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Pharmacology Chemotherapy 2002;48:280–297 DOI: 10.1159/000069712 Biliary Excretion of Antimicrobial Drugs George Karachalios a Konstantinos Charalabopoulos a, b a Department b Department of Medicine and Division of Infectious Diseases, Red Cross Hospital, Athens, and of Physiology, Clinical Unit, Medical Faculty, University of Ioannina, Ioannina, Greece Key Words Antimicrobial drugs W Biliary excretion W Antibiotics Abstract The development of drugs able to prevent and cure bacterial infections is one of the 20th century’s major contributions to human longevity and quality of life. Antibacterial agents are among the most commonly prescribed drugs of any kind worldwide. Used appropriately, these drugs are lifesaving. To eliminate an infection as rapidly as possible, a sufficient concentration of the drug(s) chosen must reach the site of infection. Serum/tissue concentration is a result of various parameters such as absorption, excretion, protein binding and metabolic inactivation. Biliary excretion is an important route for the elimination of some drugs and drug metabolites in humans. Thus, drugs with a high bile concentration are indicated for the treatment of gallbladder infectious diseases. We present a review of a large number of antimicrobial agents most commonly used in daily clinical practice, with regard to their biliary excretion. Copyright © 2002 S. Karger AG, Basel Introduction Antimicrobial agents are among the most commonly prescribed drugs. The aim of antimicrobial chemotherapy is to eliminate an infection as rapidly as possible. To achieve this, a sufficient concentration of the drug or ABC © 2002 S. Karger AG, Basel 0009–3157/02/0486–0280$18.50/0 Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com Accessible online at: www.karger.com/che drugs chosen must reach the site of infection. The concentration is governed by absorption and excretion, whereas antimicrobial activity depends on protein binding and metabolic inactivation. Bile is either sterile or contains few bacteria. Bacteria have been cultured from bile in the majority of patients with acute cholecystitis or partial obstruction of the common duct, and in one third of patients with chronic obstruction [1–3]. Gallbladder bile from patients with acute and chronic cholecystitis yields organisms in 30– 50% of patients [2]. The bacteria most commonly isolated from the infected bile are Escherichia coli, Klebsiella pneumoniae, Enterobacter species and other enteric gramnegative bacilli and enterococci [3]. Anaerobes constitute a smaller fraction. Gram-negative sepsis, due to organisms from the infected bile, contributes considerably to the mortality of patients with acute cholecystitis or acute cholangitis [4]. Biliary Excretion of Antibiotics in Bile Biliary excretion is an important route for the elimination of some drugs and drug metabolites in humans. The effect of biliary excretion on drug pharmacokinetics is unique, since drugs cleared by this route may undergo enterohepatic circulation, metabolism within the intestine or elimination in the feces [5]. The presence of adequate levels of antimicrobial agents at the infected sites in biliary infection is considered to be of great importance for the eradication of the responsible organisms. Conflict- Assoc. Prof. Konstantinos Charalabopoulos, MD, PhD Department of Physiology, Clinical Unit Medical Faculty, University of Ioannina GR–45221 Ioannina (Greece) Tel. +30 26510 97574, Fax +30 26510 97850, E-Mail [email protected] ing results among those concerned with antibiotic excretion in bile may be attributed largely to methodological differences in the selection of subjects, administration of antibiotics and collection of bile [1]. Biliary antimicrobial levels in humans have been determined in three ways: collections of duodenal juice, assay from T tube drainage and preoperative collections of bile. Collections of T tube bile have been used in the majority of studies. Unfortunately, some of these studies have been well controlled, collections have not been quantitative and the enterohepatic circulation of antimicrobials has been neglected. Several facts about the biliary excretion of antibiotics and the administration of these drugs to patients with the hepatobiliary disease are now clear [5]. (1) The biliary excretion of most antibiotics is quantitatively low (an exception being rifamycin). However, the bile to plasma concentration ratios for many antibiotics are concentrated possibly by active transport in bile. (2) The percentage of a dose of antibiotic excreted unchanged in bile is irrelevant in selecting an antibiotic for a period of time sufficient to inhibit bacterial growth. Unfortunately, in most cases antibiotic excretion has been studied several days after surgery and minimal inhibitory concentration levels have not been reported. The standard methods for evaluating biliary pharmacokinetics of antibiotics include direct sampling of gallbladder or cystic duct bile at operation or during diagnostic retrograde cholangiopancreatography [2]. These methods produce only single specimens for assay. Collections of T tube bile have been used for the majority of studies. There are, however, certain serious objections to the use of T tube drainage for bile collection. Hepatic function may be impaired by general anesthesia and the measurement of any antimicrobial drug which is reexcreted through the liver is liable to be erroneous, because the enterohepatic circulation is disturbed. This method is unsuitable for studying changes in biliary excretion immediately following relief of obstruction and may not be applicable to critically ill patients who are unsuitable for surgery. The biliary sampling method overcomes most of these problems [6]. The technique allows direct sampling of obstructed bile at the moment of decompression, measurement of intrabiliary pressure, and continuous sampling during the period following the relief of obstruction. It is nontraumatic, can be performed in patients unsuitable for general surgery and does not require general anesthesia. (3) The biliary excretion of antibiotics may be significantly reduced in the presence of an obstruction of the common bile duct [7, 8]. For example, in one study the mean bile level of ampicillin from functioning gallbladders was 13.1 Ìg/ml while that from nonfunctioning gallbladders with an obstructed cystic duct was 13.5 Ìg/ml [8]. (4) The preoperative administration of antibiotics to patients with cholecystitis associated with bile duct obstruction does not influence the pain or the jaundice, the development of gallbladder empyema and perforation or the percentage of patients with positive bile cultures at operation [9]. However, systemic symptoms do improve more rapidly. (5) The serum concentration of an antibiotic is probably more important than the concentration in bile, mainly in cases of biliary tract obstruction [2]. In the text that follows, a description of the most frequently used antimicrobial agents of the several antibiotic categories is given. Table 1 summarizes the main antimicrobial drug categories according to the presentation in the text. Biliary Excretion of Antimicrobial Drugs Chemotherapy 2002;48:280–297 Penicillins Penicillin is one of the most important antibiotics. Although numerous other antimicrobial agents have been produced since penicillin became available, it is still a widely used, major antibiotic, and new derivatives of the basic penicillin nucleus are being produced every year. The structure of the penicillin molecule has a decisive effect on antibacterial activity. The penetration of penicillins is regulated partly by passive diffusion, which – as for other classes of compounds – is regulated by the concentration of the substance, its lipid solubility, its aqueous solubility, the distance between reservoir and target and by the protein binding [9, 10]. Penicillins are widely distributed throughout the body, but the concentration in various fluids and tissues differs widely. Most of the penicillins are readily detected at all sites of the unobstructed biliary tree. Penicillin G Approximately 12% of the dose of penicillin G is recovered in bile. Brogard et al. [11] have found that only 1,200 units of administered penicillin G were recovered in T tube bile after a dose of 1,000,000 units in 10 patients. Nonetheless, the mean bile level reached 18 mg/ ml at 2 h and exceeded the serum concentration for 12 h. In patients who received the same dose prior to