ArticleLiterature Review

Antibiotic use in patients with renal or hepatic failure

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Abstract

Renal or hepatic failure implies the need adjust the dosage of antibiotics that are eliminated in active form through the kidneys or metabolized through the liver. In the first case, the dose should be reduced by 30% for each level of renal impairment (moderate and severe). In hepatic failure, there is no general rule, and the specific information provided for each antibiotic should be used. Hemodialysis clears antibiotics with a low molecular weight, and a reduced protein binding and distribution volume. Thus, the dose should be administered immediately after the session or a supplementary dose should be provided. When the most intensive extrarenal clearance techniques are used, the presence of a high volume of distribution is the only guarantee that the antibiotic will not be eliminated.

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... However, no dosage adjustments are required because it is metabolised by a non-enzymatic process. [3][4][5] Daptomycin (DAP) is a cyclic lipopeptide derived from Streptomyces roseosporus as a fermentation product. It has a minimal hepatic metabolism and it is excreted primarily unchanged in urine. ...
... 8,9 Finally, dosage adjustments are not required for doripenem and ceftaroline in patients with hepatic impairment. 4,10 In conclusion, we hope that this additional information can be included in this practical guide and can be useful to clinicians in the management of antibiotic-resistant bacterial infections in cirrhotic patients. ...
... However, no dosage adjustments are required because it is metabolised by a non-enzymatic process. [3][4][5] Daptomycin (DAP) is a cyclic lipopeptide derived from Streptomyces roseosporus as a fermentation product. It has a minimal hepatic metabolism and it is excreted primarily unchanged in urine. ...
... 8,9 Finally, dosage adjustments are not required for doripenem and ceftaroline in patients with hepatic impairment. 4,10 In conclusion, we hope that this additional information can be included in this practical guide and can be useful to clinicians in the management of antibiotic-resistant bacterial infections in cirrhotic patients. ...
... 7 In patients with CKD and CLD, the reduction in dose is required for those antibiotics which are eliminated in active form through kidneys or metabolized by liver. 8 Mostly drugs primarily involve hepatobiliary and renal system for their metabolism and elimination respectively, hence, in order to decide drug dosing in patients of CKD and CLD, three important factors need to be considered (i) pharmacokinetic alterations of drugs, (ii) pharmacodynamic alteration of drugs, and (iii) increased susceptibility of patients to adverse events particularly nephrotoxicity and hepatotoxicity. 9 For this reason purpose of this study was to evaluate prescribers' knowledge regarding the antibiotic usage in patients of CKD and CLD. ...
Article
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Objective: To evaluate the knowledge of prescriber’s regarding antibioticsprescription in patients with chronic kidney and liver disease. Study design and technique:Cross-sectional study, convenient sampling. Setting: District Faisalabad of province Punjab,Pakistan. Period: 11 months. Material & Methods: Total 250 prescribers were approached,among which 210 prescribers responded and filled the questionnaire. Data after collection wasdivided into two categories: (i) on the basis of area of practice of the prescribers (urban & rural)and (ii) on the basis of qualification of the prescribers (consultants, postgraduate residents,general practitioners & paramedics). Results: The results of the current study revealed thatknowledge of the prescribers of urban area was better as compare to the prescribers of ruralarea with significant difference of 0.001. Similarly a significant difference of 0.001 was foundbetween the knowledge of consultants, postgraduate medical residents, general practitionersand paramedics. Consultants were found to be the most knowledgeable prescribers whileparamedics were the least. Conclusion: Prescribers who were practicing in urban areas and theones who were more qualified (consultants) have sound knowledge of prescribing antibiotics inpatients of chronic kidney and liver disease.
... In this study, we identified cases without indication for antimicrobial use, including asymptomatic bacteriuria (ASB) and colonization (n = 17, 12.0%) [25]. Another issue to highlight is that no dosing adjustments were seen in eight hemodialyzed patients, bearing in mind that up to 50% of meropenem is removed during this process, and so a dose is required after each session [26,27]. These considerations for usual practice can be modified in order to prevent the development of bacterial resistance, in this case carbapenemase production. ...
