Paul M. Beringer

Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy

The recent emergence of meticillin-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin has prompted clinicians to prescribe vancomycin therapy targeting high trough concentrations (15-20 mg/L). Relevant studies (n=12) analysing the occurrence of nephrotoxicity with high-dose therapy were reviewed. Most studies were retrospective and the temporal relationship between elevated trough levels and development of nephrotoxicity was unclear, precluding a definitive cause-effect analysis. Available data suggest an association between vancomycin trough level and risk of nephrotoxicity as a function of intensity and duration of therapy (>7 days), compounded by concomitant receipt of nephrotoxins, vasopressor therapy and underlying physiological impairment. In separate studies in which a high trough concentration was measured prior to the onset of nephrotoxicity, the frequency of occurrence was 21-28% in patients with concomitant risks compared with 7% in patients without risks. A similar comparison between risk and no-risk groups who attained a standard trough concentration (10-15 mg/L) indicates the rates of occurrence as 9-21% vs. 2%. Onset of nephrotoxicity ranged from 4 days to 8 days from the start of therapy. The degree of renal dysfunction was modest, with a reported decrease of 35-45% in creatinine clearance from baseline. Resolution occurred in >70% of patients by the time of discharge. Future studies should detail clearly the temporal relationship between drug exposure and onset of nephrotoxicity, confounding risk factors, extent of injury and time course of recovery, and should also determine the relative risk versus benefit of high-dose vancomycin versus alternative agents.

Comparative Pharmacokinetics and Pharmacodynamics of the Newer Fluoroquinolone Antibacterials

A number of new fluoroquinolone antibacterials have been released for clinical use in recent years. These new agents exhibit enhanced activity against Gram-positive organisms while retaining much of the Gram-negative activity of the earlier agents within the same class. The pharmacokinetics of most of these agents are well described including serum pharmacokinetics, tissue and fluid distribution, and pharmacokinetics in renal and hepatic disease. When compared with earlier agents within this class (i.e. Ciprofloxacin), the newer agents retain the wide distribution characteristics; however, they exhibit a more prolonged elimination, which, in part, supports single daily administration for these agents. Based on their predominant renal elimination, dosage adjustment is necessary in the presence of renal disease for Ciprofloxacin, levofloxacin, gatifloxacin and sitafloxacin.Drug interactions, particularly with multivalent cations (calcium/aluminium-containing antacids and iron products), remain a problem for the newer agents, resulting in reduced absorption requiring separate administration times to maximise bioavailability. However, the newer agents do not appear to interfere significantly with the cytochrome P450 system, thus minimising the potential for interactions with other drugs metabolised by this system.The pharmacodynamic properties of the fluoroquinolones have been well described. The bactericidal activity is maximised when the ratios of peak plasma drug concentration (Cmax) : minimum inhibitory concentrations (MIC) or area under the concentration-time curve (AUC) : MIC exceed specific threshold values. Knowledge of the pharmacodynamic relationships allows for appropriate drug selection and enables design of dosage regimens to maximise the bactericidal activity. Therapeutic drug monitoring of the fluoroquinolones may provide a means of optimising the dosage regimen in certain clinical situations (that is, meningitis and hospitalised pneumonias) with the goals of achieving a more predictable therapeutic response and minimising the potential for the development of resistance.

Population pharmacokinetics and use of Monte Carlo simulation to evaluate currently recommended dosing regimens of ciprofloxacin in adult patients with cystic fibrosis.

ABSTRACT Pharmacodynamic data on ciprofloxacin indicate that a target area under the concentration-time curve from 0 to 24 h (AUC0–24)/MIC ratio of ≥125 is necessary to achieve optimal bactericidal activity for the treatment of gram-negative pneumonia. The purpose of this prospective study was to (i) develop a pharmacokinetic (PK) model to be utilized for therapeutic drug monitoring (TDM) of ciprofloxacin and (ii) evaluate current ciprofloxacin dosing regimens for pneumonias in cystic fibrosis (CF) patients. Twelve adult CF patients received a single 400-mg dose of IV ciprofloxacin. Six blood samples were obtained over a 12-h interval. Serum drug concentrations were determined by high-pressure liquid chromotography and were fitted to one- and two-compartment models by using NPEM2. Ciprofloxacin MIC data for Pseudomonas aeruginosa were obtained from 1,213 CF patients enrolled in a large clinical trial. A Monte Carlo simulation was performed to estimate the fractional attainment of an AUC0–24/MIC ratio of ≥125. A two-compartment model best describes the serum drug concentration data. The mean fitted PK parameter values are volume of distribution in the central compartment, 0.29 liter/kg; volume of distribution at steady state, 1.1 liters/kg; total clearance, 0.34 liter/h/kg; distributional clearance, 0.89 liter/h/kg; half-life at α phase, 0.16 h; and half-life at β phase, 2.9 h. The overall fractional attainment of achieving an AUC0–24/MIC ratio of ≥125 against P. aeruginosa isolates with ciprofloxacin (400 mg every 12 h [q12h] and 8 qh) were 10 and 30%, respectively. A clinical breakpoint MIC of <0.5 μg/ml for susceptibility is suggested, based on an examination of the fractional attainment of the AUC0–24/MIC target at each MIC. The recommended doses of 400 mg q8h or q12h may be inadequate to treat an acute pulmonary exacerbation when given alone. The poor and variable AUC0–24/MIC ratios support the use of TDM to monitor and adjust the dosage to optimize the efficacy of ciprofloxacin therapy in these patients.

