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Cycloserine
Adjoint Professor Schools of Pharmacy and Medicine University of Colorado Denver CO
Address: National Jewish Medical and Research Center 1400 Jackson St. Denver, CO 80206 tel: (303) 398-1427 fax: (303) 398-2229 Email: peloquinc@njc.org
CLASS Chemical Structure Cycloserine was isolated both from Streptomyces orchidaceus by Harned and Kropp and from Streptomyces garyphalus by Harris and colleagues in 1955 (12, 22, 29, 40). It is a white crystalline powder with a chemical structure of D-4-amino-s-isoxazolidone, or D-4-aminoisoxalidine-3-one. It is soluble in water and has a low molecular weight of 102.09. These properties allow cycloserine to diffuse readily into body tissues (12, 40). Cycloserine is unstable in an acid or neutral environment, but stable in an alkaline environment. Terizidone, an agent not available in the United States, is formed by reaction of two cycloserine molecules with terephthalaldehyde (29). Terizidone is similar to cycloserine in antibacterial activity and toxicity profile. Structure-Activity Relationships Cycloserine is a structural analog of D-alanine. Many analogues have been synthesized, but these were either inactive or less active than cycloserine (43, 44).
ANTIMICROBIAL ACTIVITY Spectrum Cycloserine's greatest in vitro activity is against M. tuberculosis, with MIC's of 6.2 to 25 mcg/ml in liquid media and Lowenstein-Jensen medium. Cycloserine also is active against other species of mycobacteria such as M. kansasii, M. intracellulare and M. avium, with thirty-one percent of M. avium strains being susceptible to cycloserine to 30 mcg/ml by proportion method in 7H11 agar plates (18, 22). Cycloserine possesses marginal activity against other organisms such as Staphylococcus aureus and some gram-negative bacilli, such as Escherichia coli. Although the MIC of cycloserine to E. coli is often greater than 50 mcg/ml, concentrations exceeding this value are achieved in the urine with standard doses. Thus, it has been used effectively in the treatment of urinary tract infections (22, 40). Proteus, Pseudomonas and Klebsiella species are more resistant to cycloserine. Pharmacodynamic Effects Bactericidal Effects: Cycloserine is generally bacteriostatic (41). Bactericidal activity is possible only with concentrations 50-1000 times the minimal inhibitory concentrations (MIC). Because the chemical structure of cycloserine is similar to that of D-alanine, the presence of D-alanine in the culture medium will interfere with cycloserine's antimicrobial activity, sometimes causing intensified growth (18, 41, 43, 44). Heating or autoclaving the test media often releases D-alanine, exacerbating the problem. This has made the evaluation of cycloserine's bactericidal activity technically difficult in liquid media, and contributed to disparities in MIC's determined with different media. Cycloserine's activity in vitro is optimal in neutral to slightly acidic pH (6.4-7.0) (41). Vitamin B6 complexes with cycloserine, and this can negate in vitro activity. Similar effects can be seen with various elements, including Cu, Zn, Co, Fe, as well as citrate, phosphate, and oxalate (41). Thus, in vitro testing requires careful control of the media. Cycloserine appears to act slowly, with effects becoming evident over 96 hours. Post Antibiotic Effects: Pulse exposures of cycloserine for 24 hours at 100 mcg/ml produced a 1 day delay in regrowth of mycobacteria. Because the pharmacokinetics of the drug do not allow maximum concentrations of cycloserine to be maintained for this time period, this effect can not be thought of as a post-antibiotic effect (18). Effects of Subinhibitory Concentrations: No specific activity has been attributed to subinhibitory concentrations of cycloserine. In vitro, subinhibitory concentrations may enhance the ability to isolate resistant subpopulations (41). It is not known if subinhibitory concentrations of cycloserine contribute to multidrug therapy in vivo. Effects on Host Immunity: Cycloserine does not have known direct effects on host immunity. Pharmacodynamic Correlates with Outcome: In vitro, sustained concentrations above the MIC appear to be required, as activity is not evident for several days (41). Increasing the concentration within the achievable clinical range (20-35 mcg/ml) does not produce bactericidal activity in vitro. In animals, the pharmacokinetics of cycloserine is considerably altered, with much shorter half-lives, resulting in poor activity in most models (41). In man, ~7 mg/Kg/day is generally recognized as the minimum dose. Cycloserine disrupts D-alanine incorporation into peptidoglycan during bacterial cell wall synthesis. Thus, it is natural to compare cycloserine to the ß-lactams (41, 43, 44, 46). If the drugs act in an analogous fashion, time above MIC would be the most important parameter. This is consistent with cycloserine's reduced activity in animals that rapidly clear the drug, and consistent with the extended time required to demonstrate in vitro activity. Fortunately, cycloserine has a long serum half-live in humans, making it relatively easy to achieve extended Time>MIC values.
