Antibiotics are among the medications most frequently administered to the critically ill, a population with high levels of intra- and inter-individual pharmacokinetic variability. Our knowledge of ...the relationships among antibiotic dosing, exposure and clinical effect in this population has increased in recent decades. Therapeutic drug monitoring (TDM) of serum antibiotic concentrations is the most practical means of assessing adequate antibiotic exposure, though until recently, it has been underutilised for this end. Now TDM is becoming more widespread, particularly for the beta-lactam antibiotics, a class historically thought to have a wide therapeutic range. We review the basic requirements, indications, and targets for effective TDM of the glycopeptides, aminoglycosides, quinolones and beta-lactam antibiotics in the adult intensive-care setting, with a special focus on TDM of the beta-lactam antibiotics, the most widely used antibiotic class.
Nitrofurantoin's use has increased exponentially since recent guidelines repositioned it as first-line therapy for uncomplicated lower urinary tract infection (UTI). We conducted a systematic review ...and meta-analysis to assess nitrofurantoin's efficacy and toxicity in the treatment of lower UTI.
We performed a systematic review of all human controlled clinical trials published from 1946 to 2014 and assessing short-term (≤14 days) nitrofurantoin for lower UTI. Meta-analyses assessing efficacy and adverse events were conducted on randomized trials.
Twenty-seven controlled trials including 4807 patients fulfilled entry criteria; most were conducted between the 1970s and 1990s and were at increased risk for various biases. Nitrofurantoin appears to have good clinical and microbiological efficacy for UTI caused by common uropathogens, with clinical cure rates varying between 79% and 92%. The most methodologically robust studies surveyed indicate overall equivalence between nitrofurantoin when given for 5 or 7 days and trimethoprim/sulfamethoxazole, ciprofloxacin and amoxicillin. Meta-analyses of randomized controlled trials confirmed equivalence in clinical cure, but indicated a slight advantage to comparator drugs in microbiological efficacy (risk ratio 0.93, 95% CI 0.89-0.97). If given for only 3 days, nitrofurantoin's clinical efficacy was diminished (61%-70%). Toxicity was infrequent (5%-16% in the 17 reporting studies), mild, reversible and predominantly gastrointestinal; meta-analyses confirmed no difference between nitrofurantoin and comparators. Hypersensitivity reactions such as pulmonary fibrosis and hepatotoxicity were not observed. Acquisition of resistance to nitrofurantoin is still relatively rare.
When given short term for lower UTI, nitrofurantoin has good clinical and microbiological efficacy; toxicity is mild and predominantly gastrointestinal.
MIC-based dose adjustment: facts and fables Mouton, Johan W; Muller, Anouk E; Canton, Rafael ...
Journal of antimicrobial chemotherapy,
03/2018, Letnik:
73, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Over recent decades, several publications have described optimization procedures for antibiotic therapy in the individual patient based on antimicrobial MIC values. Most methods include therapeutic ...drug monitoring and use a single MIC determination plus the relevant pharmacokinetics/pharmacodynamics to adjust the dose to optimize antimicrobial drug exposure and antibacterial effects. However, the use of an MIC obtained by a single MIC determination is inappropriate. First, routine clinical laboratories cannot determine MICs with sufficient accuracy to guide dosage owing to the inherent assay variation in the MIC test. Second, the variation in any MIC determination, whatever method is used, must be accounted for. If dose adjustments are made based on therapeutic drug monitoring and include MIC determinations, MIC variation must be considered to prevent potential underdosing of patients. We present the problems and some approaches that could be used in clinical practice.
Abstract
Background
Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic ...dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.
Methods
This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MIC
ECOFF
and ƒT > 4×MIC
ECOFF
) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.
Results
A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MIC
ECOFF
and 36.7% achieved 100%ƒT > 4×MIC
ECOFF
. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m
2
, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MIC
ECOFF
target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.
Conclusions
Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients.
Trial registration
Netherlands Trial Registry (EXPAT trial),
NTR 5632
. Registered on 7 December 2015.