cholecystectomy for cholecystitis, the mean concentration in serum, gallbladder and common bile duct 1 h after the doses 281 Table 1. Antimicrobial agents Penicillins Penicillin G Ampicillin Amoxycillin Metampicillin Phenoxypenicillins Antistaphylococcal penicillins Methicillin Isoxasolic penicillins (oxacillin, cloxacillin, dicloxacillin, flucloxacillin) Nafcillin Anti-P. aeruginosa penicillins Carbenicillin Ticarcillin Azlocillin Mezlocillin Piperacillin Other penicillins Mecillinam (amdinocillin) Temocillin Apalcillin Cephalosporins Cephalosporins of the 1st generation Cephalothin Cefazolin Cephacetrile Cephapirin Cephradine Cephalexin Cephadroxil Cephalosporins of the 2nd generation Cephamandole Ceforanide Cefoxitin Cefuroxime Cefaclor Cephalosporins of the 3rd generation Cefotaxime Ceftazidime Ceftriaxone Cephalosporins of the 4th generation Cefpirome Cefepime Less commonly used cephalosporins Cefotetan Cefotiam Cefoperazone Ceftizoxime Cefmetazole Cefonicide Cefazedone Cefpiramide Cefsulodin Cefmenoxim Moxalactan Monobactams Aztreonam Carbepenems Imipenem Meropenem were 9.9, 45.1 and 93.5 Ìg/ml, respectively, indicating an excellent penetration. Pulaski and Fusillo [12] found similar concurrent serum and bile levels at the time of cholecystectomy for acute and chronic cholecystitis after intravenous administration. Harrison and Stewart [13] described levels, which were lower than those of serum levels. In animals 4.5% of a parenteral dose of penicillin G can be recovered in the bile, and probenecid may reduce biliary excretion and possibly interfere with the penicillin G inactivation in the liver [11]. Ampicillin Ampicillin is excreted unchanged in the bile. Among patients with a normal biliary tract operated on for other 282 Chemotherapy 2002;48:280–297 Aminoglycosides Streptomycin Kanamycin Gentamycin Amikacin Netilmicin Tetracyclines Macrolides Erythromycin Josamycin Spiramycin Rosaramicin Roxithromycin Azithromycin Various other antibiotics Chloramphenicol and thiamphenicol Novobiocin Lincozamides (lincomycin, clindamycin) Glycopeptide antibiotics (vancomycin, teicoplanin) Nitrofurantoin Metronidazole Trimethoprim/sulfamethoxasole Rifampicin Rifamide Newer quinolones/fluoroquinoles (2nd generation quinolones) Norfloxacin Ciprofloxacin Ofloxacin Pefloxacin Enoxacin Grepafloxacin disorders, ampicillin levels in gallbladder bile were 3–50 times those present concurrently in the serum. In patients with T tube drainage after cholecystectomy, only 0.1% of an intravenous or oral dose of ampicillin was excreted via the bile. In these patients the biliary concentration varied from 0.4 to 6.5 Ìg/ml during a 12-hour period after an oral ampicillin dose of 0.5 g [12]. This concentration is higher than the minimal inhibitory concentration (MIC) of ampicillin for highly susceptible pathogens. In one study it was found that the ratio between bile and serum activity ranged between 3 and 48, with higher levels in common bile duct than in bile from gallbladder [14]. In nonicteric biliary tract disease the levels of ampicillin in the gallbladder considerably exceeded the serum levels. However, Karachalios/Charalabopoulos when the cystic duct was obstructed, gallbladder bile concentrations were low. When jaundice was present, the levels in common bile duct were low [13]. Other investigators found that the site of obstruction plays a crucial role. Obstruction of the cystic duct drastically reduced gallbladder bile levels although common duct levels still exceeded serum concentration. In common duct obstruction, both gallbladder and common duct levels were vastly diminished [8, 15]. Amoxycillin Amoxycillin possesses similar antimicrobial activity to ampicillin but it is not converted to ampicillin in the body. Amoxycillin is probably excreted in the bile, similarly to ampicillin [16]. Given orally it penetrates the unobstructed biliary tract well. After doses of 1–2 g per day, levels in bile ranged from 1 to 50 mg/ml, with a mean of 8 mg/ml. No drug was found in the obstructed biliary tree [17]. In patients with a normal biliary tract, bile levels of amoxycillin were usually lower than the serum levels after intravenous administration of 500 mg, the maximum levels being 60–75% of simultaneous serum levels [18]. Metampicillin Metampicillin is obtained by reacting ampicillin with formaldehyde whereby a methyleneamino group is formed. It has a wide spectrum and is slightly more stable to ß-lactamases than ampicillin [19]. In the body metampicillin converts to ampicillin. When metampicillin is measured as ampicillin, lower serum levels are seen after metampicillin, but bile levels are slightly higher after metampicillin [19]. After oral administration of metampicillin, only 0.16% is eliminated in bile and the biliary concentration of ampicillin attained is about the same as those obtained after oral administration of ampicillin. However, 500 mg metampicillin given intravenously have been reported to produce a peak biliary concentration in patients that have T tube drainage of approximately 1,500 Ìg/ml in 3 h [20]. Phenoxypenicillins Four different acid-stable phenoxypenicillins have been developed which are all suitable for oral administration: phenoxymethylpenicillin (penicillin V), phenoxymethylpenicillin (phenethicillin), phenoxypropynicillin (propicillin) and phenoxybenzylpenicillin (phenbenicillin). The phenoxypenicillins are excreted in the bile only in small amounts, mainly in their unchanged form [21]. Biliary Excretion of Antimicrobial Drugs Antistaphylococcal Penicillins Methicillin Limited studies of methicillin excretion in bile are available. A certain part of an injected dose is excreted in bile [21]. The biliary concentration of methicillin is somewhat higher than in serum specimens collected simultaneously. It was found that the levels of methicillin in the common duct varied from undetectable to 10 Ìg/ml, with most values in the 1–3 Ìg/ml range, after 1 g intramuscular dose [22]. Simultaneous serum levels were not obtained. Levels in bile were low when hepatic disease or obstruction was present [22]. Isoxazolic Penicillins (Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacillin) Oxacillin, cloxacillin, dicloxacillin and flucloxacillin are similar to methicillin and nafcillin and are effective antistaphylococcal agents. These agents are highly bound with plasma proteins and their levels in bile are higher than in serum mostly 1–10 times those of plasma levels. However, 2–10% of a dose of cloxacillin or oxacillin can be recovered from bile [21]. The excretion of oxacillin exceeds that of cloxacillin, the former producing 70% of serum level 1 h after administration. Nafcillin Nafcillin sodium is a semisynthetic, penicillinase-resistant penicillin. Approximately 30% of a parenteral dose of nafcillin may be excreted as active drug in urine; in addition microbiologically inactive metabolites are also excreted in urine. Nafcillin is also excreted in bile and undergoes enterohepatic circulation; approximately 80% of a nafcillin dose can be recovered from the bile in an active form [23]. Nafcillin appears to pass particularly efficiently into the bile and the maximum levels are 40– 400 times those in serum. Green and Gerasi [24] found that peak levels in T tube bile were 173–1,030 Ìg/ml 2 h after an intramuscular dose of 1 g. A concentration of 1.8– 20.5 Ìg/ml was still detectable 24 h later. In a patient with nonobstructive biliary tract diseases levels of nafcillin in bile, gallbladder and liver were approximately 180, 18 and 3 Ìg/ml, respectively, while serum levels were 1.6 Ìg/ ml [25]. Anti-Pseudomonas aeruginosa Penicillins Carbenicillin Carbenicillin is rapidly excreted unchanged in urine by glomerular filtration and tubular secretion. Small amounts of carbenicillin are eliminated via the bile. Pinget et al. [14] found that peak levels in T tube bile after Chemotherapy 2002;48:280–297 283 cholecystectomy were 0.19% of an intravenously administered carbenicillin dose. In another study the mean levels of carbenicillin in duodenal aspirates after an intravenous injection of 1 g into 10 patients were below the serum level in the first 2 h after the administration. At 2 h, the mean aspirate level was 39 Ìg/ml. After the administration of the same dose to 5 patients with T tube bile, the biliary level approximately equaled the serum levels at 2– 8 h after a dose. The mean peak biliary level of 27 Ìg/ml was reached at 2 h. Ticarcillin Ticarcillin is a semisynthetic penicillin with a broad spectrum of antibacterial activity. In