11 Miscellaneous Antibiotics

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From: Infectious Disease: Drug Interactions in Infectious Diseases, Second Edition Edited by: S. C. Piscitelli and K. A. Rodvold © Humana Press Inc., Totowa, NJ

11

Miscellaneous Antibiotics

Gregory M. Susla

INTRODUCTION

This chapter discusses the interactions of antibiotics that may be the only available agents from a class of antibiotics that is used clinically today. Chloramphenicol and tetra- cycline are older agents that are less frequently prescribed; so many clinicians may not be familiar with their interactions with other medications. Many of the interacting agents also are less frequently prescribed, such as first-generation oral hypoglycemic agents.

Because many of the interactions in this chapter are based on single case reports, it is difficult to determine the mechanism of the interaction and if a true interaction exists.

The existence of some interactions may be questioned because of other potential causes that may have been present when the interaction was discovered.

The interactions described in this chapter are summarized in Table 1.

CHLORAMPHENICOL

Chloramphenicol is a broad-spectrum antibiotic that has been shown to interact with a number of medications, including analgesics-antipyretics, other antibiotics, oral hypo- glycemic agents, anticoagulants, and anticonvulsants. Most of these interactions are limited to case reports with small numbers of patients. The mechanism of the interac- tion for several of the interactions is unknown or is limited to speculation.

Acetaminophen

Chloramphenicol has been reported to increase, decrease, and have no effect on the

half-life of acetaminophen. Spika and colleagues evaluated the effect of multiple doses

of acetaminophen on chloramphenicol metabolism in patients with bacterial meningi-

tis (1). Significant differences in chloramphenicol peak serum concentration, volume

of distribution, half-life, and clearance occurred between samples obtained before and

during treatment with acetaminophen. Peak serum concentrations fell, volume of dis-

tribution and clearance increased, and half-life shortened. The greatest change was in

clearance, which increased by more than 300% from baseline values. During treatment

with acetaminophen, the percentage of chloramphenicol excreted unchanged in the

urine decreased; its succinate metabolite remained unchanged; the glucuronide metab-

olite increased by approx 300%.

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Table 1 Antibiotics Interactions Primary drug Interacting drug Mechanism Effects Comments/management Chloramphenicol Acetaminophen Increased chloramphenicol Reduced chloramphenicol con- Monitor chloramphenicol concentrations clearance centrations and adjust dose as needed Potential for therapeutic failure Use alternative agent for antipyresis or analgesia Anticonvulsants Increased chloramphenicol Reduced chloramphenicol con- Monitor chloramphenicol concentrations clearance centrations and adjust dose as needed Potential for therapeutic failure Patients should be monitored for clinical and microbiological response to therapy Anticonvulsants Decreased metabolism of Increased serum concentrations Monitor phenytoin and phenobarbital concen- phenytoin and phenobarbital of these anticonvulsants with trations and adjust dose as needed increased CNS toxicity Oral hypogly- Decreased metabolism of tolbut- Increased half-life of tolbuta- Monitor blood glucose and adjust dose of oral cemic agents amide and excretion of chlorpro- mide and chlorpropamide hypoglycemic agents as needed pamide with increased risk of hypo- Monitor for clinical signs and symptoms of glycemia hypoglycemia Penicillins Antagonism of bacteriocidal Potential risk of therapeutic Monitor clinical and microbiological response agents failure when both agents are to therapy administered concurrently Monitor MIC and MBC of antibiotic combina- tion and each antibiotic alone Use alternative class of antibiotic Rifampin Increased chloramphenicol Reduced chloramphenicol con- Monitor chloramphenicol concentrations and clearance centrations adjust dose as needed Potential for therapeutic failure Patients should be monitored for clinical and microbiological response to therapy Oral anticoagulants Enhanced metabolism of warfarin Increased risk of major and Monitor PT/INR when beginning or discon- Decreased gut production of minor bleeding tinuing chloramphenicol therapy vitamin K Monitor for clinical signs of bleeding Altered production of prothrom- bin by hepatic cells

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Immunosuppres- Decreased cyclosporine and Increased cyclosporine and Monitor cyclosporine and tacrolimus concen- sive agents tacrolimus clearance tacrolimus concentrations trations and adjust dose as needed Potential for cyclosporine and tacrolimus toxicity Clindamycin Nondepolarizing Local anesthetic effect on Prolonged duration of neuromus- Patients receiving this combination of medica- neuromuscular myelinated muscle cular blockade tions should have their neuromuscular blocking agents Stimulates nerve terminal and function monitored with peripheral nerve blocks postsynaptic choliner- stimulation to access the degree of paralysis gic receptor induced by these agents Direct depressant action on Patients should be monitored for the potential muscle development of respiratory failure Aminoglycosides No clear evidence to support the hypothesis that clindamycin leads to an increased risk of nephrotoxicity when pre- scribed concurrently with aminoglycoside antibiotics Vancomycin Indomethacin Nonsteroidal antiinflammatory Increased concentrations of Serum concentrations of medications should agents may cause renal failure renally eliminated medications be monitored when possible and dosage regimens adjusted to maintain serum con- centrations within the accepted therapeutic ranges Nondepolarizing It is unclear regarding the exact High vancomycin concentrations Vancomycin dose should be adjusted for neuromuscular mechanism of this interaction may be associated with pro- body weight and infused over recommended blocking agents longed paralysis following a times to prevent excessively high peak dose of nondepolarizing block- concentrations ing agent Heparin Inactivation of vancomycin Reduced vancomycin activity Infuse the two drugs through the same intrave- nous line serially, with a 0.9% sodium chloride solution flushing the line between the two drugs to prevent mixing at high concentrations Continued on next page

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Table 1 (Continued) Antibiotics Interactions Primary drug Interacting drug Mechanism Effects Comments/management Sulfonamides Oral anticoagulants Some sulfonamides appear to An enhanced hypoprothrom- Monitor PT/INR when beginning or discon- impair the hepatic metab- binemic response to warfarin tinuing sulfonamide therapy olism of oral anticoagulants with an increased risk of Monitor for clinical signs of bleeding Competition for plasma protein- minor and major bleeding binding sites may play an additional role Tetracycline Heavy metals, Chelate tetracycline products in Impair their absorption and Tetracycline products should be administered trivalent cations the gastrointestinal tract decrease bioavailability 2 hours before or 6 hours after an antacid Potential for therapeutic failure H

