Federico Pea

Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability.

Antimicrobials are among the most important and commonly prescribed drugs in the management of critically ill patients. Selecting the appropriate antimicrobial at the commencement of therapy, both in terms of spectrum of activity and dose and frequency of administration according to concentration or time dependency, is mandatory in this setting. Despite appropriate standard dosage regimens, failure of the antimicrobial treatment may occur because of the inability of the antimicrobial to achieve adequate concentrations at the infection site through alterations in its pharmacokinetics due to underlying pathophysiological conditions.According to the intrinsic chemicophysical properties of antimicrobials, hydrophilic antimicrobials (β-lactams, aminoglycosides, glycopeptides) have to be considered at much higher risk of inter- and intraindividual pharmacokinetic variations than lipophilic antimicrobials (macrolides, fluoroquinolones, tetracyclines, chloramphenicol, rifampicin [rifampin]) in critically ill patients, with significant frequent fluctuations of plasma concentrations that may require significant dosage adjustments. For example, underexposure may occur because of increased volume of distribution (as a result of oedema in sepsis and trauma, pleural effusion, ascites, mediastinitis, fluid therapy or indwelling post-surgical drainage) and/or enhanced renal clearance (as a result of burns, drug abuse, hyperdynamic conditions during sepsis, acute leukaemia or use of haemodynamically active drugs). On the other hand, overexposure may occur because of a drop in renal clearance caused by renal impairment. Care with all these factors whenever choosing an antimicrobial may substantially improve the outcome of antimicrobial therapy in critically ill patients. However, since these situations may often coexist in the same patient and pharmacokinetic variability may be unpredictable, the antimicrobial policy may further benefit from real-time application of therapeutic drug monitoring, since this practice, by tailoring exposure to the individual patient, may consequently be helpful both in improving the outcome of antimicrobial therapy and in containing the spread of resistance in the hospital setting.

Continuous versus intermittent infusion of vancomycin for the treatment of Gram-positive infections: systematic review and meta-analysis

OBJECTIVES To summarize available evidence on the effect of continuous infusion (CoI) of vancomycin compared with intermittent infusion (InI) in adult patients with Gram-positive infections. METHODS MEDLINE, EMBASE and Cochrane databases were searched. Randomized clinical trials (RCTs) and observational studies that comparatively assessed CoI and InI of vancomycin in terms of mortality, clinical cure, toxicity rates and serum drug exposure [trough concentration (C(min)) for InI and steady-state concentration (C(ss)) for CoI; area under the curve at 24 h (AUC(24)) for both] were included. Meta-analysis was conducted combining and analysing the relative risk (RR) and computing a summary RR of the effects with 95% confidence interval (CI). The standardized mean difference was calculated for continuous outcomes. The I(2) test was calculated to assess heterogeneity across studies. RESULTS One RCT and five observational studies were included in the analysis. Compared with InI, CoI of vancomycin was associated with a significantly lower risk of nephrotoxicity (RR 0.6, 95% CI 0.4-0.9, P = 0.02; I(2)= 0). Overall mortality was not different between the two groups (RR 1.03, 95% CI 0.7-1.6, P = 0.9; I(2)= 0). CONCLUSIONS Our meta-analysis suggests that administration of vancomycin for the treatment of Gram-positive infections by CoI is associated with a significantly lower risk of nephrotoxicity when compared with InI of the drug. RCTs are needed to define the impact on mortality rate and on the pharmacodynamic activity in terms of AUC/MIC ratio.

Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions.

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase.Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance.Drugs frequently used in the ICU that are at risk of clinically relevant pharmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin).Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level.Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. β-Lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow.Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.

Pharmacokinetic Considerations for Antimicrobial Therapy in Patients Receiving Renal Replacement Therapy

Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CLCRRT), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CLCRRT of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents.Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CLCRRT may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device’s characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CLCRRT is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distribution and poor plasma protein binding. Consistently, CLCRRT should be clinically relevant particularly for most hydrophilic antimicrobial agents (e.g. β-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which generally are nonrenally cleared. However, there are some notable exceptions: ceftriax-one and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device’s surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied.Conversely, drug removal by means of CVVH or CVVHDF is unaffected by the drug size, considering that almost all antimicrobial agents have molecular weights significantly lower (<2000Da) than the haemofilter cut-off (30 000–50 000Da). Drugs that normally have high renal clearance and that exhibit high CLCRRT during CVVH or CVVHDF may need a significant dosage increase in comparison with renal failure or even IHD. Conversely, drugs that are normally nonrenally cleared and that exhibit very low CLCRRT during CVVH or CVVHDF may need no dosage modification in comparison with normal renal function. Bearing these principles in mind will almost certainly aid the management of antimicrobial therapy in critically ill patients undergoing CRRT, thus containing the risk of inappropriate exposure. However, some peculiar pathophys-iological conditions occurring in critical illness may significantly contribute to further alteration of the pharmacokinetics of antimicrobial agents during CRRT (i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residual renal function). Accordingly, therapeutic drug monitoring should be considered a very helpful tool for optimising drug exposure during CRRT.

