Aminoglycoside Antibiotics in Clinical Use

Aminoglycoside Antibiotics in Clinical Use

INFECTIONS AND ANTIBIOTICS Dosage and Safety of Long-Teirm Suppressive Acyclovir Therapy for Recurrent Genital Herpes A. MINDEL, 0. CARNEY, G. PATOU...

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Dosage and Safety of Long-Teirm Suppressive Acyclovir Therapy for Recurrent Genital Herpes A. MINDEL,

0. CARNEY, G. PATOU, Academic Department of Genitourinary Medicine, University College and Middlesex School of Medicine, London; Department of Virology, University College London, and Wellcome Research Laboratories, Beckenham, Kent, United Kingdom







Lancet, 1: 926-928 (Apr. 23) 1988 Short courses of suppressive doses of oral acyclovir have been extremely effective in reducing the frequency and severity of recurrences of genital herpes. However, several questions about this form of treatment remain, including how long the treatment should continue, whether the drug is safe, what is the ideal dose, who should be treated and whether acyclovir has any effect on the natural history of the illness. The authors determine the ideal dose of acyclovir required to control attacks in patients with frequently recurrent herpes, examine the longterm safety of the drug and determine whether treatment affected the natural history of infection. A total of 131 patients with frequently recurrent genital herpes was treated for 1 year with decreasing doses of oral acyclovir. The interval to first recurrence in patients who commenced therapy on 400 mg. twice a day was statistically significantly shorter than those on 200 mg. 4 times a day (p <0.02), and as the total daily dose and frequency of therapy were lowered so the interval to first recurrence was shortened. By the end of 60 days on 200 mg. once a day (the lowest daily dose) 56 per cent of the patients had recurrences. Patients showed a marked decrease in the frequency of recurrence during therapy (from a mean of 1.1 per 28 days before to 0.11 during treatment, p = 0.0001). After treatment was stopped the frequency of recurrences (0.7 per 28 days) was significantly less than in the pre-treatment period (p = 0.001). No important side effects were seen. It is concluded that long-term suppression with acyclovir is safe and effective for patients with recurrent genital herpes. 1 figure, 3 tables, 13 references Gerald P. Murphy, M.D. Atlanta, Georgia

Aminoglycoside Antibiotics in Clinical Use

S. J. PANCOAST, Department of Medicine, Temple University School of Medicine, Philadelphia, and Departments of Infectious Diseases and Hospital Epidemiology, Mercy and Moses Taylor Hospitals, Scranton, Pennsylvania Med. Clin. N. Amer., 72: 581-612 (May) 1988 The true beginning of effective therapy for gram-negative infections with aminoglycosides occurred with the introduction of kanamycin in 1957. Soon thereafter, newer agents in the aminoglycoside class were developed with activity against Pseudomonas aeruginosa and aminoglycosides became the standard gram-negative antibiotic agents. This period also was the beginning of the era of combination antibiotic therapy. Combinations of aminoglycosides and other agents provided powerful broad-spectrum tools for the control of infections in increasingly immunocompromised patients with complex infectious problems. Reliance on combination programs grew into the "groundwork for current antibiotic therapy practice.


