ročník 11,2003 č.4
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Antibiotics: Spectrum of Effects and Pharmacokinetics in Treatment of Biliary Tract Infections

Nyč, O.

Institute of Clinical Microbiology at University Hospital Motol,
Prague

Although infection is not a prevalent cause of gall bladder and biliary tract inflammations, in more than half of the cases are these inflammatory disorders complicated by empyema or gangrene of the gall bladder, possibly also by emphysematous cholecystitis, abscess formation (hepatic, intraabdominal or intraperitoneal), bacteremia or by sepsis.
Antibiotics administration in cholecystitis and cholangiitis is a fundamental constituent of a complex therapeutic approach. Effectiveness of the therapy is based on both the antibacterial spectrum of specific preparation with respect to the most prevalent causative organisms for the given region and its pharmacokinetic profile, particularly the drug concentrations attainable in bile, gall bladder wall and billiary ducts. Bile concentration of a drug is significantly affected by an existing biliary obstruction and its degree. It is also important that the activity of amntimicrobial agent would not be attenuated by the bile itself, like in the case of tetracyclines.
The role of antibiotics in the treatment of uncomplicated cases of acute obstructive cholecystitis is not unambiguous and, according to several trials, their use does not lead to a significant decrease in the incidence of local complications, but only to a more rapid alleviation of general symptoms. The various degree of obstruction has been identified as a probable cause of decreased treatment effectiveness, because of its effect on the amount of antimicrobial agent that reaches the gallbladder.
Eradication of the infection depends among others on adequate concentration of active antimicrobial agent at the site of infection. Serum and tissue concentrations of the drug are a result of various parameters, such as absorption, elimination, plasma binding, metabolic inactivation, etc. Biliary excretion is one of the means of elimination of certain substances and metabolites. From this point of view, antibiotics capable of reaching high biliary concentrations represent a suitable alternative for the treatment of biliary infections and undoubtedly are very important for the effective eradication of susceptible microbial flora present in the biliary tract.
Generally speaking, the majority of antibiotics are characterized by inferior biliary excretion. Nevertheless, many antibiotics are excreted by active transport mechanisms favored by plasma/bile concentration gradient and some of the antibiotics are excreted entirely (or almost entirely) in the bile.
To ensure the fastest eradication of causative organisms possible, it is advisable to employ a bactericidal agent, especially in severe cases. This group comprises generally of ß-lactams, aminoglycosides, fluoroquinolones and glycopeptides.
Bacterial spectrum commonly isolated in connection with infections of the gall bladder and bile ducts comprises of enterobacteriaceae (E.coli, Klebsiella spp., Enterobacter species, Citrobacter freundii…), enterococci or possibly anaerobic bacteria. Gram-negative sepsis resulting from gastric infection and/or biliary tract infections leads to increased mortality of patients with cholecystitis and cholangiitis. Also anaerobic bacteria, namely Bacteroides spp. a Clostridium spp., are relatively common finding depending on the overall patient status and substantial comorbidities.
In the following summary we review some of the commonly used antibiotics with respect to their antimicrobial spectrum and pharmacokinetic properties.

