Carbenicillin and Ticarcillin

872

INFECTIONS AND ANTIBIOTICS

tration, by the steady state serum concentration to yield a realistic partition ratio. Also, one must be cautious about applying values derived from the normal tissues to the disease itself. There are 4 major categories for the study of the extravascular penetration: 1) extravascular fluid models, 2) tissue sampling in animal or man, 3) in vitro systems evaluating partitioning and 4) pharmacokinetic models that may or may not be based on actual tissue sampling. The authors recommend the evaluation of partitioning at steady state and the use of simultaneous peritoneal fluid measurements as a control for any interstitial fluid mode. There are some problems in the measurement of actual tissue concentration because of the obtained tissue or because tissue contains blood and interstitial fluid. In the in vitro systems techniques for the partition ratios, such as measuring uptake by erythrocytes, white blood cells or cultured fibroblasts, are useful. However, it may not reflect physiological equilibrium relationships. In the pharmacokinetic models the authors have been using standard 2 compartments, open pharmacokinetic models to assess tissue accumulation of aminoglycosides, and have found them to be useful in describing nephrotoxicity. The physiologic models are a relatively new method. These models incorporate the drug partition ratios and the blood flows for the drug at each tissue to be described. In conclusion, the best way to assist the tissue concentration appears to be to measure the antibiotic concentration at all sites, determine the in vitro characteristic of the organism and then find the correlations predictive of cure. 5 figures, 26 references

Mark T. Tsuang University of Cincinnati Cincinnati, Ohio

to be adjusted. Nafcillin produces lower serum levels after intramuscular injection than the other agents. Intravenous administration produces adequate blood levels 15 minutes after injection and minimal penicillin remains after 6 hours. Distribution. All of the agents are distributed widely in various body fluids. Levels ofnafcillin in cerebrospinal fluid are reported to be higher than those achieved with other antistaphylococcal penicillins. Untoward reactions. Untoward reactions are less common with this group of penicillins than with penicillin G. Allergic reactions are the most common adversary action, followed by gastrointestinal, hematologic and hepatic abnormalities. Nephrotoxicity is uncommon but is seen most frequently after the use of methicillin. Clinical use. All of these drugs are indicated only for proved or suspected staphylococcal infections caused by ,8-lactamaseproducing isolates. The antibiotics should be started in hospitalacquired staphylococcal infections, since 90 per cent of these infections are ,8-lactamase positive. Seventy per cent of community-acquired infections also are ,8-lactamase positive. Nafcillin and oxacillin are the preferred parenteral antistaphylococcal penicillins for use in the United States, and cloxacillin and dicloxacillin are the oral drugs of choice. Dosages. Methicillin, nafcillin and oxacillin are given in dosages of 100 to 300 mg./kg. daily intravenously. Intramuscular dosages and those of children are different. Cloxacillin and dicloxacillin are available as capsules and oral suspension. Dosages generally range from 25 to 100 mg./kg. daily in 4 doses. S.R.S. 3 tables, 56 references

Carbenicillin and Ticarcillin

Antistaphylococcal Penicillins

H. C. NEU, Columbia University College of Physicians and Surgeons, New York, New York

H. C. NEU, Columbia University College of Physicians and Surgeons, New York, New York

Med. Clin. N. Amer., 66: 61-77 (Jan.) 1982

Med. Clin. N. Amer., 66: 51-60 (Jan.) 1982 In 1950 the first antistaphylococcal semisynthetic penicillin (methicillin) was introduced. Subsequently, oxacillin, cloxacillin, dicloxacillin, flucloxacillin and nafcillin were introduced. Mechanism of action and resistance. Penicillins interfere with cell wall synthesis. Antistaphylococcal penicillins bind to transpeptidases, which cause failure to complete cell wall formation and result in total cell lysis owing to increased osmotic pressure within the cell. Antistaphylococcal penicillins resist hydrolysis by the exocellular ,8-lactamase that is produced by Staphylococcus aureus and Staphylococcus epidermidis. Approximately 10 per cent of Staphylococcus aureus organisms are resistant to methicillin, probably because of the failure to bind penicillin-binding proteins. Gram-negative species are resistant to antistaphylococcal penicillins owing to the failure of the agents to pass through the outer wall of these species. Synergy with other antimicrobial agents. The main synergistic effect that has been shown occurs with the aminoglycosides against Staphylococcus aureus. Pharmacology and absorption. Methicillin is not absorbed when taken orally. Percentages of oral absorption of the semisynthetic penicillins are oxacillin 30 per cent, cloxacillin 50 per cent, dicloxacillin 50 per cent, flucloxacillin 50 to 70 per cent and nafcillin 10 to 20 per cent. However, absorption of nafcillin is erratic and is not recommended for oral usage. Hemodialysis has no effect and dosages in renal failure generally do not need