Transporters and Their Impact on Drug Disposition

OBJECTIVE: To review the recent advances in knowledge about human transporters and their effect on drug disposition. DATA SOURCES: A MEDLINE search (1996–March 2005) was performed to identify pertinent literature on human transporters and their impact on drug disposition. Additional articles were identified from a manual search of the references of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: Based on the identified studies, data were extracted on the impact of transporters on drug absorption, distribution, and elimination. DATA SYNTHESIS: The pharmacokinetic disposition of drugs is known to be influenced by metabolic enzymes, kidney function, and transporters. Recent research on human transporters has greatly advanced our understanding of their diversity and importance in drug disposition. In particular, members of the multidrug resistance family of transporters (MDR, MRP) are present in organs and tissues throughout the body and are known to significantly affect the absorption, distribution, and elimination of commonly prescribed drugs. A growing number of studies now demonstrate that alterations in transporter function as a result of drug interactions or genetic polymorphisms may explain a significant portion of the variability in treatment response for certain drugs. CONCLUSIONS: Human transporters contribute significantly to the pharmacokinetic disposition of drugs. Knowledge of substrates, inducers, and inhibitors of these transporters is necessary to ensure optimal patient outcomes.

Applying New Diagnostic Criteria for Acute Kidney Injury To Facilitate Early Identification of Nephrotoxicity in Vancomycin-Treated Patients

ABSTRACT Acute kidney injury (AKI) associated with high-dose vancomycin (VAN) therapy is a clinical concern, but no uniform diagnostic criteria exist. The AKI Network (AKIN) proposed new criteria to diagnose AKI based on abrupt changes in serum creatinine or urine output. We conducted a prospective observational study to determine the incidence and severity of AKI and associated outcomes using the AKIN criteria versus traditional definitions. Eligible patients (n = 227) were elderly (median, 70 years) and received VAN therapy for 8 days (median). AKI occurred in 43 patients (19%) using AKIN criteria at an onset of 6 days. AKI incidence was similar for patients with a trough level of ≥15 (24%; 17/72) versus <15 (17%; 26/155) μg/ml. Compared to non-AKI patients, more AKI patients resided in the intensive care unit (ICU) (47% [20/43] versus 27% [50/184]; P = 0.017), had a prior AKI episode (19% [8/43] versus 7% [5/184]; P = 0.001), and received vasopressor (28% [12/43] versus 14% [25/184]; P = 0.04) and/or nephrotoxins (84% [36/43] versus 67% [123/184]; P = 0.04). Seventeen of the AKI patients met traditional criteria, of whom more patients had stage 2 and 3 AKI (76% versus 8%; P = 0.0001), dosage adjustment (41% versus 15%) and renal consultation (35% versus 12%), prolonged length of stay after AKI (11 versus 7.5 days) and died (29% versus 12%) than those diagnosed by AKIN criteria (P value not significant). Use of AKIN criteria for AKI has the potential to improve care of VAN-treated patients by facilitating early detection of AKI and warrants confirmation in large prospective trials.

Pharmacokinetics of Tobramycin in Adults with Cystic Fibrosis: Implications for Once-Daily Administration