Article
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Background: To determine the therapeutic effect and tolerability of meropenem in routine clinical practice, in terms of clinical and microbiological response. Methods: A real-world, observational, descriptive, longitudinal study with daily monitoring of clinical history records was conducted on all patients who were medically prescribed meropenem during a period between October 2015 and March 2016 at a university hospital in Bucaramanga (Colombia). Results: The study evaluated 84 patients with an average age of 63.2 years, mostly older adults with multiple comorbidities, of whom 54.8% were men. A positive clinical or microbiological response was obtained in 98.8% of the patients. At the end of the treatments, significant improvements in dysthermia (0% vs. 29% at the beginning, p = 0.000), tachycardia (13% vs. 47%, p = 0.049), and leukocytosis (39% vs. 15% at the beginning, p = 0.008) were evidenced. The improvement in the indicator that combines all the Systemic Inflammatory Response Syndrome (SIRS) criteria was also significant (p = 0.000). The treatment was well tolerated, although we identified some non-serious and expected adverse reactions. Conclusions: Generic meropenem proved to be effective and well tolerated for different types of infection in routine clinical practice. The results are consistent with the findings of the clinical studies with the innovator drug.
... 7 In patients with CKD and CLD, the reduction in dose is required for those antibiotics which are eliminated in active form through kidneys or metabolized by liver. 8 Mostly drugs primarily involve hepatobiliary and renal system for their metabolism and elimination respectively, hence, in order to decide drug dosing in patients of CKD and CLD, three important factors need to be considered (i) pharmacokinetic alterations of drugs, (ii) pharmacodynamic alteration of drugs, and (iii) increased susceptibility of patients to adverse events particularly nephrotoxicity and hepatotoxicity. 9 For this reason purpose of this study was to evaluate prescribers' knowledge regarding the antibiotic usage in patients of CKD and CLD. ...
Article
Full-text available
Objective: To evaluate the knowledge of prescriber’s regarding antibiotics prescription in patients with chronic kidney and liver disease. Study design and technique: Cross-sectional study, convenient sampling. Setting: District Faisalabad of province Punjab, Pakistan. Period: 11 months. Material & Methods: Total 250 prescribers were approached, among which 210 prescribers responded and flled the questionnaire. Data after collection was divided into two categories: (i) on the basis of area of practice of the prescribers (urban & rural) and (ii) on the basis of qualifcation of the prescribers (consultants, postgraduate residents, general practitioners & paramedics). Results: The results of the current study revealed that knowledge of the prescribers of urban area was better as compare to the prescribers of rural area with signifcant difference of 0.001. Similarly a signifcant difference of 0.001 was found between the knowledge of consultants, postgraduate medical residents, general practitioners and paramedics. Consultants were found to be the most knowledgeable prescribers while paramedics were the least. Conclusion: Prescribers who were practicing in urban areas and the ones who were more qualifed (consultants) have sound knowledge of prescribing antibiotics in patients of chronic kidney and liver disease. Keywords: Antibiotic, Chronic kidney disease, Chronic hepatic disease, Glomerular fltration rate, Bioavailibility
Article
Background: To analyse the effect of haemodiafiltration (CVVHDF) flow rate on amikacin pharmacokinetics and blood concentrations. Methods: Prospective observational study. Patients receiving CVVHDF and amikacin treatment were included. Pharmacokinetic parameters were calculated using Bayesian analysis. Spearman correlation test was used in order to assess the influence of CVVHDF flux on amikacin minimum concentration (Cmin) and plasma clearance. Results: Thirty patients undergoing CVVHDF procedures were included. The treatment with amikacin started at an initial mean dose of 12.4 (4.1) mg/kg/day. An association between the flow rate and Cmin value (r = 0.261; p = 0.161) and plasma clearance was found (r = 0.268; p = 0.152). Four patients (13.3%) were not able to achieve peak concentration over MIC value higher than 8. In 4 patients, amikacin had to be discontinued due to a high Cmin value. Conclusions: Amikacin clearance in patients with CVVHDF is affected by the flow rate used. Therefore, CVVHDF dose should be taken into account when dosing amikacin.