patients with normal hepatic function or unconjugated hyperbilirubinemia the mean concentration of ticarcillin in bile from common bile ducts and functioning gallbladders exceeded the mean concentration in plasma and bile from gallbladders with poor or no function [26]. Owen and Farge [26] administered ticarcillin as a single intravenous bolus of ticarcillin/clavulanic acid of 3.2 g to 23 patients who required elective biliary with normal hepatic function. In 21 of these patients the concentration of ticarcillin in bile from the common duct exceeded the concentration in plasma and the peak levels of ticarcillin in bile were found after 2 h to be 375 Ìg/ml. In contrast, the concentration of ticarcillin in bile from gallbladders with poor or no function (mean concentration 33 Ìg/ml) was invariably lower than the concentration in bile from the common duct (mean concentration 259 Ìg/ml) and bile from gallbladders with good function (324 Ìg/ml). In patients with obstructive jaundice the concentrations of ticarcillin in the biliary tree are lower than those in plasma. Azlocillin Azlocillin is an acylureidopenicillin compound. Its principle characteristic is a broad antimicrobial spectrum activity including P. aeruginosa. The bile concentration of azlocillin is high compared to many other ß-lactam antibiotics and in normal hepatic function considerably above the serum levels [27]. Severe liver disease is accompanied by a reduced biliary elimination of azlocillin [28]. In patients with normal liver and biliary tract function biliary excretion of azlocillin is approximately 5.3% of the dose administered and the rate of elimination from bile was 3–5 times slower than the serum disposition rate [28]. Azlocillin, administered in a dose of 2.0 g intravenously, produced biliary levels of 1.137 Ìg/ml, which were still measurable after 10 h [29]. 284 Chemotherapy 2002;48:280–297 Mezlocillin It is also an acylureidopenicillin which has a broad spectrum of activity against gram-positive cocci (except penicillinase-producing strains of Staphylococcous aureus), gram-negative cocci, including P. aeruginosa, and anaerobic bacteria. Mezlocillin administered intravenously produced biliary levels as high as 25% at the dose administered [30]. Gundert-Remy et al. [30] administered 2.0 g of mezlocillin intravenously in 8 subjects and 4.0 g in 6 subjects undergoing biliary surgery and found a mean biliary concentration of 2,567 and 2,755 mg/l, respectively. In patients with impaired hepatobiliary function lower biliary levels were found. In those having cholestasis with normal or only slightly changed values of serum bilirubin of alkaline phosphatase levels, the biliary concentration of mezlocillin ranged from 8,850 to 42 mg/l. Piperacillin Piperacillin is a parenteral semisynthetic penicillin that has a broader spectrum of activity than its predecessors and often is effective against organisms that presented significant therapeutic problems notably like those of P. aeruginosa, Klebsiella spp., indole-positive Proteus, enterococci and the Bacteroides fragilis group. Piperacillin is excreted through the biliary tract in an amount of 20% of the administered dose and produces a concentration in the bile of up to 40 times that in the serum [31]. In the patients who do not have obstructed biliary systems, the concentration of piperacillin in bile may be up to 40-fold the level in the serum. Baier et al. [32] monitored the level of piperacillin in the serum and in the bile in 9 patients who had undergone cholecystectomy. The drug was administered in single doses of 2 and 4 g on the 4th and 6th postoperative days. Serum and bile samples were collected at 20-min intervals for 3 h after injection (bile samples were collected via T tube drainage). The maximum mean level in bile at 100–120 min after injection of the 2-gram dose was 1,238 Ìg/ml compared with 3,247 Ìg/ml at 80–100 min after the 4-gram dose. The authors concluded that this concentration was well above the MICs for the pathogens that most frequently cause biliary tract infections. High levels of piperacillin persist in the bile for at least 5.5 h after dosing. In one study the levels at that time point were 435 Ìg/ml after a 4-gram dose and 233 Ìg/ml after a 2-gram dose [33]. The biliary excretion of piperacillin in cholestatic patients who had undergone endoscopic cholangiography was also studied. The mean concentration of piperacillin was !5 Ìg/ml in the bile com- Karachalios/Charalabopoulos pared to the 14.3 Ìg/ml in the serum. The authors concluded that piperacillin cannot be excreted into the bile in the presence of biliary tract obstruction. Other Penicillins Mecillinam (Amdinocillin) Mecillinam (amdinocillin) is a ß-lactam antibiotic that is highly active against many aerobic gram-negative bacilli but less active against gram-positive bacteria. Mecillinam is excreted mainly unchanged in urine. Biliary levels are higher that those in the serum provided that the biliary tract is not obstructed [34]. Mecillinam, when given orally, produces levels of 6.2 Ìg/ml within 2 h of a single dose of 400 mg [35]. In another study levels of mecillinam were measured in serum and bile samples 1–3 h after the administration of 800 mg intramuscularly 1 h preoperatively in 53 patients undergoing biliary surgery, of whom 11 patients were jaundiced [36]. In the nonjaundiced group, the mean concentration of mecillinam in 26 patients with normal gallbladder function was 40 compared to 12 Ìg/ml in 16 patients with a nonfunctioning gallbladder. In the nonjaundiced patients the mean concentration of mecillinam in the common bile duct was 49 Ìg/ml. In the 11 jaundiced patients the mean concentration of mecillinam in the common duct bile was 8 Ìg/ml and in the gallbladder bile it was 12 Ìg/ml. gallbladder bile, respectively [21]. Presumably, a lower concentration would be achieved in patients with hepatobiliary disease. Cephalosporins The main route of excretion of most cephalosporins is via the kidney. More than 90% of cephalosporins is excreted by glomerular filtration. The only other recognized excretion route of cephalosporins is via the biliary system [38]. The biliary concentration of cephalosporins is generally adequate for the treatment of gallbladder infections. It has been studied by many researchers but it is difficult to compare results between different members of the cephalosporins group, since published studies vary considerably in the dose, the route of administration of the antibiotic drug, as well as the types of patients studied. The majority of studies have been done on patients undergoing cholecystectomy or with T tubes. Meanwhile, there is no data available on biliary excretion in healthy humans. Individual cephalosporins vary in the degree to which they are excreted in the bile [39, 40]. The degree of biliary excretion of cephalosporins is in direct proportion to increasing molecular weight. Apalcillin Apalcillin is excreted well in the bile at levels high enough to be sufficient for inhibition of most microorganisms responsible for biliary tract infections. In one study apalcillin was administered intravenously as a single 1gram dose on day 8 after surgery to 10 cholecystectomized patients with T tube drainage [21]. A mean bile concentration of 859 Ìg/ml was obtained 3 h after dosage. In 20 patients undergoing biliary surgery apalcillin concentration 1 g after a 1-gram dose was 6,550 B 50, 3,680 B 551 and 2,552 B 627 Ìg/ml in serum, choledochal bile and Cephalosporins of the 1st Generation Cephalothin Cephalothin shows good penetration in the bile although there have been differences between studies. Cephalothin bile concentration in patients undergoing cholecystectomy was found to be approximately the same as serum concentration 1 h after a 1-gram intravenous dose. Ram and Watanatittan [41] found mean gallbladder bile levels of 364 Ìg/ml in a group of normal patients given repeated doses of 2 g intravenously, at a time when the serum level was 16.7 Ìg/ml. In patients with chronic cholecystitis the same regimen produced levels of 159, 48 and 72 Ìg/ml in gallbladder bile, common bile duct and gallbladder wall, respectively. Even with obstructive jaundice, choledochal bile contained 2–20 Ìg/ml of cephalothin. Some investigators comparing the excretion of cefazolin, cephaloridine and cephalothin in patients undergoing cholecystectomy, being followed by a single 1-gram dose in the absence of cystic duct obstruction, found that the mean antibiotic concentration in the gallbladder bile was 17, 7 and 1 Ìg/ml for cefazolin, cephaloridine and cephalothin, respectively. In the presence of cystic obstruction none of those cephalosporins was detectable in Biliary Excretion of Antimicrobial Drugs Chemotherapy 2002;48:280–297 Temocillin Temocillin is a semisynthetic penicillin with a spectrum of activity against most aerobic gram-negative bacteria. It is excreted primarily by the kidneys. The concentration of temocillin in the bile is characterized by high quantity variation. Therefore, calculation of the mean ratio between plasma and bile concentrations would be meaningless. These differences may be mainly due to the pathological conditions of the patients. In patients who had a normal hepatobiliary system, temocillin was highly concentrated in the gallbladder [37]. 