-receptor antagonists and proton pump inhibitors may be prescribed in place of antacids Alternative antibiotics may be prescribed in place of a tetracycline Patients should be monitored for clinical and microbiological response to therapy Colestipol Bind tetracycline products in Impair their absorption and Tetracycline products should be administered the gastrointestinal tract decrease bioavailability 2 hours before or 3 hours after colestipol Potential for therapeutic failure Alternative antibiotics may be prescribed in place of a tetracycline Patients should be monitored for clinical and microbiological response to therapy Digoxin Tetracycline can suppress the Increased digoxin absorption Serum digoxin concentrations should be moni- gut flora responsible for and bioavailability may result tored and the dose adjusted with initiating metabolizing digoxin in the in toxicity or discontinuing antibiotic therapy gastrointestinal tract Anticonvulsants Anticonvulsants increase the Increased potential for thera- Patients should be monitored for clinical and hepatic metabolism of doxy- peutic failure microbiological response to therapy cycline, reducing its serum Renally eliminated tetracycline or other concentration classes of antibiotics should be prescribed to avoid this interaction

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Doxycycline should be administered twice a day in patients on chronic anticonvulsant therapy Warfarin Doxycycline enhances the anti- An enhanced hypoprothrombine- Patients should be monitored for clinical signs coagulation response to oral mic response to warfarin with and symptoms of bleeding when these drugs anticoagulants an increase risk of minor and are used concurrently major bleeding PT and/or INR should be monitored when these drugs are used concurrently Alternative antibiotics should be prescribed for patients on oral anticoagulants Lithium It is unclear if there is a direct Potential for increased serum Patients should be monitored for signs and interaction between lithium lithium concentrations and symptoms of lithium toxicity when receiv- and tetracycline lithium toxicity ing lithium and tetracycline concurrently Monitor serum lithium concentrations when receiving lithium and tetracycline Theophylline A reduction in theophylline The reduction in clearance Patients should be monitored clinically for metabolism appears to be quite variable signs and symptoms of theophylline toxicity so that it may be difficult to Serum theophylline concentration should be predict how much the theo- closely monitored in patients at high risk for phylline concentration will developing theophylline toxicity increase following the addi- tion of tetracycline to the medication regimen Oral Prospective trials have failed to Unexpected pregnancies It is not known if noncompliance played a role contraceptives documented a consistent effect in some of these unplanned pregnancies Women should be counseled to use other methods of birth control during tetracycline therapy Psychotropic In is unclear as to the exact Possible potential for acute psy- Monitor for signs and symptoms of acute agents mechanism of the interaction chotic behavior psychotic behavior Use alternative class of antibiotic Continued on next page

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Table 1 (Continued) Antibiotics Interactions Primary drug Interacting drug Mechanism Effects Comments/management Tetracycline Methotrexate Decreased methotrexate Increased methotrexate concen- Monitor methotrexate concentrations (Continued) clearance tration Maintain leucovorin rescue until methotrexate Potential for methotrexate toxicity concentrations are below the desired range Rifampin Increased doxycycline clearance Increased potential for therapeu- Monitor clinical and microbiological response tic failures in patients with to therapy Brucellosis infections Use alternative class of antibiotic Aminoglycosides Amphotericin B Additive direct nephrotoxicity The concurrent administration of Aminoglycoside concentrations should be effects on kidney aminoglycoside antibiotics monitored and the dosage regimen adjusted and amphotericin B may to maintain serum concentrations within the increase the risk of developing desired therapeutic range renal failure Attempts should be made to avoid other con- ditions that increase the risk for developing nephrotoxicity (i.e., hypotension, intrave- nous contrast media) Avoid prescribing other agents that cause nephrotoxicity Neuromuscular Aminoglycosides have been These drugs may cause post- Patient should be monitored for prolonged blocking agents shown to interfere with operative respiratory depres- postoperative paralysis if they received acetylcholine release and sion when administered neuromuscular blocking agents and exert a postsynaptic curare- before or during operations aminoglycoside antibiotics during the like action and may also cause a tran- perioperative or immediate postoperative These agents have membrane- sient deterioration in patents period stabilizing properties and with myas thenia gravis exert their effect on acetyl- choline release by interfer- ing with calcium ion fluxes at the nerve terminal, an action similar to magne- sium ions

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Aminoglycosides also possess a smaller but significant decrease in postjunct- ional receptor sensitivity and spontaneous release Indomethacin Nonsteroidal anti-inflammatory Increased concentrations of Serum concentrations of medications should agents may cause renal failure renally eliminated medications be monitored when possible and dosage regimens adjusted to maintain serum con- centrations within the accepted therapeutic ranges Cyclosporine Additive direct nephrotoxicity Concurrent administration of Aminoglycoside and cyclosporine concentra- effects on kidney aminoglycoside antibiotics and tions should be monitored and the dosage cyclosporine may increase the regimen adjusted to maintain serum concen- risk of developing renal failure trations within the desired therapeutic range Attempts should be made to avoid other con- ditions that increase the risk for developing nephrotoxicity (i.e., hypotension, intrave- nous contrast media) Avoid prescribing other agents that cause nephrotoxicity Cisplatin Additive direct nephrotoxicity Concurrent administration of Aminoglycoside concentrations should be effects on kidney aminoglycoside antibiotics monitored and the dosage regimen adjusted and cisplatin-based chemo- to maintain serum concentrations within the therapy regimens may desired therapeutic range increase the risk of develop- Attempts should be made to avoid other con- ing renal failure ditions that increase the risk for developing nephrotoxicity (i.e., hypotension, intrave- nous contrast media) Avoid prescribing other agents that cause nephrotoxicity Continued on next page

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Table 1 (Continued) Antibiotics Interactions Primary drug Interacting drug Mechanism Effects Comments/management Aminoglycosides Loop diuretics Ethacrynic acid may cause direct When ethacrynic acid is used Aminoglycoside concentrations should be (Continued) additive ototoxic effects on alone or in combination with monitored and the dosage regimens adjusted the ear amino gly cosides, it should be to maintain concentrations within the thera- used in low doses and titrated peutic range to maintain adequate urine Furosemide should be used with caution in output or fluid balance patients receiving aminoglycoside antibiot- It is unclear whether furosemide ics; careful attention should be paid to the directly increases the nephro- patient’s weight, urine output, fluid balance, toxicity and ototoxicity of and indices of renal function aminoglycosides Vancomycin Unclear if vancomycin increases The development of nephro- Aminoglycoside and vancomycin concentra- the nephrotoxicity of amino- toxicity trations should be monitored and the dosage glycosides regimen adjusted to maintain serum concen- trations within the desired therapeutic range Attempts should be made to avoid other con- ditions that increase the risk for developing nephrotoxicity (i.e., hypotension, intrave- nous contrast media) Avoid prescribing other agents that cause nephrotoxicity Anti- Penicillins combine with amino- Unexpected low serum amino- Blood samples for aminoglycosides concen- Pseudomonas glycoside antibiotics in equal glycoside concentrations for trations should be sent to the laboratory penicillins molar concentrations at a rate a given dose within 1–2 hours so that the sample can be dependent on the concentration, spun down and frozen if not assayed imme- temperature, and medium com- diately position The two antibiotics should never to be given The greater the concentration of at the same time; schedule administration the penicillin, the greater the time of the antibiotic so that the adminis- inactivation of the aminogly- tration of the aminoglycoside occurs toward coside the end of the penicillin dosing interval