1. ß-lactam antibiotics

1.1. Penicillins
Penicillins are still one of the most frequently used antibiotics for their several advantages. They are well tolerated, minimally toxic, and are characterized by intensive bactericidial effect. Their penetration is regulated mainly by passive diffusion, affected by the concentration gradient, lipid and water solubility, and plasma protein binding fraction. There are rather significant differences in tissue distribution between individual antibiotics in this group, but generally speaking, most of the penicillins are detectable in the gall bladder and bile ducts unless significant obstruction is present.
Penicilin G
From today's point of view penicillin G is a narrow spectrum agent outstandingly effective against ß-hemolytic streptococci and with a marginal activity against enterococci. From the group of anaerobes, Clostridium difficile is highly susceptible. Therefore penicillin proves to be insufficient for the initial monotherapy in majority of cases. Approximately 12% of the total dose is excreted unchanged in the bile and therefore it is realistic to reach therapeutically dependable concentrations necessary for inhibition of susceptible bacteria. We can benefit from the possibility to administer high doses of penicillin G, which guarantees high tissue concentrations.
Ampicilin, amoxicillin
Aminopenicillin derivatives with the spectrum extended to some of the gram-negative bacteria. They are excreted unchanged in the bile. In patients with normal function of biliary tract, their bile concentrations are 3 to 50 times higher that the serum concentrations. Obstruction, particularly of the cystic duct, leads to significant decrease in concentrations of both antibiotics in the bile.
Aminopenicillins combined with ß-lactamase inhibitors (clavulanic acid, sulbactam) are more resistant to hydrolysis by ß-lactamases produced by staphylococci and enterobacteriaceae spp.
Phenoxypenicillins
Their excretion in the bile is low and therapeutically insignificant.
Antistaphylococcal penicillins - Oxacillin, cloxacillin…
These substances bind readily to plasma proteins and their bile concentrations are 1 to 10 times higher than the concentrations in plasma. Their activity spectrum is confined to sensitive staphylococci or streptococci. Therefore they are not drugs of choice for the therapy of biliary infections.
Piperacillin, piperacillin/tazobactam
These drugs belong in the group of ureidopenicillins with broad spectrum of activity against gram-negative bacteria, including sensitive species of Pseudomonas aeruginosa. They are also significantly effective against anaerobic organisms and enterococci. Piperacillin is penicillin with high rate of bile excretion. Approximately 20% of total dose reaches bile unchanged and bile concentrations are up to 40 times higher than the concentrations in plasma. It is assumed that piperacillin is also excreted by active biliary secretion. The combination of pieracillin with ß-lactamase inhibitor tazobactam further extends its spectrum to include many species that are resistant by virtue of ß-lactamase production (Klebsiella spp, Proteus spp.,..). Tazobactam pharmacokinetics is not entirely identical with that of piperacillin and during a regular therapy regimen employing piperacillin/tazobactam combination, tazobactam reaches effective concentrations in the bile only during the first 3 hours following its administration. It is not completely understood how this can affect the overall efficiency of the therapy. Biliary obstruction greatly decreases concentrations of both drugs in the bile.

1.2 Cephalosporins
The majority of cephalosporins are eliminated through renal excretion, specifically by glomerular filtration; they are also excreted in the bile. Generally it is assumed that the concentrations attainable in the gallbladder are sufficient for the inhibition of sensitive microorganisms.
First-generation cephalosporins (cephalothin, cefazolin, cephalexin…)
Their spectrum includes gram-positive bacteria, staphylococci and streptococci, excluding enterococci. They are effective against some of the enterobacteriaceae, particularly E.coli, Klebsiella spp.. Activity against anaerobes is insufficient.
Second-generation cephalosporins
There is not any significant difference in pharmacokinetics compared to the first generation. Their spectrum of activity is extended to some other enterobacteriaceae. Cefoxitin, cephamycin antibiotic, occupies an exceptional position with respect to its activity against a variety of anaerobic species. According to several resources, it is also capable of infiltrating the gall bladder through its walls in patients with cystic duct obstruction. There are findings of its sufficient concentrations in the common bile duct in patients with obstructive icterus.
Third-generation cephalosporins
From the perspective of biliary tract infections, they are suitable for the treatment of gram-negative infections. Furthermore, ceftazidime falls in the group of antibiotics with high activity against Pseudomonas aeruginosa. Ceftriaxone is noted for its high portion of unchanged active substance excreted in the bile which can subsequently be detected in the stools in high concentrations reaching 56% of the total dose. Ceftriaxone is one of the antibiotics suitable for the treatment and prophylaxis of biliary sepsis caused by sensitive bacteria.
Cephoperazone is another representative of the broad spectrum cephalosporins. This drug is exceptional, for its absolute majority is excreted primarily in the bile where, depending on the dose, it can reach concentrations of over 6000 mg/ml, which is a significant difference from other cephalosporins that can, following the administration of 1 - 2 g of active substance, reach the concentrations of only 300 - 400 mg/l. Therapeutically reliable concentrations of cephoperazone have been detected even in patients with cholestatic icterus.
The combination of cephoperazone and sulbactam further extends the antimicrobial spectrum to include many species that are resistant by virtue of ß-lactamase production. In addition, sulbactam acts as an antibiotic effective in the treatment of certain acinetobacter and anaerobic infections. Cephoperazone and cephoperazone/sulbactam are the drugs of choice in the treatment of biliary infections thanks to their activity spectrum and unique pharmacokinetics.
Fourth-generation cephalosporins
This group does not defy the pharmacokinetic characteristics of the first three generations. Its activity spectrum combines the advantages of the first and second generation (high activity against gram-positive bacteria and with limitations also against gram-negative bacteria) with the high activity against the majority of enterobacteriaceae and pseudomonas spp.

