonged PAE of PrAMPs helps to explain their high in vivo efficacy despite unfavourable pharmacokinetics.

Pharmacodynamics of amoxicillin against field isolates ofStreptococcus parauberisfrom olive flounder (Paralichthys olivaceus)

Olive flounder is the most important species for the Northeast Asian fish farming industry. However, this species is substantially affected by multiple infectious agents, including Streptococcus parauberis. Evaluation of antibiotics before their application is critical to treat infections and prevent drug resistance. Therefore, in this study, the pharmacodynamics of amoxicillin (AMX) and other antimicrobials against the planktonic- and biofilm-forming bacteria were assessed. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and Time–kill curve assay were analysed using micro-dilution method. The minimum biofilm eradicating concentration (MBEC) was determined using the Calgary Biofilm device. The effects of temperature, pH, hardness and salinity were detected for both planktonic- and biofilm-forming bacteria. The MIC of AMX ranged from 0.015 to 2 μg/ml, whereas that of cephalexin (CEP), enrofloxacin (ENR) and oxytetracycline (OTC) ranged from 0.125 to 256, 0.125 to >512 and 0.25 to >512 μg/ml respectively. No bacteria were resistant against AMX, while the percentage of resistance to CEP, OTC and ENR were 68.7%, 52.6% and 11.1% respectively. The IC50 of AMX, CEP, ENR and OTC was 0.03, 0.091, 0.015 and 0.213 μg/ml respectively. The MBEC of amoxicillin against S. parauberis ranged from 0.5 to 16 μg/ml. Higher rates of bacterial growth were obtained at 30°C, pH = 8 and salinity of 7.5–10 ppt. The hardness of the media suppressed the bacterial growth. In conclusion, AMX was found to be effective against both the planktonic and the biofilm forms of the prominent fish pathogen, S. parauberis.

The role of infection models and PK/PD modelling for optimising care of critically ill patients with severe infections.

Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.