Article
Background Continuous renal replacement therapy (CRRT) is common practice in critical care patients with acute renal failure. Objectives To evaluate the adequacy of antimicrobial doses calculated based on the total drug clearance and dose recommended by different guides in critically ill patients undergoing CRRT. Methods Retrospective observational study. Patients admitted to a critical care unit during May 2014 to May 2016 and subjected to CRRT were included. The recommended dose was established as the product of the usual dose of the drug by total drug clearance. Results 177 antimicrobial agents, used in 64 patients were analysed; 45 (25.4%) antimicrobials were given in an insufficient dose (<20%) according to the theoretical calculation. Following the recommendations in the revised guidelines, between 10% and 20% of antimicrobials were given in insufficient doses. A higher success rate of treatment in those patients not receiving a low drug dosage was seen (35.2% vs 24.0%). Conclusions There is a great disparity between the antimicrobial dose prescribed, recommended and calculated based on drug clearance in critically ill patients undergoing CRRT.
Article
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Chronic liver diseases (CLD) alter the kinetics of drugs. Despite dosage adjustment is based on Child-Pugh scores, there are no available recommendations and/or algorithms of reference to facilitate dosage regimens. A literature review about dose adjustment of the drugs from the hospital guide -which are included in the list of the WHO recommended drugs to be avoided or used with caution in patients with liver disease- was carried out. The therapeutic novelties from the last few years were also included. In order to do so, the summary of product characteristics (SPC), the database DrugDex-Micromedex, the WHO recommendations and the review articles from the last 10 years in Medline were reviewed. Moreover, the kinetic parameters of each drug were calculated with the aim of establishing a theoretical recommendation based on the proposal of Delcò and Huet. Recommendations for 186 drugs are presented according to the SPC (49.5%), DrugDex-Micromedex (26.3%) and WHO (18.8%) indications; six recommendations were based on specific publications; the theoretical recommendation based on pharmacokinetic parameters was proposed in four drugs. The final recommendations for clinical management were: dosage modification (26.9%), hepatic/analytical monitoring of the patient (8.6%), contraindication (18.8%), use with caution (19.3%) and no adjustment required (26.3%). In this review, specific recommendations for the practical management of patients with chronic liver disease are presented. It has been elaborated through a synthesis of the published bibliography and completed by following a theoretical methodology.
Article
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Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment. Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft-Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required. According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics. In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.
Article
Infectious diseases and impaired renal function often occur in critically ill patients, and delaying the start of appropriate empiric antimicrobial therapy or starting inappropriate therapy has been associated with poor outcomes. Our primary objective was to critically review and discuss the influence of chronic kidney disease (CKD) and acute kidney injury (AKI) on the clinical pharmacokinetic and pharmacodynamic properties of antimicrobial agents. The effect of continuous renal replacement therapies (CRRTs) and intermittent hemodialysis (IHD) on drug disposition in these two populations was also evaluated. Finally, proposed dosing strategies for selected antimicrobials in critically ill adult patients as well as those receiving CRRT or IHD have been compiled. We conducted a PubMed search (January 1980-March 2008) to identify all English-language literature published in which dosing recommendations were proposed for antimicrobials commonly used in critically ill patients, including those receiving CRRT or IHD. All pertinent reviews, selected studies, and associated references were evaluated to ensure their relevance. Forty antimicrobial, antifungal, and antiviral agents commonly used in critically ill patients were included for review. Dosage recommendations were synthesized from the 42 reviewed articles and peer-reviewed, evidence-based clinical drug databases to generate initial guidance for the determination of antimicrobial dosing strategies for critically ill adults. Because of the evolving process of critical illness, whether in patients with AKI or in those with CKD, prospective adaptation of these initial dosing recommendations to meet the needs of each individual patient will often rely on prospectively collected clinical and laboratory data.