MECHANISMS OF ACTION Cycloserine, a structural analog of D-alanine, inhibits bacterial cell wall synthesis by acting as a competitive antagonist of the enzymes that link D-alanine molecules into peptidoglycan in the bacterial cell wall (22, 41, 43, 44, 46). Specifically, cycloserine inhibits D-alanine racemase and, less potently, D-alanine:D-alanine ligase (14). Cycloserine produces a loss of acid-fastness in mycobacteria (46). The unique susceptibility of mycobacteria to cycloserine may reflect either a special transport mechanism that allows cytoplasmic accumulation of cycloserine (43, 44). Alternatively, mycobacteria may have relatively low D-alanine content in the cytoplasm, making the threshold for inhibition lower.
MECHANISMS OF RESISTANCE Organisms Commonly Resistant Typically, cycloserine is used only against Mycobacteria, as superior agents exist for Gram negative urinary tract infections. Therefore, resistance among bacteria is rarely assessed. Cycloserine-resistant isolates of M. tuberculosis remain uncommon, largely due to limited use of cycloserine. Among the other mycobacteria, M. africanum may be naturally resistant. Cross-resistance with the other antimycobacterial drugs has not been demonstrated (22, 40). The incidence of primary resistance to cycloserine versus M. tuberculosis in the US from 1975-1982 was less than 1% (22). Mechanisms of Resistance As with other antimycobacterial agents, resistance in previously susceptible organisms may develop rapidly both in vivo and in vitro when cycloserine is used as a single agent in the treatment of tuberculosis (41, 46). This appears to be due to naturally occurring resistant mutants present in a population of mycobacteria. Under the selective pressure of a single drug, all organisms are eliminated except the resistant subpopulation, which continues to multiply, eventually becoming the dominant population. The precise defect that allows for the survival of the mutants apparently has not been described. Resistance to cycloserine in some bacteria may be due to reduced uptake of the drug into the cell, much like tetracyclines (22). More recently, a test system using M. smegmatis showed that one mechanism of resistance to cycloserine involves the over-expression of D-alanine racemase (7). Other researchers have shown that a mutant of M. smegmatis shows resistance to both cycloserine and vancomycin (37). Methods to Overcome and Prevent Resistance Acquired resistance to cycloserine may be prevented by using it in combination with at least one or two other antimycobacterial drugs (22, 33). Higher doses of cycloserine as monotherapy are not tolerated and do not prevent the emergence of resistance. In vitro, subinhibitory concentrations enhance the selection of resistant organisms (41). It is not known if this also occurs in vivo, although the possibility exists. Therefore, it appears desirable to achieve serum concentrations above the MIC of the isolate.
PHARMACOKINETICS Review Article: Nuermberger E, Grossett J. Pharmacokinetic and Pharmacodynamic Issues in the Treatment of Mycobacterial Infections. 2004. Absorption The pharmacokinetics of cycloserine were studied extensively when it was first developed for clinical use, as well as more recently (3, 9, 15, 21, 23, 26, 27, 28, 31, 45, 48, 49, 50). Cycloserine is rapidly absorbed from the gastrointestinal tract, appearing in the blood as early as 30 minutes after 250-500 mg doses (9, 15, 26, 27, 31, 49, 50). The time to maximum concentration ranges from 0.50 to 3.0 hours postdose following 250-500 mg doses, and especially within 1.0 to 2.0 hours post dose. Two subjects who received both oral and intramuscular doses showed almost identical urinary excretion of cycloserine, consistent with nearly complete absorption from the gastrointestinal tract (9). However, according to Iwainsky, oral administration produces lower serum concentrations than parenteral administration (20). The parenteral route used and the percentage difference between the routes of administration was not stated. Plasma concentrations achieved after a 250 mg dose ranged from 4-8 mcg/ml following a single dose, increasing to 15 mcg/ml with chronic daily administration (27, 50). Concentrations following a 500 mg dose were higher, with concentrations of 6-14 mcg/ml following a single dose, and up to 28 mcg/ml with chronic daily administration. This is consistent with our experience at National Jewish, where we often see increases in serum concentrations over the first 2 weeks of therapy with no change in daily dose. Simulations performed on data obtained following single oral doses predict 22% accumulation of cycloserine over 3 days with daily dosing (49). Sixty-six percent accumulation was predicted with twice-daily dosing (49). In separate studies, concentrations following higher doses of 750-1000 mg demonstrate concentrations only slightly higher (14-17 mcg/ml), although these differences may, in part, be attributed to different study conditions (45, 50). The potential for saturable absorption or nonlinear elimination of cycloserine has not been adequately studied. Food taken with cycloserine reduces and delays the drug's absorption, so cycloserine is best given on an empty stomach (20, 49). Distribution The combination of cycloserine's water solubility and its low molecular weight allow it to diffuse readily into many body compartments and tissues (9, 26, 31). In healthy volunteers, the calculated volume of distribution was 0.47 L/Kg (47). In addition, cycloserine