285 an appreciable amount in gallbladder bile. Other investigators have reported a maximum concentration in the bile of 0.6–10.6 Ìg/ml after intravenous administration of 1 g cephalothin [42]. The different and favorable results of Ram and Watanatittan [41] are probably due to their use of multiple doses prior to sampling. Cefazolin The biliary excretion of cefazolin is low and amounted to 0.03% of the administered dose; the concentration is about the same or slightly in excess of the simultaneous serum level provided that the biliary tract is not obstructed. In patients with cystic duct obstruction, cefazolin cannot be detected in gallbladder bile [41, 42]. The mean concentration in gallbladder bile after an intramuscular dose of 500 mg administered to patients with cholecystitis was 32 Ìg/ml when serum levels averaged 20 Ìg/ ml. After four preoperative doses, the perspective mean serum and gallbladder bile levels were 25 and 92 Ìg/ml; the penetration ratio was 400%. Levels in gallbladder bile of 2.8 and 13.5 Ìg/ml were found in 2 patients despite cystic duct obstruction. Levels in the common duct equaled or exceeded the concurrent serum level [41]. These authors, subsequently, reported a penetration ratio of only 15% when repeated doses were given to patients with obstructive jaundice. The peak cefazolin level in T tube bile 30 min after a single dose of 1 g was only 50% of the serum level. Cephacetrile Biliary excretion of cephacetrile is very low. In the bile, a mean peak level of 1.9 mg/ml was measured 4 h following the intramuscular administration of 1 g to 5 patients with T tube drainage [43]. Cephapirin Cephapirin excretion of the bile duct was low and amounted to less than 1% of the administered dose [43]. Cephradine Cephradine is available in both oral and injectable form. It is excreted in bile and the concentration may be about 4 times higher than the serum level at the same time [21]. Biliary excretion is reduced in biliary tract obstruction and jaundice cases. Cephalexin Cephalexin is excreted exclusively through the kidney. Cephalexin excreted in bile represents 0.29% of the administered dose [44]. After 5 doses of 500 mg per os, the 286 Chemotherapy 2002;48:280–297 concentration of cephalexin in gallbladder bile of patients with cholecystitis was 14–90 Ìg/ml if the gallbladder showed radiologic function and 1–27 Ìg/ml if it was radiologically nonfunctional. Serum levels were 3 Ìg/ml or less, indicating an excellent concentration [45]. In the presence of obstruction of the common duct, no drug was detectable in bile. Bile cephalexin was enhanced by the simultaneous administration of probenecid and decreased as much as 10-fold in patients with hepatic dysfunction [45, 46]. Cefadroxil In two Belgian studies the penetration of cefadroxil into gallbladder, bile duct, bile and liver parenchyma was studied. Twenty patients were enrolled, who had cholelithiasis and were to undergo cholecystectomy. No patient had an acute obstruction. Cefadroxil was administered in a single 1,000-mg oral dose at specific time intervals prior to surgery. The results demonstrate satisfactory tissue levels of cefadroxil in the liver, gallbladder and bile duct as well a high concentration in bile. The mean liver tissue concentration, in samples collected between 2 and 5 h, was 13.5 mg/kg while the corresponding serum concentration was 11.5 Ìg/ml. The peak concentration of cefadroxil after oral administration occurred at 2–3 h in gallbladder and bile duct (9.5 and 12.8 Ìg/kg, respectively). These levels gradually decreased during the next 6 h. The concentration of cefadroxil in the bile was 8.2 Ìg/ml at 2–3 h and 9.9 Ìg/ml at 6–8 h. This represents a bile/serum ratio of 0.78 and 2.60, respectively [47]. Cephalosporins of the 2nd Generation Cefamandole Cefamandole is excreted in bile at a high concentration and may therefore be useful in the treatment and prophylaxis of biliary tract infections [48]. In one study, the mean biliary tract levels of cefamandole were measured to be as high as 220 Ìg/ml in the gallbladder and 1,100 Ìg/ml in the common duct [48]. In 6 patients studied for 6 h the rate of the elimination of cefamandole in T tube bile was 3 times that of cefazolin and 18 times that of cephalothin. Mean peak levels in bile were 352 Ìg/ml 0.5 h after a dose of 1 g. Levels of cefamandole in bile are 400-fold those of cephalothin and 50-fold those of cefazolin in patients with obstructed cholelithiasis. Maximum biliary levels of cefamandole reach approximately 340 Ìg/ml 2 h after intravenous administration of a 2-gram dose [49]. However, in the presence of a biliary obstruction, hepatic excretion of cefamandole is very low [50]. Karachalios/Charalabopoulos Ceforanide Ceforanide is eliminated by the kidney (80%) and only a small amount via the bile, but reaches therapeutic levels in the gallbladder and the bile [51]. In one study, Kenady and Ram [52] observed the ceforanide levels in plasma, gallbladder bile and tissue, and common bile duct in 10 patients with normal biliary tracts and in 35 patients with biliary disease at various intervals after intravenous injection of 1 g of the drug. The levels of ceforanide in patients with a normal biliary tract were 76 and 182 Ìg/ml in the gallbladder at 2 and 4 h, respectively. But, in all patients with chronic cholecystitis and occluded cystic duct a very low drug concentration in the gallbladder bile (14 Ìg/ml at 2 h) was observed. Cefoxitin Cefoxitin maintains a high concentration in bile, which reaches a peak about 2–4 h after administration [6]. In the presence of cystic duct obstruction the concentration is reduced. Levels of cefoxitin in common bile duct in patients with various forms of chronic cholecystitis after a dose of 1 g ranged from approximately 50 to 250 Ìg/ml. Hansbrough and Clark [53] intravenously administered a dose of 2 g to 17 patients scheduled for cholecystectomy and produced concentrations in excess of 10 Ìg/ml in the gallbladder bile of 12 of 13 patients from samples obtained between 35 and 165 min after cefoxitin infusion. Greddes et al. [54] found biliary levels of cefoxitin as much as 4–12 times higher than those in the simultaneous serum levels in 2 patients after cholecystectomy. Cefoxitin enters the gallbladder bile via the gallbladder wall in patients with cystic duct obstruction. A therapeutically effective concentration of the drug may be found in the common bile duct in patients with obstructive jaundice. Cefoxitin levels in gallbladder bile were similar to those in the common bile duct in patients with a functioning gallbladder. In contrast, those levels were substantially lower in patients without gallbladder function [54]. wide variation from 1.2 to 58 Ìg/ml 2 h after the last dose of cefuroxime. The cefuroxime levels in the common bile duct were 13.2 Ìg/ml (mean level) for 4 patients compared with the mean level in gallbladder of 29 Ìg/ml. These levels of cefuroxime exceeded the minimum inhibitory concentration of many common gallbladder pathogens including E. coli and Salmonella spp. Cefaclor Cefaclor in studies in dogs appears to be actively excreted in bile at a concentration more than sufficient to be effective against susceptible pathogens [56]. Cephalosporins of the 3rd Generation Cefotaxime Cefotaxime at therapeutic doses penetrates easily into all body fluids and tissues. Therapeutic doses of cefotaxime showed significant levels in the bile and gallbladder wall [57]. Soussy et al. [57] used a bioassay to measure cefotaxime concentration in the bile of 5 postoperative patients with a biliary cannula; the drug was administered intramuscularly. One patient received 1,000 mg and 4 patients 500 mg every 8 h (total 7 doses). In the first 2 h following administration, concentration