Wide use of aminoglycosides brought out new problems of toxicity, bacterial resistance and superinfection, and stimulated intense interest in less toxic agents that could mimic the broad spectrum of aminoglycosides. Many new antibiotics resulted from these efforts and ironically they currently are direct competitors. Despite many concerns regarding safety, aminoglycoside antibiotics still are used widely, with about 3 million doses being given each year in the United States. This heavy use has continued despite growing competitive pressure from expanded spectrum /3-lactam antibiotics with established equal activities. It was realized long ago that with our present tools the aminoglycoside molecule could not be modified further to decrease toxicity without a major decrease in levels of antibacterial activity. Ironically, the recent explosion in therapeutic drug monitoring techniques began with the need to monitor drug levels of gentamicin because of toxicity potential. Readily available aminoglycoside drug level readings have made dosing a less formidable clinical task but the developments have come too late, because this class of agents has evolved as far as possible for the moment. New agents are not expected in this group, and research and development of aminoglycosides are at a standstill. In general, when resistant bacterial strains are seen gentamicin demonstrates a lesser degree of activity against resistant organisms than tobramycin or netilmicin. These last two in their turn exert less activity than amikacin. These differences are caused by a progressive decrease in susceptibility to bacterial inactivating enzymes, proceeding from gentamicin to tobramycin/netilmicin to amikacin. Because generalizations are dangerous the microbiology laboratory should frequently review its cumulative sensitivity profile for aminoglycosides and advise clinicians of any changing institutional trends so that empire aminoglycoside use can be adjusted accordingly. The main block to greater use of aminoglycosides has always been believed to be the toxicity problem. When there were no good alternatives the toxic risks inherent in the use of aminoglycosides were accepted more readily. Now, with proper aminoglycoside level monitoring and dosage adjustments, much of the toxicity associated with aminoglycoside use can be avoided. However, aminoglycoside toxicity monitoring procedures, while widely available to date, suffer from the disadvantage of being added costs in an era of heated cost-containment. The main toxic effects of aminoglycosides are renal failure and deafness but there are many other potential toxicities. No well designed complete report of the toxicities, incidences of toxicity or relative toxic potentials of all of the aminoglycosides has been published, although many studies have appeared comparing the toxic potential of 2 of the drugs. These studies are not adequate to define relative toxic potential for these drugs. Information on exact risks of aminoglycoside toxicity and on probably outcomes of toxicity is extremely difficult to obtain. Because of the ototoxic potential of aminoglycosides, serial audiometric testing has been recommended for patients on long-term therapy with these drugs. Despite its advisability, such testing requires a level of patient cooperation that almost never is present in patients ill enough to require aminoglycoside therapy. In practice, in fact, audiometric testing is not done because patients cannot cooperate and because audiometric capability (even for well patients) is not uniformly available. The aminoglycosides may differ in their ototoxic and vestibular toxic potential. Gentamicin is believed to be the most



toxic, followed by tobramycin and amikacin. Netilmicin perhaps is the least vestibular toxic and ototoxic. These relationships were developed based on animal experimental models and are confounded by the human condition. The problem of idiopathic rapid nephrotoxicity with aminoglycosides is even less well defined but it is well recognized. In a patient who receives an aminoglycoside for only a few doses increasing creatinine levels and renal failure develop explosively. This phenomenon also can occur in a patient who already is on the drug. The hallmark is an increase in creatinine from normal (or baseline) to renal failure levels in 1 to 2 days. Hypersensitivity or perhaps unrecognized major pre-existing disease may be a mechanism. Almost no proved explanation is available. In such circumstances aminoglycosides should be stopped. In some patients renal failure also has developed some time after cessation of drug therapy, perhaps related to residual levels of antibiotic in the renal cortex. Aminoglycosides used in combination with first generation cephalosporins appear to be more toxic than when used alone. The effect is less important with the higher generations of cephalosporins and it is not seen frequently when aminoglycosides are used with penicillins. An especially close watch should be kept on patients on high risk combinations, such as cephalothin or cefazolin and an aminoglycoside, especially when other toxicity risks are present. The aminoglycosides have an excellent record in the treatment of mixed infections of the abdomen and gynecological pelvis. They penetrate well into the peritoneum, whether inflamed or not. Sterilization of abscesses is difficult with these agents because of poor activity in the chemical presence of divalent cations and anaerobic conditions. The limited grampositive bacterial spectrum they possess and lack of activity against anaerobes mandate the addition of other drugs when aminoglycosides are used for severe abdominal infections. Because effective newer agents in the ~-lactam class combine the requisite gram-negative, gram-positive and anaerobic activities, these slowly are replacing the aminoglycosides for use in abdominal and pelvic infections. In cases of peritonitis after peritoneal dialysis, aminoglycosides have been used effectively as lavage agents. They are absorbed efficiently, so systemic levels must be followed closely. Aminoglycosides do not achieve useful levels in prostate tissue and they are not considered effective therapy for infections in that organ, although they may have to be used if highly resistant organisms are present. The fate of aminoglycoside antibiotics already in clinical use also is not settled. A considerable quantity of these drugs continues to be prescribed and at those centers in which bacterial resistance is a factor this use level probably will continue and perhaps increase. Elsewhere (when the bulk of antibiotics are prescribed), use probably will decrease slowly until we hit the peak of the ~-lactam antibiotic boom. The safest statement to be made currently seems to be that aminoglycosides always will be with us, although perhaps more as backup drugs in the future. We must be sure that we do not forget them or how to use them safely in the future. The renaissance of the aminoglycoside perhaps awaits a molecular miracle (decreased toxicity with increased spectrum of activity) or a bacterial revolt similar to the staphylococcal uprising that brought back vancomycin. 7 tables, 278 references Geral,d P. Murphy, M.D. Atlanta, Georgia