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The inactivation is thought to If a patient is receiving this antibiotic combi- occur by way of a nucleophilic nation and unusually low aminoglycoside opening of the β -lactam ring, concentrations occur, the above factors which then combines with an should be checked amino group of the aminogly- coside, leading to the forma- tion of a microbiologically inactive amide Linezolid Selective serotonin Decreased serotonin metabolism Development of the serotonin Review patient profile before prescribing reuptake inhibitors by inhibition of monoamine syndrome linezolid oxidase Use alternative class of antibiotic If necessary, treat serotonin syndrome with serotonin antagonist cyproheptadine Systemic Decreased metabolism by Increased blood pressure Review patient profile before prescribing decongestants inhibition of monoamine linezolid oxidase Use alternative class of antibiotic Consider using topical nasal decongestants Quinupristin- Medications Decreased metabolism of medi- Prolonged therapeutic effects or Review patient profile before prescribing dalfopristin metabolized by cations by cytochrome P450 increased adverse reactions quinupristin-dalfopristin cytochrome 3A4 enzyme Use alternative class of antibiotic P450 3A4 enzyme Monitor patients closely for signs of adverse effects Telithromycin Azole antifungal Decreased telithromycin Increased telithromycin Use alternative class of antibiotic agents metabolism concentrations Cisapride Decreased cisapride metabolism Increased cisapride concentra- Avoid concomitant use of telithromycin and tions resulting in QTc interval cisapride prolongation Use alternative class of antibiotic Simvastatin Decreased simvastatin Increased simvastatin and Similar interaction possible with atorvastatin metabolism metabolite concentrations and lovastatin Increased the risk of developing Use alternative class of antibiotic myopathy Continued on next page

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Table 1 (Continued) Antibiotics Interactions Primary drug Interacting drug Mechanism Effects Comments/management Midazolam Decreased midazolam Increased midazolam Reduce midazolam dose metabolism concentrations Monitor patient’s level of consciousness and Increased risk for CNS and respiratory status respiratory depression Warfarin Enhanced metabolism of Increased risk of major and Monitor PT/INR when beginning or discon- warfarin minor bleeding tinuing telithromycin therapy Decreased gut production of Monitor for clinical signs of bleeding vitamin K Alternative antibiotics should be prescribed in Altered production of pro- patients on oral anticoagulants thrombin by hepatic cell Verapamil Decreased metabolism of Increased risk of cardiac Monitor cardiac function and ECG verapamil decompensation, heart block, Use alternative class of antibiotic or bradycardia Rifampin Increased telithromycin Reduced telithromycin Patients should be monitored for clinical and clearance concentrations microbiologic response to therapy Potential for therapeutic failure Anticonvulsants Increased telithromycin Reduced telithromycin concen- Patients should be monitored for clinical and clearance trations microbiologic response to therapy Potential for therapeutic failure Metoprolol Decreased metoprolol Increase metoprolol concentra- Monitor patient’s cardiac status metabolism tions potentially precipitating Use alternative class of antibiotic acute decompensated heart failure Digoxin Unknown Increased digoxin absorption Serum digoxin concentrations should be moni- and bioavailability may tored and the dose adjusted with initiating result in toxicity or discontinuing antibiotic therapy

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Theophylline A reduction in theophylline The reduction in clearance Patients should be monitored clinically for metabolism appears to be quite variable signs and symptoms of theophylline toxicity so that it may be difficult to Serum theophylline concentration should be predict how much the theo- closely monitored in patients at high risk for phyline concentration will developing theophylline toxicity increase following the addi- Alternative antibiotics should be prescribed in tion of tetracycline to the patients on theophylline medication regimen Sotalol Decreased sotalol absorption Decreased sotalol concentration Monitor patient’s ECG Loss of antiarrhythmic effects Use alternative class of antibiotic Oral contraceptives Prospective trials have failed to Unexpected pregnancies It is not know if noncompliance played a role documented a consistent effect in some of these unplanned pregnancies Women should be counseled to use other meth ods of birth control during tetracycline therapy MBC, minimum bactericidal concentration; MIC, minimum inhibitory concentration.

Kearns et al. evaluated the effect of acetaminophen in acutely ill pediatric patients (2). Chloramphenicol pharmacokinetic parameters were compared between a group of patients receiving acetaminophen and a group not receiving acetaminophen. There was no statistical difference in the chloramphenicol pharmacokinetic parameters between the two groups. However, there was a clinically significant increase in chlorampheni- col clearance and decrease in half-life between the initial dose and final dose in the patients receiving acetaminophen. Following acetaminophen therapy, the chloram- phenicol half-life decreased by approx 33%, from 3.4 to 2.2 hours, and its clearance increased by more than 50%, from 5.5 to 8.9 mL/minute/kg. The peak chloramphenicol serum concentrations were lower after the final dose than at steady state, 15.7 vs 22.7 mg/L, respectively.

Stein et al. were unable to document any effect of acetaminophen on chlorampheni- col metabolism in hospitalized adult patients (3). In a randomized crossover design, patients received either chloramphenicol or chloramphenicol with acetaminophen for 48 hours. There was no significant difference in peak and trough chloramphenicol con- centrations, half-life, or area under the concentration–time curve (AUC) between the two treatment periods.

Although the mechanism of this interaction is unclear, it appears to be an alteration in clearance. This interaction may take several days to manifest its full effect, and in some studies patients may not have been studied for a long enough period of time to evaluate fully the effects of acetaminophen on chloramphenicol pharmacokinetic parameters. Although Spika et al. (1) suggested that the increase in chloramphenicol clearance was caused by an increased in glucuronidation, this has not been confirmed by other investigators.

This interaction may be important in patients receiving chloramphenicol for the treat- ment of central nervous system (CNS) infections or infections caused by organisms resistant to more traditional antibiotics. Reduced peak concentrations or increases in clearance without appropriate adjustments in dosage regimens to account for these changes may result in therapeutic failures. Patients receiving chloramphenicol and acetaminophen should have chloramphenicol serum concentrations monitored every 2–3 days during a course of therapy, especially during the later part of therapy when it appears that chloramphenicol levels may begin to decline. Dosage regimens should be adjusted to maintain chloramphenicol concentrations within the desired therapeutic range. Other agents such as aspirin or ibuprofen may be used as alternatives to acetami- nophen for antipyresis and analgesia.