of cefotaxime in the bile ranged from 0.8 to 7.8 Ìg/ml. When 1 g of cefotaxime was given intravenously every 6 h prior to cholecystectomy, the gallbladder contained 33.7–82.4 Ìg/ml, while the gallbladder wall, by using a bioassay, contained 100 Ìg/ml. Wittman and Schassan [58] found a maximal level of 22 Ìg/ml of cefotaxime 1 h after intravenous administration of 2 g in 18 patients with T tube drainage. Pelz et al. [59] found an average of 87.6 Ìg/ml in the bile of 10 subjects after intravenous administration of 2 g of cefotaxime while the wall of the gallbladder contained an average of 15.8 Ìg/ml. Cefuroxime Biliary levels are lower than simultaneous serum levels even in cases where the biliary tract is not obstructed. Semern and Powis [55] found that after an intravenous dose of 750 mg of cefuroxime, the mean biliary levels in diseased gallbladder were 4.8 Ìg/ml. The mean drug level was only 9 Ìg/ml in the common bile duct in patients without any biliary tract obstruction [55]. Sales and Rimmer [49] administered 750 mg intramuscularly at 8-hourly intervals to 20 patients undergoing cholecystectomy for cholecystitis. They found that gallbladder bile levels had a Ceftazidime Ceftazidime is a parenteral cephalosporin which is stable to a wide range of ß-lactamases. Biliary excretion probably accounts for less than 1% of nonrenal excretion of ceftazidime in healthy subjects, despite mean biliary concentrations reaching 38 Ìg/ml after a single 2-gram intravenous dose. Levels of ceftazidime in the bile reached 36.4 Ìg/ml at 90 min and were 4.2 Ìg/ml at 12 h after a single intravenous bolus injection of 2 g [60]. These levels are only 50% of peak serum levels of ceftazidime. Tanimura et al. [61] intravenously administered 1 g of ceftazidime to patients with T tube drainage and found a peak biliary level of ceftazidime of 46.7 Ìg/ml, of which 63–96% remained after 6 h. Shiramatsu et al. [62] mea- Biliary Excretion of Antimicrobial Drugs Chemotherapy 2002;48:280–297 287 sured the concentration of ceftazidime in bile duct and gallbladder in 16 patients after intravenous administration of 1 g of ceftazidime. Concentration in the common bile was 55.4 Ìg/ml. Concentration in the gallbladder tissues tended to be lower in chronic cholecystitis cases with a more severe fibrous and inflammatory change in the gallblader wall (mean value 9.1 B 1.6 Ìg/ml). In patients with a T tube drainage the peak biliary levels of ceftazidime were observed 180 min after the administration and an effective concentration excretion of ceftazidime in healthy subjects, despite mean biliary concentrations reaching 38 Ìg/ml after a single 2-gram intravenous dose. Levels of ceftazidime in the bile reached 36.4 Ìg/ml at 90 min and it was 4.2 Ìg/ml at 12 h after a single intravenous bolus injection of 2 g [60]. These levels represent only 50% of peak serum levels of ceftazidime. Tanimura et al. [61] intravenously administered 1 g of ceftazidime to patients with T tube drainage and found a peak biliary level of ceftazidime of 46.7 Ìg/ml, of which 63–96% remained after 6 h. Shiramatsu et al. [62] measured the concentration of ceftazidime in bile duct and gallbladder in 16 patients after intravenous administration of 1 g of ceftazidime. The concentration in the common bile was 55.4 Ìg/ml. The concentration in the gallbladder tissues tended to be lower in chronic cholecystitis cases with a more severe fibrous and inflammatory change in the gallbladder wall (mean value 9.1 B 1.6 Ìg/ml). In patients with a T tube drainage the peak biliary levels of ceftazidime were observed 180 min after the administration and an effective concentration remained for a relatively long time. However, Aoki et al. [63] reported that peak biliary concentration was inversely proportional to the creatinine clearance, ranging from less than 27 Ìg/ml in normal renal function to 133 Ìg/ml in creatinine clearance of 0 ml/min. Ceftriaxone Ceftriaxone is excreted primarily in the urine and bile. Significant amounts of ceftriaxone are eliminated via the bile and excreted unchanged. Forty-four percent of parenterally administered labeled ceftriaxone is recovered in the stool, collected during the 100 h following its injection, suggesting a significant biliary excretion [64]. Arvidsson et al. [65] found that 11–65% of a dose of ceftriaxone, administered by a constant infusion (0.5–1 mg/min) to 5 healthy volunteers, was recovered in the bile, and 56% of a dose of 14C-labelled ceftriaxone was eliminated unchanged in the feces. Data obtained from the manufacturers showed that in patients with T tube drainage, biliary levels ranged between 25.6 and 4,633 Ìg/ml after a 1gram intravenous administration of ceftriaxone. Hayton 288 Chemotherapy 2002;48:280–297 and Stoeckel [66] studied the biliary excretion in three groups of patients with biliary tract disease treated by cholecystectomy. Ceftriaxone was administered in different doses and different times in each group. The results of the study indicated that the usual adult dose of ceftriaxone of 1–2 g/day is sufficient for prophylaxis or treatment of biliary tract sepsis from susceptible organisms and that a 1-gram dose produced an average bile concentration of 250 Ìg/ml. The average fraction of a dose of ceftriaxone excreted in bile in this study is 15%. Cephalosporins of the 4th Generation Cefepime Cefepime is a new semisynthetic cephalosporin derivative with a broad antimicrobial spectrum with both a high stability and low affinity for ß-lactamase. Pharmacokinetics values for cefepime were determined in patients with acute cholecystitis who had undergone cholecystectomy. In one study Okamoto et al. [67] administered the cefepine to 15 patients with acute cholecystitis and found that cefepime concentration in bile ranged from 0.2 to 70 Ìg/ ml 8 h after administration of the dose. However, the volume of bile and the total amount of cefepime excreted in the bile in these patients are not known [68]. Cefpirome Cefpirome has to be used parenterally. It is eliminated via the kidneys. There are no data available on biliary excretion of cefpirome [69]. Less Commonly Used Cephalosporins Cefotetan Cefotetan is a parenteral cephamycin derivative and is therefore structurally related to cefoxitin and moxalactam. It is not significantly metabolized, being excreted predominantly in the urine. It is also excreted in the bile. Owen et al. [70] studied the cefotetan excretion in patients who had undergone biliary or pancreatic surgery. Cefotetan was detected in bile taken from the common bile duct within 15 min of a 1-gram intravenous bolus. Therapeutic plasma levels were found up to 10 h after the drug administration. A higher concentration of cefotetan was measured in the bile of patients with functioning gallbladder, despite the presence of gallstones. This concentration exceeds the in vitro minimum inhibitory concentration of the most common biliary tract pathogens. Cefotiam Cefotiam is a semisynthetic parenteral cephalosporin. Approximately 50% of the administered dose is excreted Karachalios/Charalabopoulos in the urine as an active unchanged drug [71]. Biliary excretion varies considerably among different species. In rats 32.9% of the administered dose was found in the bile sampled over the 24 h following injection; in rabbits only 1.52% and in dogs 2.95 +12.11% of the administered dose were found in the bile collected in the same manner [72]. Satake et al. [73] found that the concentration of cefotiam in gallbladder bile and in the wall of the gallbladder were 17.7 and 31.8 Ìg/ml, respectively, 30 min after an intravenous administration of 1 g of cefotiam in patients with cholelithiasis. In patients with obstructive jaundice who had T tube drainage, the mean concentration in hepatic bile 1 h after injection was 19.5 Ìg/ml; this concentration decreased to 5.9 Ìg/ml after 6 h. It should be noted that these patients had some kind of liver dysfunction [73]. Cefoperazone Cefoperazone is excreted primarily in bile. Cefoperazone has a unique biliary pharmacokinetic activity and is excreted in large part in the bile where it can achieve a concentration of more than 6,000 Ìg/ml [74]. In contrast to other cephalosporins which may reach maximum biliary concentrations of less than 364 Ìg/ml after a 1- or 2gram dose, cefoperazone may reach maximum biliary levels of more than 6,000 Ìg/ml in the common bile duct and 680 Ìg/ml in gallbladder bile after a 2-gram dose [74]. Aoki et al. [63] reported a mean peak bile concentration of 1,928 Ìg/ml after administration of 1 g of