In the late 1960s it became apparent that an anti-Pseudomonas antimicrobial was needed. This fact became apparent because of the lack of the polymyxin's clinical usefulness and the apparent toxicity of the aminoglycosides, and led to the introduction of carbenicillin, ticarcillin, azlocillin, mezlocillin and piperacillin. Each of these ,8-lactam drugs has a different mechanism of action for different organisms. Most of them effect a lysis or death without lysis, or cause round forms or long forms as a means of bacterial toxicity for gram-positive and Enterobacteriaceae organisms. They affect Pseudomonas aeruginosa by preferentially binding penicillin-binding protein involved in septum formation. Carbenicillin and ticarcillin are less active against most grampositive organisms than penicillin-G or ampicillin. Neisseria gonorrheae are relatively resistant to these agents. These agents inhibit Escherichia coli, Proteus mirabilis, some Enterobacter, Proteus vulgaris, Morganella, Proteus rettgeri, Proteus stuarti, Salmonella and some strains of Serratia. Klebsiellas generally are significantly resistant. Ticarcillin is in general more toxic to Pseudomonas aeruginosa than carbenicillin. Ticarcillin and carbenicillin are synergistic with gentamicin, tobramycin, sisomicin, netilmicin, amikacin and dibekacin. This synergistic action is effective even in neutropenic (compromised) patients. These 2 agents reach peak serum levels 30 to 60 minutes after a 1 gm. intramuscular injection and decrease to inactive levels by about 6 hours. The intravenous adminis-

tration of 2 gm. of these causes a reasonable serum level of the for 6 to 7 hotffs. High renal tissue levels of the develop and may be as high as 15 times the serum level. The presence of chronic renal disease (scarred kidney) may inhibit the rich levels of the drug in kidney parenchyma. Both drugs are excreted by the kidney and recoverable in the urine, making the drug effective in the treatment of renal, ureteral and bladder infections. Hypersensitivity reactions are not common. Rashes may occur but are seldom a problem. Occasional pseudomembranous colitis may occur because of Clostridium difficile. N eutropenic toxic reaction is rare and reversible, and eosinophilia has been reported, as has failure of normal platelet aggregation. Carbenicillin more frequently than ticarcillin may cause mild reversible hepatic toxicity. The primary use of ticarcillin and carbenicillin is for the treatment of Pseudomonas aeruginosa infections. However, the drugs have a place in the treatment of other gram-negative infections. The use of a combination of 1 of these drugs and an aminoglycoside to treat suspect gram-negative bacteremia of unknown organism origin has merit. Carbenicillin should be administered in doses of 24 to 40 gm. daily for adults and 400 to 600 mg./kg. daily in children weighing >60 pounds. Ticarcillin is administered in doses of 200 to 300 mg./kg. daily" However, the dosage should be adjusted to the severity of the infection, the susceptibility of the organism and the size of the patient. The drugs should be given in divided doses every 4 hours. A. T.E. 7 tables, 127 references

Chloramphenicol

J. G. BARTLETT, Infectious Disease Division, John Hopkins University School of Medicine, Baltimore, Maryland Med. Clin. N. Amer., 66: 91-102 (Jan.) 1982 Chloramphenicol is produced by an actinomycete, Streptomyces venezuelae, which was discovered initially in Venezuela in 1947. It was synthesized successfully in 1948 and marketed for general use in 1949. It is a derivative of dichloroacetic acid with a nitrobenzene moiety and a mohicular weight of 324 daltonso It is extremely stable to temperature and pH changes, and has a solubility of about 0.25 mg./ml. in water and 400 rrJ, in alcohol. The acts on the 50 S subunit of