The Clinical Relevance of Plasma Protein Binding Changes

Controversy reigns as to how protein binding changes alter the time course of unbound drug concentrations in patients. Given that the unbound concentration is responsible for drug efficacy and potential drug toxicity, this area is of significant interest to clinicians and academics worldwide. The present uncertainty means that many questions relating to this area exist, including “How important is protein binding?”, “Is protein binding always constant?”, “Do pH and temperature changes alter binding?” and “How do protein binding changes affect dosing requirements?”. In this paper, we seek to address these questions and consider the data associated with altered pharmacokinetics in the presence of changes in protein binding and the clinical consequences that these may have on therapy, using examples from the critical care area. The published literature consistently indicates that a change in the protein binding and unbound concentrations of some drugs are common in certain specific patient groups such as the critically ill. Changes in pharmacokinetic parameters, including clearance and apparent volume of distribution (Vd), may be dramatic. Drugs with high protein binding, high intrinsic clearance (e.g. clearance by glomerular filtration) and where dosing is not titrated to effect are most likely to be affected in a clinical context. Drugs such as highly protein bound antibacterials with multiple half-lives within a dosing interval and that have some level of renal clearance, such as ertapenem, teicoplanin, ceftriaxone and flucloxacillin, are commonly affected. In response to these challenges, clinicians need to adapt dosing regimens rationally based on the pharmacokinetic/pharmacodynamic characteristics of the drug. We propose that further pharmacokinetic modelling-based research is required to enable the design of robust dosing regimens for drugs affected by altered protein binding.

Therapeutic drug monitoring may improve safety outcomes of long-term treatment with linezolid in adult patients

OBJECTIVES Prolonged treatment with linezolid may cause toxicity. The purpose of this study was to define pharmacodynamic thresholds for improving safety outcomes of linezolid. METHODS We performed a retrospective study of patients who had trough (C(min)) and peak (C(max)) plasma levels measured during prolonged linezolid treatment. Dosage adjustments were performed when C(min) ≥10 mg/L and/or AUC₂₄ ≥400 mg/L · h. Patients were divided into two subgroups according to the absence or presence of co-treatment with rifampicin (the linezolid group and the linezolid + rifampicin group, respectively). Data on demographic characteristics, disease, microbiology and haematochemical parameters were collected and outcomes in relation to drug exposure were compared between groups. RESULTS A total of 45 patients were included. Dosage adjustments were needed in 40% versus 0% of patients in the linezolid group (n = 35) versus the linezolid + rifampicin group (n = 10), respectively. Patients in the linezolid group had either significantly higher C(min) [3.71 mg/L (1.43-6.38) versus 1.37 mg/L (0.67-2.55), P < 0.001] or AUC₂₄ [212.77 mg/L · h (166.67-278.42) versus 123.33 mg/L · h (97.36-187.94), P < 0.001]. Thrombocytopenia appeared in 51.4% versus 0% of cases in the linezolid group versus the linezolid + rifampicin group, respectively. In 33.3% of those patients who were experiencing thrombocytopenia, therapeutic drug monitoring (TDM)-guided dosage reductions allowed recovery from toxicity and prosecution of therapy with good outcome. A logistic regression model for thrombocytopenia estimated a probability of 50% in the presence of C(min) of 6.53 mg/L and/or of AUC₂₄ of 280.74 mg/L · h. CONCLUSIONS Maintenance over time of C(min) between 2 and 7 mg/L and/or of AUC₂₄ between 160 and 300 mg/L · h may be helpful in improving safety outcomes while retaining appropriate efficacy in adult patients receiving prolonged linezolid treatment.

The Antimicrobial Therapy Puzzle: Could Pharmacokinetic- Pharmacodynamic Relationships Be Helpful in Addressing the Issue of Appropriate Pneumonia Treatment in Critically Ill Patients?