cefoperazone. Mean peak levels were 352.46 and 12 Ìg/ml, respectively, compared to a mean level of 3,642 Ìg/ml after intravenous administration of 2 g of cefoperazone in the study of Kemmerich et al. [74]. Thus in specimens sampled during surgery, 1 h after a 1-gram drip infusion of cefoperazone, Kazmierczak et al. [75] reported levels ranging from 700 to 1,300 Ìg/ml in common bile duct and from 14 to 190 Ìg/ml in gallbladder bile. Assaying bile collected by external biliary drainage dose, cefoperazone levels ranged between 300 and 550 Ìg/ml. After intravenous infusion of 2 g cefoperazone over 2 h, peak biliary values ranging from 1,000 to 2,000 Ìg/ml were observed [75, 76]. A therapeutic biliary concentration of cefoperazone was reported even in patients with cholestatic jaundice. Ceftizoxime Ceftizoxime is not metabolized and is excreted predominantly in urine (58–92%). Biliary excretion probably accounts for less than 1% of nonrenal excretion of the ceftizoxime. The extent of biliary ceftizoxime excretion varies among different species: 3.7% in rats, 0.59% in dogs and 0.11% in humans [77]. Tanimura et al. [61] observed Biliary Excretion of Antimicrobial Drugs a mean ceftizoxime concentration of 44.0 B 13.7 Ìg/ml in common bile duct, 71.3 B 22.5 Ìg/ml in functional gallbladder bile and 68.4 B 26.0 Ìg/ml in gallbladder walls, during surgery, 1–2 h after a 1-gram intravenous ceftizoxime dose. After administration of a similar dose, the mean concentrations in bile collected through a T tube in 5 patients were 39.0 B 22.4 Ìg/ml during the 2nd hour, 17.4 B 6.5 Ìg/ml during the 4th hour and 0.5 B 2.8 Ìg/ml during the 6th hour. Tanimura et al. prophylactically gave 1 g ceftizoxime as an intravenous bolus dose at the induction of anesthesia to 15 patients with cholelithiasis and reported that mean peak bile levels of 26 Ìg/ml were observed 35 min after injection. Mean peak gallbladder wall levels were of approximately 23 Ìg/ml 35 min after injection. However, despite the very limited biliary excretion, a drug concentration likely to be clinically effective against sensitive bacteria was obtained in bile and gallbladder tissue. Cefmetazole Cefmetazole, a semisynthetic derivative of cephamycin, is a parenteral cephalosporin which possesses a broad antimicrobial spectrum [78]. Cefmetazole is excreted via urine and bile with significant species differences in both excretion routes [79]. The biliary excretion of cefmetazole has been shown to be closely related to the bile/plasma ratio of bile acids and to depend on the amount of bile flow and liver function [80]. Biliary elimination of cefmetazole accounts for only 0.03–0.32% of the injected dose [81]. The mean biliary peak concentration of cefmetazole was 50 mg/ml after 3–4 h of intravenous administration of a 2-gram dose [81]. In patients with cholecystitis, the concentration of cefmetazole in bile was much higher [82]. Gonzalez et al. [83] found that greater amounts of cefmetazole were excreted in the bile as the dose increased, until a maximum was reached at a dose of 200 Ìmol/kg. Cefonicid Cefonicid is excreted almost exclusively in the urine, with 84–98% of an intravenous or intramuscular dose being recovered in the urine within 24 h [84]. Maki et al. [85] administered 1 g cefonicid intramuscularly or intravenously to 64 patients undergoing biliary tract operation and found that the mean concentration in the gallbladder wall was 30.5 Ìg/ml 2–3 h after administration. Cefazedone Cefazedone is a parenterally administered cephalosporin and is excreted mainly in the kidney [86]. Adam et al. Chemotherapy 2002;48:280–297 289 [86] studied the biliary excretion of cefazedone in 4 patients with a T tube drainage after intravenous administration of 0.5 g and found a biliary concentration of 71.4–2.10, 83.2 and 5.0–11.6 Ìg/ml at the 1st, 2nd and 5th hour, respectively. Cefpiramide Cefpiramide is a new semisynthetic cephalosporin which is structurally related to cefoperazone [87]. Cefpiramide is characterized by high biliary elimination. A high biliary concentration was reported by Nishida et al. [42] in choledochal bile 436–3,250 Ìg/ml and gallbladder 1,570–1,770 Ìg/ml after intravenous administration of 0.5 g of cefpiramide. Allan et al. [87] found that biliary excretion of cefpiramide, over a 24-hour period, was 60 and 19% in rats and rabbits, respectively. The mean biliary peak concentration of 1,161 B 39 Ìg/ml is reached during a 2-hour period and high concentrations are still observed 12 and 24 h (approximately 258 B 40 Ìg/ml) after intravenous administration of 1 g of cefpiramide to 10 cholecystectomized patients with T tube drainage [88]. These studies indicated that biliary elimination of cefpiramide is superior to that of all other ß-lactam antibiotics studied under similar clinical conditions. Cefsulodin Cefsulodin is a unique narrow-spectrum cephalosporin antibiotic particularly effective against most of the P. aeruginosa strains [89]. Cefsulodin elimination is mainly renal and not enough studies have been performed on bile excretion. Cefmenoxime Biliary excretion of cefmenoxime is only a minor route of excretion in comparison to the urinary excretion. Cefmenoxime concentration achieved in bile and gallbladder tissue was much higher in patients with cholelithiasis than in those undergoing cholecystectomy [90]. Smith et al. [31] studied concentrations of cefmenoxime in gallbladder bile and tissue in patients undergoing cholecystectomy. A 0.5-gram intravenous dose produced a mean concentration in bile of 54.1 Ìg/ml at 62.9 min and 56.3 mg/ ml at 194 min after the dose had been given. A 1-gram intravenous dose produced concentrations in bile of 117.9 mg/ml at 53 min and 169.7 Ìg/ml of 194 min after the dose had been given. In cholecystectomized patients the cefmenoxine concentration reported in gallbladder bile approximately 2 h following administration of a single 2-gram intravenous dose was lower than the concentration in bile duct (812 vs. 1,051 Ìg/ml). In conclusion, 290 Chemotherapy 2002;48:280–297 cefmenoxime produced both antibacterial activity and a very high concentration in both the gallbladder and bile duct. Moxalactam Moxalactam is excreted by the kidneys as an active unchanged drug. A large amount of moxalactam is excreted in the bile and produces levels which are as high as 7.0-fold that in serum. The mean biliary excretion of moxalactam after the administration of 1 g is 38.1–65.8 Ìg/ml. The same results were reported by many investigators. Monobactams Aztreonam Aztreonam is a parenterally administered synthetic antibiotic representing the first member of the monobactams [91]. It has been found to be highly effective against gram-negative bacteria that have been found to be the commonest infectious organisms in bile [91, 92]. Aztreonam is eliminated primarily in the urine in its unchanged form, although it is secreted into the bile, being metabolized to a minor extent. Thus, it is found unchanged in the feces [91, 92]. Martinez et al. [93] found that aztreonam undergoes biliary secretion and reached a peak concentration of 43 mg/ml at 2.4 h after administration of a 1-gram intravenous dose to patients who had undergone cholecystectomy with a T tube biliary drainage. In contrast, an average maximal biliary concentration of aztreonam reached only 14 mg/ml at 1 h after drug administration to patients with T tubes inserted for management of complete biliary obstruction. Only 0.2% of the 1-gram dose was recovered in the 12-hour quantitative bile collections from the latter patients. Mosley et al. [94] found that following intravenous injection of 2 g aztreonam preoperatively to 14 patients undergoing elective cholecystectomy the antibiotic drug reached bacteriocidal levels in the common bile duct within 30 min of injection and such levels were maintained in the gallbladder for at least 4 h after injection. Carbapenems Imipenem Imipenem is the first ß-lactam antibiotic in the group of carbapenems. It is excreted primarily in the urine. The bile imipenem/plasma imipenem ratio was less than 1 at all points measured. Graziani et al. [95] studied the biliary Karachalios/Charalabopoulos excretion of imipenem in patients undergoing cholecystectomy after intravenous administration of 0.5 g (12 patients) and 1.0 g (12 patients). Peak imipenem concentration in bile was 4.4 mg/ml after the 0.5-gram dose and 8.6 mg/ml after the 1-gram dose. These concentrations occurred within 2.5 h of administration and remained detectable for up to 6 h postinfusion. Mayer et al. [96] found