Anticonvulsants

Anticonvulsants have been shown to increase the metabolism of chloramphenicol by increasing its hepatic metabolism. Phenobarbital has been shown to stimulate the me- tabolism of chloramphenicol in several case reports (4,5). In addition, chloramphenicol has been shown to reduce the metabolism of phenytoin and phenobarbital when both agents are administered concurrently (6–10). The onset of these interactions appears to be rapid and may persist for several days after chloramphenicol is discontinued.

The reduction in phenytoin and phenobarbital metabolism is mostly likely because of

a competition for metabolic enzymes. The clinical significance of the interaction is the

potential for patients to develop phenytoin or phenobarbital toxicity after beginning

chloramphenicol therapy. Patients may show signs of lethargy, excessive sedation, nys- tagmus, hallucinations, or other mental status changes. Because phenytoin undergoes nonlinear metabolism, toxic serum concentrations may not occur for several days after starting chloramphenicol. After the maximum rate of phenytoin metabolism is exceeded, serum concentrations will rise rapidly and may remain elevated for a period of time after the chloramphenicol is discontinued. Because of phenobarbital’s long half-life, its seda- tive effects can be expected to resolve slowly as the serum concentration falls.

Patients receiving chloramphenicol with either phenytoin or phenobarbital must have their anticonvulsant serum concentrations monitored frequently, preferably every 3–5 days if possible, to detect increases in the concentrations. Patients also should be moni- tored clinically for the development of signs and symptoms of phenytoin or phenobar- bital toxicity.

Phenobarbital has been shown to increase the metabolism of chloramphenicol, result- ing in a reduction in its peak serum concentrations. Bloxham reported two patients who received chloramphenicol and phenobarbital for the treatment of meningitis (4). In one patient, peak chloramphenicol serum concentrations fell from 31 mg/L on days 2 and 3 to less than 5 mg/L on day 5. Patients receiving concurrent therapy with chlorampheni- col and phenobarbital should have chloramphenicol concentrations monitored daily for reductions in the serum concentration. The chloramphenicol dosage regimen needs to be adjusted to maintain therapeutic concentrations and prevent therapeutic failures.

Oral Hypoglycemic Agents

Several investigators have documented chloramphenicol’s ability to decrease the hepatic metabolism of tolbutamide, resulting in increases in its half-life and serum concentrations (10,11). Patients receiving tolbutamide and chloramphenicol concur- rently may experience greater reductions in their serum glucose values and hypoglyce- mia with its associated complications. However, frank hypoglycemia has not been reported when this combination has been given together.

Petitpierre and Fabre reported the ability of chloramphenicol to inhibit the renal excretion of chlorpropamide (12). They reported that five patients taking these agents together experienced an increase in their chlorpropamide half-lives from 30–36 hours to up to 40–146 hours. Hypoglycemia was not documented in these patients.

Patients taking oral hypoglycemic agents should monitor their blood glucose fre- quently when taking chloramphenicol. The oral hypoglycemic dosage regimen may need to be adjusted to maintain the blood glucose within a desirable range. Patients should also be instructed to monitor for signs of hypoglycemia and to carry glucose- containing products to reverse any episodes of hypoglycemia that may develop. If pos- sible, alternative antibiotics should be selected to avoid this interaction. Because a patient’s blood glucose may be controlled on a stable oral hypoglycemic dose, switch- ing oral hypoglycemic agents to avoid this interaction is not recommended.

Antibiotics Penicillins

Chloramphenicol has been reported to antagonize the effect of β-lactam antibiot-

ics. A number of reports have been published suggesting that bacteriostatic and bac-

tericidal antibiotics may antagonize each other in vitro (13,14) and in vivo (15,16).

Despite this information, many authorities do not believe that this is a clinically sig- nificant interaction and have used this combination of antibiotics as a standard of practice for many years for the treatment of bacterial meningitis.

French and colleagues described a case in which chloramphenicol and ceftazidime were used together to treat an infant with Salmonella meningitis (16). The combination failed to eradicate the infection, but subsequent treatment with ceftazidime alone was successful. In vitro tests of serum and cerebrospinal fluid taken at that time showed that the serum could inhibit the growth of an inoculum of the salmonella at a dilution of 1:2 and the cerebrospinal fluid at a dilution of 1:16, but neither fluid could kill the organ- ism at any dilution. A specimen of cerebrospinal fluid taken during treatment with ceftazidime alone inhibited and killed the standard inoculum of salmonella in vitro at a dilution of 1:32.

Minor degrees of antagonism have been demonstrated in occasional laboratory experi- ments between almost any pair of drugs, but generally the most consistent interfering drugs are bacteriostatic agents such as chloramphenicol, tetracyclines, and macrolides (14). All these agents appear to act predominantly as inhibitors of protein synthesis in microorganisms. They actively antagonize agents such as the penicillins, which primarily block the synthesis of cell wall mucopeptides. It is believed that pro- tein synthesis must proceed actively to permit active mucopeptide synthesis; therefore, inhibitors of protein synthesis can antagonize inhibitors of cell wall synthesis.

Rifampin

Prober (17) and Kelly et al. (18) each reported two cases in which the coad- ministration of rifampin and chloramphenicol resulted in significantly lower chloram- phenicol serum concentrations. Two patients were treated with chloramphenicol for Haemophilus influenzae. During the last 4 days of treatment, the patients received 20 mg/kg/day of rifampin. After 12 doses of chloramphenicol, the peak serum concentra- tions of chloramphenicol in these two patients were 21.5 and 38.5 mg/L, respectively, and trough concentrations were 13.7 and 28.8 mg/L. After the administration of rifampin, peak chloramphenicol concentrations progressively declined. By day 3 of rifampin coadministration, the peak concentration of chloramphenicol was reduced by 85.5% to 3.1 mg/L in one patient and by 63.8% to 8 mg/L in the second patient. Serum concentrations increased back into the therapeutic range after the daily dose of chloram- phenicol was increased to 125 mg/kg/day. The reduction in serum concentrations was most likely caused by rifampin stimulating the hepatic metabolism of chlorampheni- col, increasing its clearance and decreasing its serum concentrations.

Patients should have chloramphenicol concentrations monitored daily while they are receiving rifampin. The chloramphenicol dosage regimen may need to be adjusted to maintain concentrations within the therapeutic range because subtherapeutic con- centrations may result in therapeutic failure. Patients also should be monitored clini- cally for their response to therapy.