Temocillin is used for the treatment of various infections caused by
. The pharmacokinetic (PK)/pharmacodynamic (PD) index that is best correlated with the activity of beta-lactams is the percentage ...of time that the unbound concentration exceeds the MIC (%
T>MIC). However, the %
T>MIC needed for a bacteriostatic or killing effect of temocillin is unknown in thigh and lung infection models. In the present study, we studied the temocillin PK in plasma and epithelial lining fluid (ELF) of infected neutropenic mice and determined the plasma exposure-response relationships for Escherichia coli and Klebsiella pneumoniae. Neutropenic murine thigh and lung infection models were used. The bacterial loads in the thighs or lungs were determined. A sigmoid maximum-effect model was used to fit the plasma exposure-response relationship. A one-compartment model with first-order absorption best described temocillin PK (clearance CL, 1.03 L/h/kg; volume of distribution
, 0.457 L/kg). Protein binding was 78.2% ± 1.3% across different plasma concentrations. A static effect was achieved for all strains in both the thigh and lung infection models. However, the median %
T>MIC needed for a static effect was much lower in the lung infection model (27.8% for E. coli and 38.2% for K. pneumoniae) than in the thigh infection model (65.2% for E. coli and 64.9% for K. pneumoniae). A 1-log kill was reached for all strains in the lung infection model (median %
T>MIC values of 42.1% for E. coli and 44.1% for K. pneumoniae) and 7 out of 8 strains in the thigh infection model (median %
T>MIC values of 85.4% for E. coli and 74.5% for K. pneumoniae). These data support the use of temocillin in patients with pneumonia.
Abstract
Background
Very limited studies, so far, have been conducted to identify the pharmacodynamic targets of cefepime, a well-established fourth-generation cephalosporin. As a result, ...conventional targets representing the cephalosporin class are used for cefepime target attainment analysis.
Objectives
We employed both a neutropenic murine lung infection model and an in vitro pharmacokinetic model (IVPM) to determine cefepime’s pharmacodynamic target percentage of the dosing interval during which unbound drug concentrations remain higher than the MIC (%fT>MIC) for bacteriostatic and 1 log10 kill effects.
Methods
Ten strains with cefepime MICs ranging from 0.03 to 16 mg/L were studied in the lung infection. In the IVPM, five cefepime-resistant strains with cefepime/tazobactam (fixed 8 mg/L) MICs ranging from 0.25 to 8 mg/L were included. Through 24 h dose fractionation, both in lung infection and IVPM (in the latter case, tazobactam 8 mg/L continuous infusion was used to protect cefepime), varying cefepime exposures and corresponding pharmacodynamic effect scenarios were generated to identify the pharmacodynamic targets.
Results
Using a non-linear sigmoidal maximum-effect (Emax) model, the cefepime’s plasma fT>MIC for 1 log10 kill in lung infection ranged from 17% to 53.7% and a combined exposure–response plot yielded 30%. In the case of IVPM, T>MIC ranged from 6.9% to 75.4% with a mean value of 34.2% for 1 log10 kill.
Conclusions
Both in vivo and in vitro studies showed that cefepime’s pharmacodynamic requirements are lower than generally reported for cephalosporins (50%–70% fT>MIC). The lower requirement for cefepime could be linked with factors such as cefepime’s better permeation properties and multiple PBP affinity-driven enhanced bactericidal action.
Nitrofurantoin and nitroxoline are oral antibiotics for the treatment or prophylaxis of acute urinary tract infections. New interest in both these drugs is increasing because of the emergence of ...resistance to other antibiotics, but knowledge of their pharmacokinetics (PK) is lacking since they were developed before the advent of standardized research for drug approval. The aims of this review were to (i) summarize the PK data reported in the literature and (ii) to identify PK knowledge gaps. The current body of PK knowledge of both drugs appears to be poor and mainly based on old studies. Nitrofurantoin PK values were obtained from studies using many variables, e.g. formulations, crystal sizes and analytical methods, resulting in high interindividual variability in PK parameters and no uniform PK profile. Clinical experience and PK data for nitroxoline are even more limited since the drug is registered in only Germany and a few (Eastern European) countries. Clinical studies in relevant patient populations are needed with commercially available nitrofurantoin and nitroxoline formulations at approved dosing regimens to more fully characterize their PK profiles, and to investigate the influence of patient characteristics on these profiles in order to optimize efficacy and avoid toxicity and emergence of resistance. Only with this updated knowledge and efficacy data from well-structured trials can both drugs maintain their antimicrobial activity against uropathogens.