that imipenem reached a mean peak concentration of 10.5 Ìg/ml in bile fluid 10 min after intravenous administration of 500 mg imipenem/cilastatin in 12 patients undergoing gallbladder surgery and T tube drainage; 60 min after the end of infusion the imipenem concentration was between 8 and 9 Ìg/ml. With a dose of 1,000 mg imipenem/cilastatin in the same group of patients (12 patients) the mean peak level in bile fluid was 17.5 Ìg/ml. The authors concluded that 4 h after the administration of either 1,000 or 500 Ìg imipenem serum and bile concentrations were markedly above the MIC values for pathogens found in infections of the biliary tract. Meropenem Studies have demonstrated that meropenem penetrates well into bile. For example, peak meropenem concentration of 14.58 Ìg/ml was obtained between 2.5 and 3.5 h after administration of a 1-gram dose [97]. Aminoglycosides Streptomycin It is excreted in the bile in small amounts, probably only 1% of the total dose in the unchanged form. A streptomycin concentration of 10–20 Ìg/ml in bile has been reported after the administration of the usual doses. Moreover, a significant concentration has been detected in bile 8 h or more after intramuscular injection of streptomycin. Kanamycin After intramuscular administration, only about 1% of the dose is excreted in the bile. The biliary concentration of kanamycin was 23 Ìg/ml 6 h or more after a single dose of 500 mg [101]. Gentamicin Gentamicin is excreted in small amounts in bile. The mean biliary concentration of gentamicin is usually only of the mean serum level. Riff and Jackson [102] observed a concentration of gentamicin in bile of 1–2 Ìg/ml in 3 patients. Smithivas et al. [103] reported gentamicin levels in bile of 0.2–2.2 Ìg/ml in 5 patients with significantly decreased hepatic function. Pitt et al. [104] reported mean gentamicin levels in bile of 2.0 Ìg/ml in 10 patients without obstruction of the cystic duct 2–3 h after injection of 1 mg/kg gentamicin. Six patients with cystic duct obstruction had no detectable gentamicin in gallbladder bile, despite the presence of gentamicin in the common bile duct in 3 of these patients [104]. Aminoglycosides are excreted primarily by the kidneys [98].The levels of aminoglycosides reported to occur in bile, whether with normal hepatic function or when there is obstruction to the flow of bile, are extremely variable and usually less than 1 Ìg/ml or less than 10% of the initially administered dose [99, 100]. Blockage of the cystic duct will prevent entry of the aminoglycosides into bile, just as is the case with the antibiotics of all other classes. Underlying disease can change this pattern. The inability to detect gentamicin and streptomycin in gallbladder bile has been noted in patients with cholecystitis due to cystic obstruction [100], despite the eventual presence of gentamicin in the common induct bile [100]. After having considered all aspects, and even though a therapeutic concentration can be obtained in some patients, the penetration of aminoglycoside antibiotics into the biliary tract remains somewhat uncertain, particularly in patients suffering from biliary lithiasis or from severe hepatic damage. Amikacin Amikacin is excreted entirely by glomerular filtration. However, it penetrated the biliary tract to a smaller extent: bile concentration averaged 5.5, 15 and 9% of the concomitant serum concentrations, respectively, 1–2, 2–3 and 3–4 h after a 500-mg intramuscular injection [105]. Simultaneously, the gallbladder wall concentration ranged from 10 to18% of the serum concentration [101]. Bernudez at al. [106] found that amikacin concentration in gallbladder wall ranges from 4.1 to 34 Ìg/ml after administration of 500 mg. All studies have shown that amikacin produces a concentration equal or greater than other aminoglycoside agents do. Biliary Excretion of Antimicrobial Drugs Chemotherapy 2002;48:280–297 Netilmicin It is excreted via the kidney. Small amounts of netilmicin are excreted into bile. Pollock et al. [107] studied the biliary excretion of netilmicin after administration of 2 mg/kg to 1 patient and found a mean concentration in the bile of 0.9 and 0.54 Ìg/ml at 0.5 and 1 h after injec- 291 tion, respectively. Martineto et al. [108] administered 2 mg/kg netilmicin to 14 patients and found a mean concentration in the gallbladder wall of 1.3 and 0.7 Ìg/ml at 1 and 4 h after injection, respectively. Spiramycin Spiramycin is excreted in the bile in a significant concentration and levels 15–40 times higher than the serum levels are obtained [116]. Nevertheless, high biliary levels of spiramycin (60 Ìg/ml) are rapidly achieved in humans after oral dosing at 500 mg t.i.d. Tetracyclines Tetracyclines are a group of antibiotics with a similar structure and virtually the same spectrum of antimicrobial activity. They are excreted in both bile and urine. Barza et al. [109] suggested that the excretion of tetracyclines into the bile is in direct proportion to their lipophilicity. In the absence of biliary obstruction, the concentration of tetracyclines in the bile may be 10–15 times that found in serum [110]. A large proportion of the tetracyclines excreted in bile is reabsorbed from the intestine. Of the older tetracyclines, chlorotetracycline is excreted in a significantly high concentration in bile. Among the various tetracyclines, two forms have a major role in medicine: doxycycline and minocycline. The levels of doxycycline in bile are 8–10 times those in the serum, but in the gallbladder wall they are 60% of the serum levels [109]. It was found that the biliary concentration is 8 times higher than liver concentration, but in hepatocellular insufficiency it may be quite low [111]. The gallbladder concentration reaches almost 75% of that in serum [112]. A high concentration of minocycline has been detected in bile (76 Ìg/ml) and the ratios for bile in liver and gallbladder are 38.12 and 6.5, respectively [112, 113]. Macrolides Macrolides are widely used antibiotics. It is a large family, with erythromycin being the most commonly used around the world. Erythromycin Erythromycin is concentrated by the liver and excreted into the bile in a high concentration in the absence of a biliary obstruction. It is excreted into bile, producing levels which range from 4 to 30 times the serum activity. The levels of erythromycin in the bile may exceed 250 Ìg/ml [114]. Josamycin Josamycin is metabolized in the liver and excreted in the bile in an inactive form [115]. 292 Chemotherapy 2002;48:280–297 Rosaramicin Rosaramicin is excreted primarily into the feces (87% of the dose). The extensive fecal excretion is not an indication of poor absorption but is probably due to extensive biliary excretion [117]. Roxithromycin There are no studies available on roxithromycin excretion into bile [118]. Azithromycin This drug represents a relatively new macrolide. No relevant data is available on biliary infection cases. Various Other Antibiotics Chloramphenicol and Thiamphenicol Chloramphenicol Chloramphenicol is excreted by the kidneys (90%). Small amounts of chloramphenicol, probably 2–3% of the administered dose, are excreted into bile, mostly in the inactive form. In one study, maximum biliary concentration occurred 3 h after administration and amounted to 50% of the peak level in serum [119]. The concentration of active chloramphenicol in bile is usually lower than in serum at the same time. Thiamphenicol The concentration of thiamphenicol in bile has been 2–3 times that in serum during most of the dosage intervals. The peak is observed 1–3 h after dosage [119]. Novobiocin Novobiocin is excreted primarily into the bile and reaches a high concentration [120]. However, novobiocin is not useful in the treatment of biliary tract infections. Lincozamides Lincomycin and Clindamycin Lincomycin and clindamycin are excreted in urine and bile. Both appear to be extensively eliminated by hepatic mechanisms [121]. The penetration of lincomycin in cho- Karachalios/Charalabopoulos ledochal bile, cholecystic bile, gallbladder tissue and liver tissue was found to be good. An intravenous dose of 1.5 g of lincomycin showed the following concentration: 34 Ìg/ ml in serum at 2 h, 215 Ìg/ml in choledochal bile at 3 h 15 min, 28 Ìg/ml in cholecystic bile at 3 h 36 min, 28 Ìg/ ml in gallbladder tissue at 2 h 55 min and 15.4 Ìg/ml in liver tissue at 4 h. Medina et al. [122] found mean bile levels of 42 mg/ml (6 times serum activity), 14 h after a single oral dose of 1 g of lincomycin. This concentration covered the MIC at