1.3 Carbapenems
Iimipenem/cilastin and meropenem reach therapeutic concentrations, effectively inhibiting a broad spectrum of aerobic and anaerobic microbial agents. They are held in reserve as therapy for severe polymicrobial and complicated infectious diseases. Their availability is greatly reduced in patients with biliary obstruction.

2. Aminoglycosides

Gentamicin, netilmicin, tobramycin, amikacin and other preparations are highly active against gram-negative bacteria including pseudomonas and acinetobacter spp. Their activity against gram-positive bacteria is not reliable, especially with respect to streptococci and enterococci. They have no activity against anaerobic bacteria. Their transport into the biliary tract is not standard and is reduced in biliary tract lithiasis and liver failure. Based on these facts, aminoglycosides are not advisable for the monotherapy of biliary infections. Anyway they can be administered, for example in combination with ß-lactam antibiotics, in the treatment of biliary sepsis to increase the antimicrobial spectrum and to take the advantage of their synergic modes of action.

3. Tetracyclines

Tetracyclines are bacteriostatic antibiotics with relatively broad spectrum of activity and good availability in the bladder wall and bile. Their suitability for the treatment of biliary infections is not clear-cut because their activity can possibly diminish in the presence of bile.

4. Macrolides

Bacteriostatic antibiotics with no activity against enterobacteriaceae, which renders them unsuitable for the use as drugs of choice.

5. Fluoroquinolones

Chemotherapeutical agents with excellent bioavailability, eliminated by renal, hepatal and biliary excretion. Their biliary concentrations are generally 2 to 10 times higher then the concentrations in the plasma. Ciprofloxacin has been proven to reach high biliary concentrations in patients with obstruction due to the anticipated secretion of quinolone by biliary epithelium. Commonly used fluoroquinolones (ofloxacin, ciprofloxacin, pefloxacin, levofloxacin…) are active against gram-negative bacteria, variably active against gram-positive bacteria and against anaerobes.

6. Glycopeptides

Vancomycin and teicoplanin do not reach therapeutically effective concentrations in respective tissues and fluids and their use in the treatment of biliary infections is marginal.

7. Imidazoles

Metronidazole and ornidazole are chemotherapeutic agents with excellent activity against anaerobic organisms and due to their superior distribution in the tissues and bile (even in patients with existing obstruction) are considered the drug of choice for the treatment of anaerobic and mixed bacterial infections (in combination with other antibiotics).

8.Lincosamides

Antibiotics active predominantly against gram-positive microflora and anaerobes. They are largely metabolized in the liver and their concentrations in the biliary tract reach therapeutic concentrations, effectively inhibiting sensitive bacterial species. Their activity against enterobacteriaceae is limited and their combination with other antibiotics (aminoglycosides, fluoroquinolones) is essential during the course of empirical therapy.

Conclusion:

Empirical choice of appropriate agents and their combination in the treatment of biliary infections should be based on an array of informations, including data on activity spectrum, pharmacokinetic and pharmacodynamic characteristics, drug tolerance, toxicity and regional resistance profile of the most common causative agents responsible for the infectious complications in gall bladder and biliary tract. The choice of particular antimicrobial agent is comparatively easier after the pathogens have been identified in cultures and their resistance profile determined in antibiogram. However, it is still necessary to assess local availability in bile and respective tissues. Ignorance of pharmacokinetic properties of certain antibiotic increases the chances that therapeutical regimen will fail and escalates the risks for further infectious complications, including biliary sepsis.

Address for correspondence:

MUDr. O. Nyč
Institute of Clinical Microbiology
University Hospital Motol
Prague