Anticoagulants

Chloramphenicol may enhance the hypoprothrombinemic response to oral antico-

agulants. Christensen and Skovsted documented a two- to fourfold increase in dicuma-

rol half-life when coadministered with chloramphenicol (10).

Several potential mechanisms may be responsible for this interaction. Chlorampheni- col has been shown to inhibit the metabolism of dicumarol, probably by inhibiting hepatic microsomal enzymes (10). Some investigators have proposed that chloram- phenicol decreases vitamin K production by gastrointestinal bacteria (19,20); however, bacterial production of vitamin K appears to be less important than dietary intake.

Moreover, chloramphenicol does not usually have much effect on bowel flora (21).

Vitamin K depletion by chloramphenicol may affect the production of vitamin K-de- pendent clotting factors in the hepatocyte (22).

The clinical consequences of an increased prothrombin time (PT) or international normalized ratio (INR) would be increased risk of bleeding. This includes not only minor bleeding such as nosebleeds and bleeding from the gums, but also major bleed- ing into the gastrointestinal tract, CNS, or retroperitoneal space. The PT/INR should be monitored daily when chloramphenicol is started or discontinued in patients taking oral anticoagulants. There may be an increase in clot formation and thromboembolic complications if the warfarin dose is not increased after the chloramphenicol is stopped.

Immunosuppressive Agents Cyclosporine and Tacrolimus

Several reports have appeared in the literature describing an interaction between chloramphenicol and immunosuppressive agents, specifically cyclosporine and tacrolimus. Bui and Huang reported the interaction in a renal transplant patient receiv- ing cyclosporine (23). The patient required cyclosporine 50–75 mg twice daily to main- tain trough concentrations in the 100–150 mg/L prior to hospital admission. The patient’s cyclosporine dose required increasing to 300 mg twice daily during her hospi- tal admission to maintain similar trough concentrations because of rifampin therapy for the treatment of line sepsis. Ten days after the rifampin was stopped, 875 mg chloram- phenicol every 6 hours was started for the treatment of an Enterococcus sinusitis. The trough cyclosporine concentration on the following day increased to 280 mg/L. De- spite stepwise lowering of the cyclosporine dose to 50–100 mg daily, the concentra- tions continued to rise for the next 2 weeks, reaching a plateau of 600 mg/L. After stopping the chloramphenicol, the cyclosporine concentration stabilized between 100 and 150 mg/L on a dose of 50 mg twice daily. Steinfort and McConachy reported a similar experience in a heart transplant patient receiving chloramphenicol and cyclosporine (24).

Two reports have documented a similar interaction between chloramphenicol and

tacrolimus in transplant patients (25,26). Schulman and colleagues reported a 7.5-fold

increase in tacrolimus dose-adjusted AUC, 22.7 vs 171 mg·h/L and an increased in

tacrolimus half-life from 9.1 to 14.7 hours following the addition of chloramphenicol

to a stable tacrolimus regimen (25). Taber and colleagues documented the chloram-

phenicol–tacrolimus interaction in a liver transplant patient. The patient was stabilized

on an outpatient tacrolimus dose of 5 mg twice daily with trough concentrations rang-

ing between 9 and 11 ng/mL. The tacrolimus 12-hour trough concentration increased

to more than 60 ng/mL after 3 days of 1850 mg chloramphenicol every 6 hours. The

patient complained of lethargy, fatigue, headaches, and tremors. The tacrolimus con-

centration decreased to 8.2 ng/mL 7 days after the chloramphenicol was stopped. The

tacrolimus regimen was restarted at 5 mg twice daily, resulting in stable trough con-

centrations between 6.7 and 11.0 ng/mL (26).

The mechanism of the interaction is most likely caused by chloramphenicol’s inhi- bition of the cyctochrome P450 3A4 enzyme, which is responsible for the metabolism of cyclosporine and tacrolimus. If chloramphenicol has to be used in a patient receiv- ing cyclosporine or tacrolimus, a prospective decrease in dose may be warranted.

Cyclosporine and tacrolimus concentrations should be closely monitored with appro- priate dose adjustments while patients are receiving chloramphenicol. Cyclosporine and tacrolimus administration should be stopped in patients with elevated trough con- centrations, especially in patients slowing signs of cyclosporine or tacrolimus toxicity until the concentrations returned to the normal therapeutic range. The agents may be restarted at appropriately adjusted doses to maintain the trough concentrations within the therapeutic range.

CLINDAMYCIN

Nondepolarizing Neuromuscular Blocking Agents

Clindamycin has been shown to interact with nondepolarizing neuromuscular block- ing agents and aminoglycoside antibiotics. Becker and Miller investigated the neuro- muscular blockade induced by clindamycin alone and when mixed with d-tubocurarine or pancuronium in an in vitro guinea pig lumbrical nerve-muscle preparation (27).

Clindamycin initially increased twitch tension, but with higher concentrations twitch tensions subsequently decreased. With 15–20% twitch depression induced by clindamycin, neostigmine or calcium slightly but not completely antagonized the block- ade. Clindamycin at a dose that did not depress twitch tension potentiated d-tub- ocurarine- and pancuronium-induced neuromuscular blockade.

Several clinical reports documented clindamycin’s ability to prolong neuromuscular blockade following depolarizing and nondepolarizing neuromuscular blocking agents (28–30). Best and colleagues reported on a patient who received 300 mg clindamycin intravenously 30 minutes before surgery to repair a nasal fracture (28). To facilitate intubation, 120 mg succinylcholine was administered, with no additional nondepolar- izing neuromuscular blocking agents administered during the surgery. Approximately 5 hours after surgery and 20 minutes after receiving 600 mg clindamycin intravenously, the patient complained of profound overall body weakness and was noted to have bilat- eral ptosis, difficulty speaking, and rapid shallow respirations. After several minutes, her weakness rapidly became more profound, with one-fifth muscle strength noted in all extremities. Nerve stimulation showed marked neuromuscular blockade with the train-of-four (TOF) stimulation noted to be 0/4. The patient was treated with 4 mg neostigmine iv and 0.8 mg glycopyrrolate iv, enabling the patient to move all extremi- ties and develop a more normal respiratory pattern. Follow-up nerve stimulation showed a TOF of 4/4, and within 20 minutes of the reversal agent, the patient returned to baseline muscle strength (5/5) in all extremities.