Until recently, the in vitro susceptibility of microorganisms was considered the only fundamental aspect for antibiotic efficacy in treating pneumonia. However, the relevance of pharmacokinetic-pharmacodynamic relationships in optimizing drug exposure has been progressively highlighted. Antimicrobial agents were divided into concentration-dependent or time-dependent groups, with the most consistently relevant pharmacodynamic parameters for efficacy being either the ration of the plasma peak concentration to the minimum inhibitory concentration or the time the plasma concentration persists above the minimum inhibitory concentration of the etiological agent, respectively. For the adequate treatment of pneumonia, optimal pharmacodynamic exposure should be ensured also at the infection site. To investigate this, a methodologically correct approach may be to detect drug concentration levels in the epithelial lining fluid and in the alveolar macrophages for extracellular and intracellular pathogens, respectively. From this perspective, the pharmacokinetic factors--only in some instances--support the achievement of optimal exposure during the treatment of pneumonia with fixed standard dosing regimens of antimicrobials; conversely, in other instances, the pharmacokinetic factors suggest the need for an implemented dosage regimen or even the choice of a different drug.

Bench-to-bedside review: Appropriate antibiotic therapy in severe sepsis and septic shock--does the dose matter?

Appropriate antibiotic therapy in patients with severe sepsis and septic shock should mean prompt achievement and maintenance of optimal exposure at the infection site with broad-spectrum antimicrobial agents administered in a timely manner. Once the causative pathogens have been identified and tested for in vitro susceptibility, subsequent de-escalation of antimicrobial therapy should be applied whenever feasible. The goal of appropriate antibiotic therapy must be pursued resolutely and with continuity, in view of the ongoing explosion of antibiotic-resistant infections that plague the intensive care unit setting and of the continued decrease in new antibiotics emerging. This article provides some principles for the correct handling of antimicrobial dosing regimens in patients with severe sepsis and septic shock, in whom various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs.

The effect of pathophysiology on pharmacokinetics in the critically ill patient — Concepts appraised by the example of antimicrobial agents☆

Critically ill patients are at high risk for development of life-threatening infection leading to sepsis and multiple organ failure. Adequate antimicrobial therapy is pivotal for optimizing the chances of survival. However, efficient dosing is problematic because pathophysiological changes associated with critical illness impact on pharmacokinetics of mainly hydrophilic antimicrobials. Concentrations of hydrophilic antimicrobials may be increased because of decreased renal clearance due to acute kidney injury. Alternatively, antimicrobial concentrations may be decreased because of increased volume of distribution and augmented renal clearance provoked by systemic inflammatory response syndrome, capillary leak, decreased protein binding and administration of intravenous fluids and inotropes. Often multiple conditions that may influence pharmacokinetics are present at the same time thereby excessively complicating the prediction of adequate concentrations. In general, conditions leading to underdosing are predominant. Yet, since prediction of serum concentrations remains difficult, therapeutic drug monitoring for individual fine-tuning of antimicrobial therapy seems the way forward.

Therapeutic Drug Monitoring of Linezolid: a Retrospective Monocentric Analysis

ABSTRACT The objective of the present retrospective observational study carried out in patients receiving a standard dosage of linezolid and undergoing routine therapeutic drug monitoring (TDM) was to assess the interindividual variability in plasma exposure, to identify the prevalence of attainment of optimal pharmacodynamics, and to define if an intensive program of TDM may be warranted in some categories of patients. Linezolid plasma concentrations (trough [Cmin] and peak [Cmax] levels) were analyzed by means of a high-performance liquid chromatography (HPLC) method, and daily drug exposure was estimated (daily area under the plasma concentration-time curve [AUC24]). The final database included 280 Cmin and 223 Cmax measurements performed in 92 patients who were treated with the fixed 600-mg dose every 12 h (q12h) intravenously (n = 58) or orally (n = 34). A wide variability was observed (median values [interquartile range]: 3.80 mg/liter [1.75 to 7.53 mg/liter] for Cmin, 14.70 mg/liter [10.57 to 19.64] for Cmax, and 196.08 mg·h/liter [144.02 to 312.10 mg·h/liter] for estimated AUC24). Linezolid Cmin was linearly correlated with estimated AUC24 (r2 = 0.85). Optimal pharmacodynamic target attainment (defined as Cmin of ≥2 mg/liter and/or AUC24/MIC90 ratio of >80) was obtained in about 60 to 70% of cases, but potential overexposure (defined as Cmin of ≥10 mg/liter and/or AUC24 of ≥400 mg·h/liter) was documented in about 12% of cases. A significantly higher proportion of cases with potential overexposure received cotreatment with omeprazole, amiodarone, or amlodipine. Our study suggests that the application of TDM might be especially worthwhile in about 30% of cases with the intent of avoiding either the risk of dose-dependent toxicity or that of treatment failure.