viridans streptococci, enterococci, N eisseria gonorrhoeae, Hemophilus species, Bacillus, Listeria monocytogenes, Bartonella, Brucella, Pasteurella multocida, Corynebacterium diphtherias, Aeromonas hydrophila, treponemes and virtually all obligately anaerobic bacteria. Chloramphenicol generally is regarded as the standard antimicrobial for typhoid fever throughout most of the world and remains a dependable agent for salmonellosis in this country. It is commonly recommended for central nervous system infections because of the excellent penetration of the blood-brain barrier and an attractive agent for deep ocular infections because of good penetration into the vitreous body. Virtually, all anaerobic bacteria are susceptible to chloramphenicol. The drug is available for oral, intravenous and topical administration. The intramuscular route should not be used because of incomplete hydrolysis of succinate ester to active drug. The usual loading

dose is 20 to achieve a level of 10 to 20 No modification of dosage is necessary for with renal insufficiency or patients on but the half-life of the may be prolonged in patients with impaired hepatic function. Plasma levels >25 ,ug./mL have been considered potentially toxic to bone marrow. Levels of 40 to 200 µ,g./ml. have been observed with the gray syndrome in neonates or encephalitis in adults. Levels in the uninflamed prostatic gland are relatively low or nil. The most dreaded complication of chloramphenicol therapy is aplastic anemia that usually is irreversible. Other complications are gray syndrome, and gastrointestinal and neurologic disorders. Drug interactions include inhibition of bishydroxycoumarin, tolbutamide and diphenylhydantoin metabolisms that are thought to be caused by the inhibition of hepatic microsomal enzymes, while phenobarbital metabolism is accelerated owing to enzyme induction. F. T.A. 135 references

Clindamycin

J.

L. LEFROCK, A. MOLAVI AND R. A. PRINCE, Division of Infectious Diseases and Clinical Microbiology, Hahnemann Medical College and Hospital, Philadelphia, Pennsylvania, and University of Iowa College of Pharmacy, Iowa City, Iowa

Med. Chn. N. Amer., 66: 103-120 (Jan.) 1982 Clindamycin, 7(8)-chloro-7-deoxylincomycin, is the lincomycin nucleus with a 7(8)-chloro substitution of the 7(R)hydroxyl group. It was first approved by the Food and Drug Administration for oral use in 1970, and for intramuscular and intravenous administration in 1972. It is effective against grampositive aerobes and highly active against gram-positive and gram-negative anaerobic bacteria. It is extensively absorbed from the gastrointestinal tract and has low untoward effects. The minimal inhibitory concentration for susceptible organism generally is <1.6 mg./ml. Clindamycin inhibits bacterial protein synthesis but the exact mode of action is unknown. It is pribacteriostatic but it may be either bacteriostatic or bactericidal, depending upon the susceptibility of the organism and the concentration of the antibiotic. Clindamycin resembles erythromycin in its activity in vitro against Staphylococcus pneumoniae, pyogens and Staphylococcus viridans. Almost all strains are inhibited 0004 mg./ml. It is inactive against Neisseria rneningitidis but some strains of Neisseria nnrrtrnc,» are EssentiaJly all aerobic gram-negative bacilli are resistant. The interaction of clindawith gentamicin and amikacin Escherichia coli, Klebsiella pneum()nJ1ae and Pseudomonas 1s variable. Ciindamycin and metronidazole are against Bacillus fragilis. Because of an association of clindamycin pseudomernbranous colitis the absolute indications for treatment with clindamycin are few. The major indication for using clindamycin is the treatment of anaerobic infections, including actinomycosis. It is effective for the treatment of severe bacteroides infections and pulmonary, intra-abdominal and pelvic anaerobic infections. It also is effective for the treatment of septicemia associated with decubitus ulcers. The mean peak serum concentrations of clindamycin in adults l hour after a single oral dose of 150, 300 or 450 mg. were 1.9 to 2.7, 3.6 and 5.8 µg./ml., respectively. The half-life was 2 to 3.8 hours. The mean peak serum concentrations 2 to 4 hours after an intramuscular injection of 300, 450 and 600 mg. were 3.8 to 4.9, 5.3 and 6.2 to 6.3 µg./ml., respectively. The half-life was 4.5 to 5.3 ~,rAA~mM,,A