Clindamycin-induced neuromuscular blockade is difficult to reverse. No reversal

could be obtained by using either calcium or neostigmine (31). The mode of action of

clindamycin on neuromuscular function is complex. Although it has a local anesthetic

effect on myelinated nerves, it also stimulates the nerve terminal and simultaneously

blocks the postsynaptic cholinergic receptor. It appears that its major neuromuscular

blocking effect is a direct depressant action on the muscle by the un-ionized form of

clindamycin (32). Clindamycin also has been shown to decrease the quantal content of

acetylcholine released with presynaptic stimulation in vitro (33), possibly the result of effects on presynaptic voltage-gated Ca

channels (34).

This pharmacodynamic interaction may be of clinical significance in patients receiv- ing clindamycin and depolarizing or nondepolarizing neuromuscular blocking agent dur- ing the perioperative period or in an intensive care unit. This interaction may result in a prolonged period of neuromuscular blockade, resulting in recurarization with respiratory failure and an extended period of mechanical ventilation.

Patients receiving this combination of agents should be monitored clinically with peripheral nerve stimulation using TOF or other mode of nerve stimulation to assess neuromuscular function and degree of neuromuscular blockade.

Aminoglycosides

One report suggested that clindamycin may increase the risk of nephrotoxicity when administered concurrently with aminoglycoside antibiotics. Butkus and colleagues reported three patients who developed acute renal failure when gentamicin and clindamycin were administered concurrently (35). The evidence for combined nephro- toxicity consisted of the temporal relationship between administration of the antibiot- ics and the development of acute renal failure with rapid recovery after the antibiotics were stopped.

This interaction is supported by circumstantial evidence. Although both agents were administered concurrently, none of the patients had gentamicin concentrations moni- tored during therapy. The reversible renal failure is consistent with that seen with aminoglycosides. It occurs during the course of therapy and resolves rapidly once the aminoglycoside antibiotic is stopped. There is no evidence to suggest that the adminis- tration of clindamycin in the setting of appropriately dosed aminoglycoside antibiotics leads to an increased risk of nephrotoxicity.

VANCOMYCIN

Nonsteroidal Anti-Inflammatory Agents

Spivey and Gal compared the vancomycin pharmacokinetic parameters in six neo- nates with patent ductus arteriosus treated with indomethacin and vancomycin to five patients receiving vancomycin alone (36). The vancomycin half-life (24.6 vs 7.0 hours) and volume of distribution (0.71 vs 0.48 L/kg) increased, and the clearance decreased (23 vs 54 mL/kg/hour) in the indomethacin-treated group compared to the control group. This may have been because of the ability of nonsteroidal anti-inflammatory agents to cause reversible renal failure, impairing the elimination of all renally elimi- nated medications.

Renal function should be closely monitored in patients receiving nonsteroidal anti- inflammatory agents. If renal failure develops, the doses of all renally eliminated medi- cations should be adjusted to the level of residual renal function. Serum concentrations of medications should be monitored and dosage regimens adjusted to maintain serum concentrations within the accepted therapeutic ranges.

Vecuronium

Huang and colleagues described the depression of neuromuscular function that

developed after the intravenous administration of vancomycin (37). Tracheal intuba-

tion was facilitated with vecuronium. Twenty minutes after induction of anesthesia, T1 had returned to 35% of the preinduction baseline, but T4 was barely perceptible.

An infusion of 1 g vancomycin was administered, and the T1 decreased immediately after the start of the infusion to less than 10% of the preinduction level; T4 was totally absent. The infusion lasted 35 minutes. A blood sample was drawn 25 minutes after stopping the infusion to determine the vancomycin concentration; it was 70 mg/L.

Within 3 minutes after stopping the vancomycin infusion, the electromyogram (EMG) began to recover. Twenty minutes later, the operation was completed, and the vecuronium was reversed with atropine and edrophonium. Initially, the EMG response demonstrated the recovery of the neuromuscular function to near-preinduction levels, but the responses decreased approx 5 minutes later to the same level they were before the edrophonium was given. The patient was awake and breathing spontaneously but was unable to sustain a headlift. Twenty minutes after the injection of edrophonium, the patient’s muscle tone was judged to be adequate by both clinical assessment and EMG.

The exact mechanism of this pharmacodynamic interaction is unclear. The patient was administered a rather large dose of vancomycin for her body size, and the infusion was infused over 35 minutes rather than the usual recommended infusion time of 60 minutes. Both of these factors resulted in the high postinfusion peak serum concentra- tion. The neuromuscular depression seen in this patient may have been because of the high serum concentration of vancomycin, but this level can occur during treatment of patients with vancomycin.

Vancomycin should be administered cautiously to patients undergoing surgery with neuromuscular blocking agents and patients in the intensive care unit receiving chemi- cal paralysis. The doses should be adjusted for body weight and infused over recom- mended times.

Heparin

Barg and colleagues described the inactivation of vancomycin by heparin when the substances were infused simultaneously through the same intravenous line, resulting in a reduction in vancomycin activity (38). Mixtures of heparin and vancomycin in vari- ous concentrations were made and tested against a clinical isolate of methicillin-resis- tant Staphylococcus aureus. A precipitate formed at the concentrations achieved in the intravenous line, and when the vancomycin concentrations were measured by bioas- say, a 50–60% reduction in vancomycin activity was noted. When these two solutions were prepared and mixed at microgram concentrations, concentrations typically seen in patients, a precipitate was no longer observed, and vancomycin activity was not reduced. Heparin appeared to inactivate vancomycin at the concentrations typically achieved when these two agents are administered simultaneously though the same intravenous catheter. The authors concluded that infusions of the two drugs through the same intravenous line could be done serially, with a 0.9% sodium chloride solution flushing the line between the two drugs to prevent mixing at high concentrations.

The interaction between vancomycin and aminoglycosides is discussed in the

section Aminoglycosides. Angaran and colleagues determined that vancomycin had

no effect on the PT response to warfarin in patients undergoing prosthetic value sur-

gery (39).

SULFONAMIDES Warfarin

Several reports have described an enhanced hypoprothrombinemic response to war- farin when sulfamethoxazole (SMX), usually in combination with trimethoprim (TMP), was added to a patient’s therapy (40–43). Two pharmacokinetic studies in healthy adults confirmed that SMX enhances the hypoprothrombinemic response to warfarin in most people (43,44). Although the SMX seems more likely to have been responsible than the TMP, a TMP effect cannot be ruled out.