The %fT>MIC of ceftazidime has been shown to correlate with microbiological outcome of Gram-negative bacteria (GNB) in preclinical studies. However, clinical data are still lacking. We explored the ...relationship of ceftazidime exposure and outcome in patients with nosocomial pneumonia using data from a recent randomized, double-blind Phase 3 clinical trial.
Pharmacokinetic (PK) and demographic data from three clinical trials were used to construct a population PK model using non-linear mixed-effects modelling. Individual concentration-time curves and PK/pharmacodynamic indices were determined for individual patients. The MICs used in the analyses were the highest MICs for any GNB cultured at baseline or end of therapy.
A two-compartment model best fit the data, with creatinine clearance as covariate on clearance and age on the central compartment. Classification and regression tree analysis showed a breakpoint value of 44.9% (P<0.0001) for GNB in 154 patients. The Emax model showed a good fit (R(2) =0.93). The benefit of adequate treatment increased from an eradication rate of 0.4848 at %fT>MIC of 0% to 0.9971 at 100%. The EC50 was 46.8% and the EC90 was 95.5% for %fT>MIC. Exposure correlated significantly with both microbiological and clinical outcome at test-of-cure.
We conclude that exposures to ceftazidime predict microbiological as well as clinical outcome, and the %fT>MIC required to result in a likely favourable outcome is >45% of the dosing interval. This value is similar to that observed in animal models and underscores the principle that adequate dosing can be predicted and is beneficial to patient care.
Purpose
Individualising drug dosing using model-informed precision dosing (MIPD) of beta-lactam antibiotics and ciprofloxacin has been proposed as an alternative to standard dosing to optimise ...antibiotic efficacy in critically ill patients. However, randomised clinical trials (RCT) on clinical outcomes have been lacking.
Methods
This multicentre RCT, including patients admitted to the intensive care unit (ICU) who were treated with antibiotics, was conducted in eight hospitals in the Netherlands. Patients were randomised to MIPD with dose and interval adjustments based on monitoring serum drug levels (therapeutic drug monitoring) combined with pharmacometric modelling of beta-lactam antibiotics and ciprofloxacin. The primary outcome was ICU length of stay (LOS). Secondary outcomes were ICU mortality, hospital mortality, 28-day mortality, 6-month mortality, delta sequential organ failure assessment (SOFA) score, adverse events and target attainment.
Results
In total, 388 (MIPD
n =
189; standard dosing
n =
199) patients were analysed (median age 64 IQR 55–71). We found no significant differences in ICU LOS between MIPD compared to standard dosing (10 MIPD vs 8 standard dosing; IRR = 1.16; 95% CI 0.96–1.41;
p =
0.13). There was no significant difference in target attainment before intervention at day 1 (T1) (55.6% MIPD vs 60.9% standard dosing;
p =
0.24) or at day 3 (T3) (59.5% vs 60.4%;
p =
0.84). There were no significant differences in other secondary outcomes.
Conclusions
We could not show a beneficial effect of MIPD of beta-lactam antibiotics and ciprofloxacin on ICU LOS in critically ill patients. Our data highlight the need to identify other approaches to dose optimisation.
Nitrofurantoin is an old antibiotic and an important first-line oral antibiotic for the treatment of uncomplicated urinary tract infections. However despite its long term use for over 60 years, ...little information is available with respect to its dose justification and this may be the reason of highly variable recommended doses and dosing schedules. Furthermore, nitrofurantoin is not a uniform product -crystal sizes of nitrofurantoin, and therefore pharmacokinetic properties, differ significantly by product. Moreover, pharmacokinetic profiling of some products is even lacking, or difficult to interpret because of its unstable chemical properties. Pharmacokinetic and pharmacodynamic data is now slowly becoming available. This review provides an overview of nitrofurantoins antibacterial, pharmacokinetic and pharmacodynamic properties. This shows that a clear rationale of current dosing regimens is scanty.
PDF