Aztreonam: The First Monobactam H. C. NEU, Division of Infectious Diseases, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York

Med. Clin. N. Amer., 72: 555-566 (May) 1988 Aztreonam is a synthetic monobactam antibiotic. It differs from currently available ~-lactams that contain a ring fused to the ~-lactam ring, such as cephalosporins and penicillins. Aztreonam inhibits murine synthesis of the bacterial cell wall. It binds preferentially to penicillin binding protein 3 of susceptible gram-negative bacteria. This causes the formation of elongated or filamentous forms in susceptible gram-negative bacteria, ultimately resulting in lysis and bacterial cell death. Aztreonam does not bind to the essential penicillin binding proteins of gram-positive bacteria and has poor affinity for the penicillin binding proteins of anaerobic bacteria, such as Clostridium and Bacteroides. Therefore, the drug is inactive against these organisms. In general, the minimal bactericidal concentration of aztreonam is equal to or only 2 to 4 times higher than the minimal inhibitory concentration for Enterobacteriaceae. For Pseudomonas aeruginosa the minimal bactericidal concentration of aztreonam may be higher than the minimal inhibitory concentration by 4 to 16-fold, as occurs with other ~-lactams. Aztreonam has a restricted spectrum of activity limited to gram-negative aerobic bacteria, including most Enterobacteriaceae and most P. aeruginosa. Aztreonam inhibits all Neisseria meningitidis and N. gonorrhoeae at 0.03 to 0.06 µg./ml. for N. meningitidis and 0.06 to 0.25 µg./ml. for penicillinase and nonpenicillinase-producing N. gonorrhoeae. ~-Lactamase and non~-lactamase-producing Hemophilus influenzae are inhibited by 0.06 to 0.25 µg./ml., and even strains of H. influenzae resistant to ampicillin, chloramphenicol and trimethoprimsulfamethoxazole are inhibited. Aztreonam is not hydrolyzed by most of the common plasmid-mediated and chromosomally mediated ~-lactamases. It is more stable than cefoperazone or the antipseudomonas penicillins, and it is not hydrolyzed by staphylococcal ~-lactamases or most ~-lactamases produced by Bacteroides. Therefore, it is not destroyed in abscesses caused by mixed bacteria. Aztreonam is hydrolyzed to a slight degree by a chromosomally mediated Richmond-Sykes type IV enzyme (K-1) produced by some strains of Klebsiella oxytoca. Strains of K. oxytoca that produce this enzyme, which are relatively uncommon, usually are resistant. Aztreonam does not induce ~-lactamase production in Pseudomonas, Citrobacter, Enterobacter and Serratia species. Aztreonam has been used to treat a variety of infections, such as urinary tract infections (including pyelonephritis and cystitis), lower respiratory tract infections (including pneumonia and bronchitis), septicemia, skin and skin structure infections (including those associated with postoperative wounds or ulcers and burns), intra-abdominal infections (including peritonitis) and gynecological infections (including endometritis and pelvic cellulitis caused by gram-negative aerobic bacteria). An anti-infective agent effective against the suspected organism(s) should be used as well. Aztreonam has been used safely and effectively in conjunction with clindamycin, erythromycin, metronidazole, penicillins and vancomycin. The adverse effects encountered with aztreonam are similar to those noted with other ~-lactam antibiotics. Over-all, adverse