appears to have very low protein binding (20). Cycloserine concentrations near that of plasma concentrations can be found in ascitic fluid, pleural fluid and human breast milk (9, 26, 31). Cerebrospinal fluid concentrations 54-79% of plasma cycloserine concentrations have been reported. Measurable cycloserine concentrations, some greater than plasma concentrations, have been found in sputum, lung tissue and lymph nodes (27). No significant amounts of cycloserine have been found in the feces, while urine cycloserine concentrations greatly exceed those of the serum (31, 45). Cycloserine concentrations as high as 52-1138 mcg/ml have been found in the urine (26, 27, 45). Metabolism and Excretion Cycloserine has been reported to be eliminated primarily by urinary excretion (31). Cycloserine can be found in the urine as soon as 2 hours after a 250 mg dose. Earlier reports showed 47-80% percent of the total amount of cycloserine eliminated occurs within 24 hours following standard doses (9, 20). The percent of cycloserine excreted varies greatly among individuals (15, 31, 50). In a recent healthy volunteer study, 24 hour urine collections produced 26-29% urinary recovery of cycloserine following single oral doses of 500 mg (49). In general, elderly patients, or those with diminished renal function, have slower excretion rates. At 30 hours following a 500 mg dose, a group of young patients (mean age 29 years) showed 49.1% of the dose being excreted, while the elderly patients (mean age 67 years) only showed 28.9% of the dose being excreted (50). This was attributed to differences in renal and hepatic function and perhaps also absorption. As expected with such variations in urinary excretion, the serum half-life of cycloserine also varies greatly. The reported serum half-life ranges from 8-25 hours following standard doses (9, 50). In healthy volunteers, the median half-life was 8.7 hours (49). While there appears to be great variation in the urinary excretion among individuals, there is not as much variation across the standard doses (250-750 mg) of cycloserine (45, 50). Probenecid reportedly does not alter cycloserine's renal elimination, suggesting that tubular secretion is not an important excretory route (20).
DOSAGE REGIMENS Normal The usual dose of cycloserine ranges from 250-750 mg per day, typically divided every 12 hours. Occasionally, doses as high as 1000 mg per day are necessary to achieve adequate serum concentrations. However, due to the risk of CNS toxicity, dose increases to this range should be undertaken only with the guidance of serum concentrations. Doses of 250 mg produce concentrations of 8-20 mcg/ml (31). Higher doses generally produce proportionally higher concentrations, although some reports show that concentrations following doses greater than 500 mg do not produce proportionally higher doses (31, 50). As noted above, some studies have shown that cycloserine accumulates over the first three days of therapy with no change in dose (9). Our experience at National Jewish has shown that cycloserine concentrations may increase over the first 1-2 weeks of therapy with no change in dose or renal function. Given that cycloserine is typically dosed at intervals approximating its half-life, accumulation over the first 5-7 doses would be expected. Pediatric doses of 10-20 mg/kg/day (maximum 1000 mg) in 2 equally divided doses have been employed. Serum concentrations should be monitored, as experience in this population is limited. Renal Failure Cycloserine dosages need to be adjusted in renal impairment (22, 25, 31). Depending upon the degree of impairment, usual doses given once daily or every other day should initially be employed (23, 31). Cycloserine serum concentrations should be checked after 1-2 weeks of treatment to evaluate the patient's clearance of the drug; dosages can then be individually adjusted (31, 33). Patients on hemodialysis should receive the drug less frequently (usually 3 times per week, after hemodialysis sessions), and their serum concentrations should be monitored closely (23). In a study of volunteer dialysis patients, over half of a 500 mg oral dose of cycloserine was removed by hemodialysis, so doses should be given after the procedure (23). Because the CNS toxicity of cycloserine appears to be closely related to serum concentrations of the drug, the use of cycloserine in renal impairment should be avoided if alternative agents exist (22, 25). Hepatic Failure Unless ascites exists, dosage adjust in hepatic failure is usually unnecessary. However, these patients may have various physiological derangements, so therapeutic drug monitoring is advisable. Obesity, Ascites, and Edema Because cycloserine is relatively hydrophilic, it will distribute into ascites and edema (9, 26, 27). Given these larger volumes of distribution, larger doses may be necessary; dosages should be adjusted according to serum concentrations. No dosage adjustment is necessary in obesity; however, serum concentrations of cycloserine should be monitored to assure that adequate concentrations are being achieved. Pregnancy Although no prospective studies exist regarding the use of cycloserine in pregnant women, it has been used safely (17, 22, 25, 31, 42). As with most drugs, cycloserine should be avoided during the first trimester if possible. Studies in rats have revealed no teratogenicity at dosages up to 100 mg/kg/day. It should be used with caution in nursing mothers due to the risk of adverse effects to the infant.