Article
The liver plays a central role in the pharmacokinetics of the majority of drugs. Liver dysfunction may not only reduce the blood/plasma clearance of drugs eliminated by hepatic metabolism or biliary excretion, it can also affect plasma protein binding, which in turn could influence the processes of distribution and elimination. Portal-systemic shunting, which is common in advanced liver cirrhosis, may substantially decrease the presystemic elimination (i.e., first-pass effect) of high extraction drugs following their oral administration, thus leading to a significant increase in the extent of absorption. Chronic liver diseases are associated with variable and non-uniform reductions in drug-metabolizing activities. For example, the activity of the various CYP450 enzymes seems to be differentially affected in patients with cirrhosis. Glucuronidation is often considered to be affected to a lesser extent than CYP450-mediated reactions in mild to moderate cirrhosis but can also be substantially impaired in patients with advanced cirrhosis. Patients with advanced cirrhosis often have impaired renal function and dose adjustment may, therefore, also be necessary for drugs eliminated by renal exctretion. In addition, patients with liver cirrhosis are more sensitive to the central adverse effects of opioid analgesics and the renal adverse effects of NSAIDs. In contrast, a decreased therapeutic effect has been noted in cirrhotic patients with beta-adrenoceptor antagonists and certain diuretics. Unfortunately, there is no simple endogenous marker to predict hepatic function with respect to the elimination capacity of specific drugs. Several quantitative liver tests that measure the elimination of marker substrates such as galactose, sorbitol, antipyrine, caffeine, erythromycin, and midazolam, have been developed and evaluated, but no single test has gained widespread clinical use to adjust dosage regimens for drugs in patients with hepatic dysfunction. The semi-quantitative Child-Pugh score is frequently used to assess the severity of liver function impairment, but only offers the clinician rough guidance for dosage adjustment because it lacks the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. The recommendations of the Food and Drug Administration (FDA) and the European Medicines Evaluation Agency (EMEA) to study the effect of liver disease on the pharmacokinetics of drugs under development is clearly aimed at generating, if possible, specific dosage recommendations for patients with hepatic dysfunction. However, the limitations of the Child-Pugh score are acknowledged, and further research is needed to develop more sensitive liver function tests to guide drug dosage adjustment in patients with hepatic dysfunction.
Article
The prevalence and course of renal dysfunction in hospitalized patients and the prescribing of renally eliminated drugs in these patients were studied. All adult inpatients at a large teaching hospital who had a serum creatinine concentration assay performed were screened for renal dysfunction (an estimated creatinine clearance of < 40 mL/min). Renally compromised patients were monitored for changes in renal function. The regimens of selected renally eliminated drugs prescribed for these patients were compared with the manufacturers' recommended dosages for patients with renal compromise. Of the 3800 patients screened, 195 (5%) had renal dysfunction; most of these patients were older than 65 years. Although improvements in renal function were noted in 49 (30%) of the 169 patients with renal dysfunction who were not receiving hemodialysis, elderly patients were less likely to show an improvement in renal function. Of the 60 patients with renal dysfunction for whom a renally eliminated drug was prescribed, 27 (45%) were receiving dosages in excess of the manufacturers' recommendations. Changes in creatinine clearance estimates are common in hospitalized patients with renal impairment. Programs designed to alert physicians to potentially excessive dosages of renally eliminated drugs need to be sensitive to these changes.
Article
The advantages of continuous haemofiltration and haemodialysis over intermittent haemodialysis for the treatment of acute renal failure are well recognised. In intensive care patients, 4 different continuous procedures, arteriovenous and venovenous haemofiltration (CAVH and CVVH) or haemodialysis (CAVHD and CVVHD), are employed. These effective detoxification treatments require knowledge of their influence on drug disposition. Data on kinetics of drugs during continuous treatment are scarce and limited almost exclusively to the oldest and least effective procedure (CAVH). Selected dialysis membranes may adsorb drugs, as in the case of aminoglycosides. In addition, elimination of substances with large molecular weights may vary depending on the pore size of the membrane, as in the case of vancomycin. Thus, even if drug dosages can be based on pharmacokinetic studies, selection of a dialysis membrane not studied may cause unpredictable drug concentrations. With these limitations in mind and considering the available literature on pharmacokinetics in patients with renal failure, general guidelines for drug dosage during continuous renal replacement therapy can be given. In haemofiltration, drug protein binding is the major factor determining sieving, i.e. the appearance of the drug in the ultrafiltrate. In haemodialysis, diffusion is added to ultrafiltration, and therefore the saturation of the combined dialysate and ultrafiltrate will decrease further with increasing dialysate flow rate. In continuous haemofiltration or haemodialysis the extracorporeal clearance can be calculated by multiplying the saturation value (estimated or, better, measured) with the ultrafiltrate and dialysate flow rate. Dividing the extracorporeal clearance by the total clearance (including the nonrenal clearance) gives the fraction of the dose removed due to extracorporeal elimination. Whether dosage recommendations available for anuric patients have to be modified or not can be decided on the basis of this value. In case of high nonrenal clearance, the degree of saturation is without clinical significance. Based on these considerations guidelines have been constructed for the effect of extracorporeal elimination on more than 120 different drugs commonly used in intensive care patients.