O’Reilly conducted two studies evaluating the stereoselective interaction between TMP-SMX and warfarin. In one study, patients received 1.5 mg/kg of racemic war- farin with and without 320 mg TMP-1600 mg SMX beginning 7 days before warfarin and continuing daily throughout the period of hypoprothrombinemia (44). There was a significant increase in the areas of the one-stage PT, from 53 to 83 units, during the administration of TMP-SMX. In a follow-up study, O’Reilly studied the effects of TMP-SMX on each of the warfarin enantiomers (45). Subjects received each enanti- omer alone and in combination with 80 mg TMP-400 mg SMX. TMP-SMX had no effect on the R-isomer. The areas of the one-stage PT increased by approx 70%, from 40 to 67 units, when the S-isomer and TMP-SMX were given together. Additional case reports described the prolongation in PT following the addition of TMP-SMX to medi- cation regimens containing warfarin (40–43).

Some sulfonamides appear to impair the hepatic metabolism of oral anticoagulants.

Competition for plasma protein-binding sites may play an additional role. Although sulfonamides reportedly decrease vitamin K production by the gastrointestinal bacte- ria, evidence for such an effect is lacking.

Patients should be monitored closely for an increase in PT/INR when SMX-contain- ing products are coadministered with warfarin. Patients should be monitored clinically for signs of bleeding with initiating and decreased effects on discontinuing TMP-SMX.

Other antibiotics may be prescribed to avoid this interaction, or other forms of antico- agulation such as unfractionated or low molecular weight heparin may be used as alter- natives to warfarin.

TETRACYCLINES

Tetracyclines have been documented to interact with a number of medications. The most common interaction is with heavy metals, which chelate tetracyclines and impair their absorption from the gastrointestinal tract. More important interactions may occur with oral contraceptives, for which tetracycline may reduce effectiveness and increase the risk of pregnancy.

Heavy Metals

Numerous studies have documented the ability of heavy metals to chelate tetracy-

cline products and impair their absorption (46–48). These products contain divalent

and trivalent cations such as aluminum, magnesium, and calcium. Antacids also may

impair the dissolution of tetracyclines. Bismuth subsalicylate, a common ingredient in

antidiarrheal medications, also has been shown to impair the absorption of tetracy-

clines through a similar chelation mechanism (49,50).

This is a pharmacokinetic interaction because it impairs absorption and reduces oral bioavailability. The clinical consequences of this interaction could be potential thera- peutic failure because of inadequate tetracycline serum and tissue concentrations.

Oral tetracycline products should be taken 2 hours before or 6 hours after antacids.

This may not completely avoid the interaction but should minimize it. Because this interaction is not based on an alteration in pH, H

-receptor antagonists and proton pump inhibitors may be alternative medications. In addition, other antibiotics may be pre- scribed to avoid the interaction.

Bismuth can reduce the bioavailability of tetracycline, similar to heavy metals.

Ericsson and colleagues evaluated the influence of a 60-mL dose of bismuth subsalicylate on the absorption of doxycycline (49). Doxycycline bioavailability was reduced by 37 and 51% when given simultaneously and as a multiple-dose regimen, respectively, before doxycycline. Peak serum concentrations of doxycycline were sig- nificantly decreased when bismuth subsalicylate was given 2 hours before doxycycline but not when given 2 hours after doxycycline. Albert and coworkers documented a 34% reduction in doxycycline bioavailability when the two products were adminis- tered simultaneously (50). A further discussion on the effect of various foods contain- ing divalent cations is given in Chapter 12.

Colestipol

Colestipol reduces the bioavailability of tetracycline by impairing its absorption in the gastrointestinal tract. Friedman et al. showed that when colestipol and tetracycline were given together, there was a 50% reduction in tetracycline bioavailability (51). In a single dose, three-way crossover study, subjects ingested 500 mg tetracycline with 180 mL water, 180 mL water and 30 g colestipol, and 180 mL orange juice and 30 g colestipol. There were significant differences in the 48-hour urinary excretion of tetra- cycline. More than 50% of the dose was recovered in the urine when the tetracycline was administered with water. Only 23–24% was recovered in the urine when it was administered with colestipol. There was no significant difference among the three groups in the mean value excretion half-life.

This is a pharmacokinetic interaction because it impairs absorption and reduces oral bioavailability as a result of tetracycline adsorbing onto colestipol-binding sites. The clinical consequences of this interaction could be potential therapeutic failure because of inadequate tetracycline serum and tissue concentrations.

Oral tetracycline should be taken 2 hours before or at least 3 hours after a dose of colestipol. In addition, other antibiotics may be prescribed to avoid the interaction.

Digoxin

Tetracycline can reduce the gastrointestinal bacterial flora responsible for metabo-

lizing digoxin in the gastrointestinal tract and increase digoxin absorption and

bioavailability in some patients. Lindenbaum and colleagues administered digoxin to

healthy volunteers for 22–29 days. After 10 days, 500 mg tetracycline every 6 hours

for 5 days was started (52). During the period of antibiotic administration, digoxin

reduction products fell, urine digoxin output rose, and digoxin steady-state serum con-

centrations increased by as much as twofold in some subjects. Preantibiotic serum

digoxin serum concentrations ranged between 0.37 and 0.76 μg/L and increased to 0.8–1.33 μg/L following antibiotic therapy. It also was noted that these effects per- sisted for several months after the antibiotics were stopped. There were no reports of digoxin toxicity in the patients who experienced an increase in their digoxin concen- trations.

The mechanism of this pharmacokinetic interaction appears to be the inhibition of digoxin metabolism by suppression of gut bacteria. The clinical implications of this interaction are the possibility that therapy with antibiotics in subjects producing large amounts of digoxin reduction products may precipitate toxicity. Unrecognized changes in gut flora might result in variability in digoxin response in the direction of either drug toxicity or therapeutic failure.

Anticonvulsants

Phenobarbital and phenytoin have been shown to reduce the serum concentrations of doxycycline (53–55). Penttilla and colleagues conducted three trials to evaluate the effect of anticonvulsants on doxycycline metabolism (53). In one study, they com- pared the half-life of doxycycline in patients taking long-term phenytoin or carbam- azepine therapy to a control group of patients not receiving anticonvulsants. The doxycycline half-life in the patients receiving chronic anticonvulsants ranged between 7 and 7.5 hours compared to 15 hours in the control subjects. In a second crossover trial, they determined the half-life of doxycycline in five patients after 10 days of phenobarbital therapy and in another five patients taking phenobarbital chronically (54). The half-life of doxycycline was 15 hours in the control patients before phe- nobarbital therapy began. After 10 days of therapy, the half-life was reduced to 11 hours. The doxycycline half-life was 7 hours in the patients taking phenobarbital chronically. In a third trial, they evaluated the effect of chronic anticonvulsant therapy on a variety of tetracycline products and compared this to results in control patients (55). The doxycycline half-life averaged 7 hours, and the peak concentrations were lower in the patients on chronic anticonvulsant therapy compared to the control group.