ADVERSE EFFECTS The primary adverse effect of cycloserine is central nervous system toxicity. As mentioned previously, the chemical structure and properties of cycloserine allow it to easily cross the blood-brain barrier (9, 26, 27). In addition, cycloserine inhibits the enzyme glutamic-decarboxylase, which is necessary to form gamma-amino-butyric acid (GABA) (6, 10). The resulting reduced production of GABA is thought to contribute to cycloserine's neurotoxicity, as it is the regulator of neural activity. The neurotoxicity of cycloserine may be exhibited in many ways, including hyper-excitability, dizziness, lethargy, depression including suicidal tendencies, anxiety, confusion, memory loss and rarely, either focal and grand mal seizures (1, 4, 6, 16, 19, 22, 24, 30, 39). There are conflicting reports whether these changes are associated with electroencephalograph (EEG) changes (6, 16, 19, 30). It should be noted that neither the author nor his colleagues have witnessed such seizures, despite considerable use of the drug. Although these effects are usually associated with elevated serum cycloserine concentrations (>35 mcg/ml) and larger doses (750-1500 mg per day), some CNS disturbances are often seen at "normal' concentrations (1, 4, 24, 30, 36). In our experience, patients may complain of difficulty concentrating even though their serum concentrations are normal. There is a single case report of Stevens-Johnson syndrome in an AIDS patient (2).
MONITORING REQUIREMENTS Therapeutic Drug Monitoring Therapeutic drug monitoring of cycloserine is our standard of practice at National Jewish for a number of reasons (31, 33, 34, 35). The patients requiring cycloserine in their regimens are generally harboring very resistant organisms, therefore making adequate serum concentrations of the utmost importance. Also, because cycloserine is associated with concentration-related toxicities and its clearance affected by changing renal function, therapeutic drug monitoring is necessary to assure safe use of the medication. We measure 2 and 10 hour postdose cycloserine concentrations on our patients weekly, until stable serum concentrations in the normal range are obtained. Thereafter, patients are monitored periodically, particularly if the experience a change in renal function. The two-hour concentration provides us with the maximum concentration, while the ten-hour concentration yields information on the clearance of the drug (33). When indicated, more frequent time-points are obtained. Also, if a patient is exhibiting signs of CNS toxicity, we will often determine serum concentrations at that time to determine if the CNS symptoms are indeed related to excessive cycloserine concentrations (33). Clinicians interested in obtaining serum concentrations can find additional information at www.njc.org/idpl.html.
DRUG INTERACTIONS The fluoroquinolones are now being used for the treatment of multi-drug resistant tuberculosis. This has lead to a recent report of increased neurological symptoms seen when ofloxacin and cycloserine were given together (47). We suspect that this occurred with one of our patients. However, a retrospective review of our experience did not reveal either a significant increase in CNS effects nor an apparent pharmacokinetic interaction between cycloserine and ofloxacin (5, 32). Clearly, prospective studies are needed. It is thought that the co-administration of pyridoxine (vitamin B-6) at doses of 50-60 mg per day may prevent some of the CNS effects of CS, and there is no clear evidence that this antagonizes cycloserine's action in vivo (6, 19, 39). Other rare side effects reported include GI disturbances rash, drug fever and cardiac arrhythmias (16, 19, 22, 25).
CLINICAL INDICATIONS Cycloserine's primary clinical application is in the treatment of Mycobacterium tuberculosis. Because cycloserine is bacteriostatic and is associated with toxicities at achievable serum concentrations, it is usually reserved as a second-line agent (8, 11, 18, 22, 38, 40). Although it was initially used with isoniazid alone to treat some refractory tuberculosis cases it is now being used in combination with 2 or more other second-line antituberculosis agents, such as PAS, ethionamide and ofloxacin, for the treatment of multi-drug resistant tuberculosis (1, 8, 11, 13, 36). Cycloserine is used occasionally in the treatment of Mycobacterium avium-intracellulare infections (18, 22). Historically, cycloserine was used to treat urinary tract infections caused by Gram-negative bacteria, but superior agents are now available. Because cycloserine has direct effects upon the CNS, it is being studied either as a probe or potential therapeutic agent for several non-infectious disease indications, including seizure disorders, Alzheimer's disease and other memory disorders, and the effects of ethanol on the CNS.
Acknowledgment The author thanks Shaun E. Berning, Pharm.D., who wrote a significant portion of this chapter for the first edition of this text, and Kayte Fulton for editing the text.
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