Article
Renal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient’s degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency. The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function. Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium loading and use of pharmacological interventions [e.g. furosemide (frusemide) dopomine/dobutamine, calcium antagonists and mannitol] have resulted in limited success. The mechanisms responsible for altered dynamic responses of some agents (benzodiazepines, theophylline, digoxin and loop diuretics) in renally compromised patients include enhanced receptor sensitivity secondary to the accumulation of endogenous uraemic toxins and competition for secretion to the renal tubular site of action. Application of the pharmacotherapeutic principles discussed into clinical practice will hopefully enhance the safety of these agents and optimise patient outcomes.
Article
Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide) — the disposition of which is not substantially modified in liver disease — appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminoglycosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some β-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of hepatotoxicity. Special caution should be exercised, however, in patients with alcoholic liver disease because excessive alcohol intake may potentiate the hepatotoxic effect of paracetamol (acetaminophen).
Article
Some drugs are removed significantly by continuous renal replacement therapies (CRRTs), and a substitutional dose is required to prevent underdosing of the substance. This review outlines the basic pharmacokinetic principles that determine whether a dose adjustment is required. Only the free non-protein-bound fraction of a drug can pass through the dialyzer membrane. In postdilution hemofiltration the drug clearance equals the ultrafiltration rate, while in predilution hemofiltration, the dilution of the blood prior to filtration needs to be considered when calculating clearance. In continuous hemodialysis, drugs are eliminated by diffusion. Drugs with a higher molecular weight will diffuse more slowly and show a lower clearance than smaller drugs. The clinical relevance of a given drug clearance caused by CRRT will mainly depend on the competing drug clearance by other elimination pathways. Even a high clearance for a drug may be irrelevant for overall drug removal if nonrenal clearance pathways provide a much higher clearance rate. The ideal drug to be removed by CRRT that requires a dose adjustment has: a low protein binding, a low volume of distribution, and a low nonrenal clearance. Examples include aminoglycosides, vancomycin, fosfomycin, and flucytosine. Even if there are no studies available on the pharmacokinetics of a particular drug during CRRT, knowledge of the basic concepts of drug elimination by continuous hemodialysis allows a prediction of whether or not a dose adjustment will be required during CRRT.
Article
Unfortunately, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. In order to predict the kinetic behaviour of drugs in cirrhotic patients, agents can be grouped according to their extent of hepatic extraction. For drugs with a high hepatic extraction (low bioavailability in healthy subjects), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drugs are administered orally to cirrhotic patients, their initial dose has to be reduced according to hepatic extraction. Furthermore, their maintenance dose has to be adapted irrespective of the route of administration, if possible, according to kinetic studies in cirrhotic patients. For drugs with a low hepatic extraction, bioavailability is not affected by liver disease, but hepatic clearance may be affected. For such drugs, only the maintenance dose has to be reduced, according to the estimated decrease in hepatic drug metabolism. For drugs with an intermediate hepatic extraction, initial oral doses should be chosen in the low range of normal in cirrhotic patients and maintenance doses should be reduced as for high extraction drugs. In cholestatic patients, the clearance of drugs with predominant biliary elimination may be impaired. Guidelines for dose reduction in cholestasis exist for many antineoplastic drugs, but are mostly lacking for other drugs with biliary elimination. Dose adaptation of such drugs in cholestatic patients is, therefore, difficult and has to be performed according to pharmacological effect and/or toxicity. Importantly, the dose of drugs with predominant renal elimination may also have to be adapted in patients with liver disease. Cirrhotic patients often have impaired renal function, despite a normal serum creatinine level. In cirrhotic patients, creatinine clearance should, therefore, be measured or estimated to gain a guideline for the dosing of drugs with predominant renal elimination. Since the creatinine clearance tends to overestimate glomerular filtration in cirrhotic patients, the dose of a given drug may still be too high after adaptation to creatinine clearance. Therefore, the clinical monitoring of pharmacological effects and toxicity of such drugs is important. Besides the mentioned kinetic changes, the dynamics of some drugs is also altered in cirrhotic patients. Examples include opiates, benzodiazepines, NSAIDs and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use. However, it is important to realise that the recommendations for dose adaptation remain general and cannot replace accurate clinical monitoring of patients with liver disease treated with critical drugs.
Article
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.
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