which 90% of clinical anaerobic strains are inhibited. Clindamycin is partially metabolized in liver. However, the resultant biliary tract excretion product is more active than the parent compound [121]. After intravenous doses of 600 mg of clindamycin every 6 h in 2 patients, mean levels of 33.9 Ìg/ml in gallbladder bile and 41.1 Ìg/ml in common bile duct were found. Sales et al. [121] found a mean bile duct level of 26.2 and 41.3 Ìg/ml in gallbladder bile. Glycopeptide Antibiotics Glycopeptide antibiotics, including vancomycin and teicoplanin, are large, rigid molecules that inhibit a late stage in bacterial cell wall peptidoglycan synthesis. Vancomycin Vancomycin is usually administered intravenously and orally. It is not concentrated in the bile. Biliary levels are generally low and they are not reliably adequate to treat biliary tract infection. In one study, Geraci et al. [123] found small quantities of vancomycin in bile and feces after intravenous administration. The mean bile vancomycin concentration was 3.6 Ìg/ml and the bile/ serum ratio was 0.36. Teicoplanin Teicoplanin is distributed widely into body fluids and tissues. No data is available on its biliary excretion. Nitrofurantoin Nitrofurantoin is eliminated via the bile and studies in dogs showed a concentration in the bile 200 times that in the serum [124]. It was also found that nitrofurantoin increased the rate of the bile flow. Metronidazole was evaluated in jaundiced patients with external bile drainage and it was found that the biliary and serum concentrations were above the MIC for anaerobic organisms for 24 h after an intravenous infusion. Trimethoprim and Sulfamethoxazole In the biliary tree, the sulfamethoxazole concentration represents about 40% of plasma values [126]. A single oral dose of 800 mg of sulfamethoxazole and 160 mg of trimethoprim was administered to 10 adult female patients without biliary obstruction. The mean concentration of sulfamethoxazole and trimethoprim in bile 12 h later was 12 and 0.10 Ìg/ml, respectively, while 24 h later the concentration was 26.1 and 1.44 Ìg/ml, respectively [126]. Rifampicin Rifampicin is metabolized in the liver to a deacetylated derivative, which also possesses antibacterial activity. The drug and its deacetylated derivative are excreted mainly via bile. Rifampicin levels attained in bile are about 100 times higher than those in serum at the same time provided there is no biliary obstruction or impaired liver function [127]. Rifamide Rifamide, a synthetic derivative of rifamycin B, is excreted almost entirely in bile, and the serum concentration, even in patients with liver disease or obstructive jaundice, is too low to be of therapeutic value [127]. The concentration of rifamide required to inhibit 85% of biliary organisms was 30 mg/ml. In the nonobstructed biliary tract, the rifamide concentration ranged from 300 to 10,000 Ìg/ml. In jaundiced patients levels ranged from only 1.1 to 60 mg/ml and gallbladder bile concentrations in patients with cystic duct occlusion were even lower (1.4–4.5 Ìg/ml). Acocella et al. [128] found that in patients with external biliary drainage after cholecystectomy, 80% or more of an administered dose of rifamide is eliminated in the bile. Metronidazole High levels of metronitazole are excreted into bile. Nielsen and Justesen [125] found that the concentration of metronitazole in the hepatic bile duct was 25% higher than in serum. The concentration in gallbladder bile and common bile duct was 67 and 99% of that in serum. Newer Quinolones/Fluoroquinolones (2nd Generation Quinolones) Several compounds of newer quinolones have been released for general use in recent years. Norfloxacin, ciproflocacin, enoxacin, pefloxacin, ofloxacin and fleroxacin are some members of this category. The fluoroquinolones are excreted by renal, biliary or hepatic metabolic pathways. The biliary concentration of all fluoroquinolones is high: 2–10 times higher than the plasma concentration [129]. Biliary Excretion of Antimicrobial Drugs Chemotherapy 2002;48:280–297 293 Norfloxacin The biliary concentration of norfloxacin is higher than the concentration of the drug in serum, reaching 19.8 Ìg/ ml after a single dose of 800 mg [130]. Following a 200-mg oral dose, bile levels of norfloxacin are reported to be 5 Ìg/ml 2 h later (about 10 times those found in serum). The relative proportion of metabolites in bile is similar to that found in serum, with the exception of metabolite 2 (ethylenediamine) whose levels are disproportionately higher. Ciprofloxacin Biliary excretion of ciprofloxacin contributes less than 1% of the total clearance of the drug, although its concentration in bile was on average 10 times higher than the corresponding serum concentration [131]. Direct evidence of biliary excretion of ciprofloxacin has been obtained in patients with T tube drainage. A peak biliary concentration of 11 Ìg/ml was found 4 h after a single oral dose of 400 mg of ciprofloxacin. Strachan and Thoru [132] administered a single 400-mg oral dose of ciprofloxacin to 12 patients 1 h before surgery for cholecystectomy and found a mean concentration in the common bile duct and gallbladder bile of 7.55 and 47.9 Ìg/ml, respectively. In patients given the ciprofloxacin orally, the respective values, after a 500-mg single dose in 12 cholecystectomized patients, were 21.2 and 16.0 Ìg/ml peak bile concentration by microbiological and HPCC methods 4.1 h later, respectively. This suggests hepatic biotransformation of ciprofloxacin into microbiologically inactive metabolites. Also, the glycuronic acid conjugate of ciprofloxacin accounted for approximately 30% of the total ciprofloxacin excreted in bile. Saye et al. [133] administered a single dose of 300 mg ciprofloxacin to patients undergoing elective cholecystectomy. The gallbladders were removed 30, 60 or 120 min after the end of the infusion. The mean concentration of ciprofloxacin in the gallbladder wall was 6.23 B 1.1, 5.43 B 2.58 and 6.08 B 2.71 mg/kg tissue. In the gallbladder mucosa the concentration was 9.52 B 1.31, 14.8 B 4.51 and 10.21 B 4.08 mg/kg tissue at 30, 60 and 120 min, respectively. The mean concentration of ciprofloxacin in the gallbladder bile was 4.45 B 2.14 mg/l. The results of all these studies indicated a high concentration of ciprofloxacin in the gallbladder tissue. patients 4 h after the fifth 200-mg dose administered at 8-hour intervals. In patients with T tube biliary drainage, the ofloxacin concentration in T tube bile, 2 h after a single 200-mg dose, was 7.28 B 3.45 Ìg/ml. Duben et al. [135] reported an ofloxacin concentration of 3.31 B 2.05 Ìg/ml in serum, 11.85 B 4.75 Ìg/ml in gallbladder bile, 4.59 B 2.72 Ìg/ml in gallbladder wall and 4.59 B 3.46 Ìg/ml in liver during cholecystectomy scheduled 9– 10 h after a 400-mg single dose. Pefloxacin Biliary excretion of pefloxacin is an important way of elimination, since recoveries of 35 and 20% as free plus conjugated pefloxacin are achieved in rat and dog bile. Montay et al. [136] found that pefloxacin concentration in bile was 10–20 Ìg/ml at 2–12 h after the administration of 800 mg per os as a single dose. Wittke and Adam [137] reported pefloxacin concentrations in gallbladder tissue of 7.80 B 4.68 Ìg/ml and bile of 26.0 B 26.2 Ìg/ml in 12 patients undergoing biliary tract surgery 1–3 h after a single dose of 800 mg intravenously. Enoxacin The extent of biliary excretion of enoxacin is not clear. In a study by Flowerdew et al. [138] the biliary concentration of enoxacin was 7- to 10-fold higher than the serum concentration. After administration of a single dose of 600 Ìg to 12 patients the mean concentration in bile was 13–25 Ìg/ml and in serum it was 0.5–2.1 Ìg/ml 2–3.75 h after the administration. Grepafloxacin The penetration of bile and gallbladder tissues by grepafloxacin and the extent of its biliary excretion have been studied [139]. Three hundred milligrams of grepafloxacin was given to 6 patients undergoing cholecystectomy, with dosing starting 3 days before surgery. Grepafloxacin concentration in serum, gallbladder tissue and bile at 2–5 h was 1.8 mg/l (mean 0.9 mg/l), 9.6 mg/kg (mean 5.6 mg/kg) and 189 mg/l (mean 50.8 mg/l), respectively. The common bile duct concentration determined in these patients was 6.7 mg/l. The concentration in gallbladder tissue and bile was higher than that obtained in blood, and by far exceeded the MICs against common biliary pathogens. Ofloxacin Ofloxacin is excreted well into bile. Tanimura et al. 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