ABSTRACT Once-daily administration of aminoglycosides is routinely used in many institutions. However, comparative efficacy data for patients with cystic fibrosis (CF) are lacking. The purpose of the present study was to compare the predicted pharmacodynamic activity of tobramycin at 10 mg/kg of body weight/day administered every 24 h (q24h), q12h, and q8h. Pharmacokinetic (PK) data were derived from analysis of data on the drug concentration in sera from 60 adult CF patients. Individual maximum a posteriori probability Bayesian PK parameter values were used to construct serum concentration-versus-time curves and to determine various indices (peak concentration/MIC ratio [peak/MIC], area under the concentration-time curve/MIC ratio [AUC/MIC], and time that the concentration was less than the MIC [T<MIC]) for the three regimens described above. MICs of 1, 2, and 4 μg/ml forPseudomonas aeruginosa were assumed in the simulations. Irrespective of the MIC, significantly lower peak/MIC but shorterT<MIC were noted when regimens of q8h versus q12h (P < 0.001), q8h versus q24h (P < 0.001), and q12h versus q24h (P < 0.001) were compared. This analysis suggests that the potential benefit of achieving a greater peak/MIC with once-daily aminoglycoside administration may be offset by the significantly greaterT<MIC in CF patients compared with that achieved with multiple-daily-dosing regimens. Clinical trials are necessary to determine if once daily aminoglycoside administration is efficacious in the CF population before its routine use can be recommended.

Absolute Bioavailability and Pharmacokinetics of Linezolid in Hospitalized Patients Given Enteral Feedings

ABSTRACT Linezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups: F, Ka, Vs, K23, K32, Vmax, Km, and K20 (bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period.

Economic Aspects of Antibacterial Adverse Effects

SummaryThe economic impact of adverse effects is often understated. Increased hospitalisations attributed to adverse drug reactions alone account for billions of dollars each year within the US healthcare system. Although most classes of antibacterials are well tolerated, severe reactions do occur and can add significantly to the cost of care. Among hospitalised patients, antibacterial adverse effects account for nearly 25% of adverse drug reactions. Published pharmacoeconomic data on direct and indirect costs of antibacterial adverse effects are lacking.The importance of determining the most cost-effective treatment regimen is becoming more apparent due to limited resources available within the healthcare system. When considering the cost of new antibacterials, a simple comparison of acquisition costs may not accurately reflect the true costs of treatment. A drug with a lower acquisition cost may be more toxic and/or less effective, resulting in higher complication rates and/or treatment failures, thus leading to a higher overall treatment cost. In addition, nephrotoxic agents such as aminoglycosides and vancomycin often require close monitoring of serum drug concentrations and creatinine levels, which also contributes to the total cost of therapy. Indirect costs as a result of reduced quality of life or loss of productivity are certainly not reflected in the acquisition costs of antimicrobials. Institutions must evaluate a drug’s potential for causing an adverse event, among various other factors, when considering drugs for inclusion on their formularies. Drugs with good safety profiles may minimise hospitalisation or facilitate early discharge.Thus, the adverse effect profile of an antimicrobial agent can contribute significantly to its overall direct costs, primarily as a result of higher monitoring costs and additional days of hospitalisation. For example, in the US, the cost associated with adverse effects, such as nephrotoxicity, observed with aminoglycosides and vancomycin, may add approximately

GFR estimates using cystatin C are superior to serum creatinine in adult patients with cystic fibrosis

US2500 per patient with nephrotoxicity (1990 values). Indirect costs can also be substantial as a result of reduced productivity. Many adverse effects of antibacterial agents are predictable and may be minimised with appropriate monitoring and care. This article reviews the pharmacoeconomic aspects of adverse effects associated with some of the more important antibacterial classes such as the β-lactams, aminoglycosides, vancomycin, macrolides and fluoroquinolones.

Potential role of macrolide antibiotics in the management of cystic fibrosis lung disease.

BACKGROUND Accurate assessment of renal function in patients with cystic fibrosis (CF) is vital for determining the appropriate dose of medications and for early detection of renal disease. Cystatin C (CysC) is a new marker of GFR with reportedly improved accuracy and precision compared to methods incorporating serum creatinine. The purpose of this study is to evaluate the predictive performance of cystatin C in estimating GFR in adult patients with CF. METHODS Iothalamate was administered to enable measurement of GFR in 38 adult patients with CF and control subjects. Creatinine clearance (C&G) and GFR estimates (cystatin C clearance [Cys C] and abbreviated modified diet in renal disease [aMDRD]) were compared using Bland-Altman and receiver operating characteristic (ROC) analysis. GFR cutoff values of 80 and 90 mL/min-1.73 m(2) were used in the analysis. RESULTS The measured GFR was similar in both the CF and healthy volunteers 104 (32.2) and 105 (29.9), P=0.969 respectively. No significant difference in mean bias was noted between the predictive methods within the CF population. Cys C provided the most precise estimates of GFR in both populations. ROC curves demonstrated that CysC provided greater sensitivity and specificity compared to the aMDRD (AUC 0.93 vs. 0.54, P=0.003) and C&G (AUC 0.93 vs. 0.56, P=0.005) in CF at a cutoff GFR of 90 mL/min-1.73 m(2). CONCLUSION Cystatin C clearance provides an improved marker of glomerular filtration rate in CF patients.