There was no difference in the half-lives of oxytetracycline, methacycline, chlortetra- cycline, and demethylchlortetracycline between the patients on anticonvulsants and control patients.

The enhanced hepatic metabolism of doxycycline is the mechanism of this pharma- cokinetic interaction. The clinical consequences of this interaction could be a reduction in serum doxycycline concentrations and the potential for therapeutic failure. An alter- native class of antibiotics should be selected for these patients because they may be receiving anticonvulsants for the control of a seizure disorder, and it would not be wise to switch anticonvulsants to avoid this interaction.

Warfarin

Tetracyclines may be associated with an increased hypoprothrombinemic response

in patients taking oral anticoagulants. Several case reports described patients stabilized

on chronic warfarin therapy who experienced increases in PT after the addition of doxy-

cycline to their medication regimens (56,57). Westfall and coworkers described a

patient maintained on warfarin therapy with stable PT values approximately two times

the control value (56). After the initiation of 100 mg doxycycline twice a day, the patient’s PT increased to 51 s and was associated with unusually heavy menstrual flow.

On medical evaluation, her hemoglobin and hematocrit had dropped to 5.7 g/dL and 18.9%, respectively.

Caraco and Rubinow described two patients taking chronic oral anticoagulation who presented with severe hemorrhage and disturbed anticoagulation tests after the addi- tion of doxycycline to their medication regimens (57). In the first patient, the PT ratio increased from 1.49 to 3.82 following the addition of 100 mg doxycycline daily. In the second patient, the PT ratio increased from between 1.5 and 2.5–4.09 following the addition of 100 mg doxycycline twice daily.

The mechanism of this pharmacodynamic interaction is unclear but may involve a reduction in the plasma prothrombin activity by impairing prothrombin utilization or decreasing vitamin K production by the gastrointestinal tract.

The clinical significance of this interaction is the increased anticoagulant effect, which may result in an increased risk of bleeding. Patients should be closely monitored for clinical signs of bleeding, such as nosebleeds or bleeding from the gums, and the PT monitored and warfarin dose adjusted to maintain the PT/INR in the therapeutic range. Other antibiotics may be prescribed to avoid this interaction, or other forms of anticoagulation such as unfractionated or low molecular weight heparin may be used as alternatives to warfarin.

Lithium

One case report described the increase in lithium concentrations following a course of tetracycline (58). However, a prospective trial documented small decreases in the serum lithium concentration when both agents were administered concurrently (59).

McGennis reported a patient taking lithium chronically for a history of manic depression (58). Two days after starting tetracycline, it was noted that her serum lithium level increased from 0.81 to 1.7 mmol/L. The patient exhibited slight drowsiness, slurred speech, and a fine tremor of both hands consistent with lithium toxicity. At the time lithium and tetracycline were stopped, the serum lithium concentration was 2.74 mmol/L. The concentration declined to within the therapeutic range 5 days after stop- ping both agents.

Fankhauser and coworkers evaluated the effect of tetracycline on steady-state serum lithium concentrations in healthy volunteers and compared the frequency and severity of adverse effects in the lithium and lithium-tetracycline treatment phases (59). There was a significant decrease in the serum lithium concentration between the control and treatment phases (0.51 vs 0.47 mEq/L, p = 0.01). It is unclear whether this is a clini- cally significant decrease in the serum lithium concentration. There was no difference in adverse effects between the control and treatment phases of the trial.

The mechanism of this interaction is not known. One possibility may be that tetra-

cycline-induced renal failure may reduce urinary lithium excretion. Although it is

unlikely that a significant interaction exists, patients should be monitored for signs

of lithium toxicity when this combination is prescribed. Renal function should also

be monitored to prevent increases in the serum lithium concentrations secondary to

reductions in renal function. Another class of antibiotics should be prescribed to avoid

this interaction.

Psychotropic Agents

Steele and Couturier reported the possible interaction between tetracycline and respiradone and/or sertraline in a 15-year-old male with Asperger’s disorder, Tourette’s disorder, and obsessive-compulsive disorder (60). Tetracycline was added to a respiradone-sertraline treatment regimen, resulting in an acute exacerbation of motor and vocal tics. The authors postulated that the increase in tics may have resulted from a tetracycline-respiradone interaction leading to a reduction in respiradone levels, a tetracycline-sertraline interaction leading to increased levels of sertraline, or the natu- ral course of Tourette’s disorder. The sertraline dose was increased with no concomi- tant increase in tics, and subsequent discontinuation of tetracycline resulted in an improvement in tics, which suggests the possibility of an interaction between tetracy- cline and respiradone. The mechanism of this potential interaction is unknown, but the authors recommended that the addition of antibiotics to psychotropic medications requires close monitoring because of the potential for the interaction.

Theophylline

Several case reports described increases in theophylline serum concentrations dur- ing a course of tetracycline administration (61,62). However, prospective trials have failed to document a consistent effect (63–66).

Four prospective studies have evaluated the interaction between theophylline and tet- racycline. Pfeifer et al. gave nine patients tetracycline for 48 hours and did not observe a statistically significant interaction (63). However, six subjects had a decrease in theo- phylline clearance during the combined tetracycline-theophylline period, and in four of the subjects, the decrease was greater than 15%. Mathis and colleagues studied eight healthy volunteers by giving them a single intravenous injection of aminophylline before and after 7 days of tetracycline (64). Theophylline clearance decreased by an average of 9%, but four patients had greater than 15% decrease in clearance; one patient had a 32%

decrease in clearance. Gotz and Ryerson evaluated the interaction between tetracycline and theophylline in five patients with chronic obstructive airways disease (65). Theo- phylline clearance decreased by an average of 11% following the 5-day course of tetra- cycline. Jonkman et al. evaluated the effects of doxycycline on theophylline pharma- cokinetic parameters in healthy volunteers during a 9-day course of theophylline alone and with the coadministration of doxycycline (66). There was no influence of doxycy- cline on absorption, elimination, and volume of distribution of theophylline. Mean steady-state plasma concentrations were not significantly different between the two treat- ment periods.

The mechanism for the interaction is unknown but appears to be a reduction in the hepatic metabolism of theophylline. The reduction in metabolism appears to be quite variable. It may take several days for the interaction to occur, so increases in serum theophylline may not be clinically significant after short courses of tetracycline.

Patients taking longer courses of tetracycline may be at risk for developing theophyl- line toxicity.

Patients should be closely monitored when tetracycline is added to a medication

regimen containing theophylline. Although short courses may not result in clinically

significant increases in the serum theophylline concentration, patients maintained in

the upper end of the therapeutic range may be at risk of developing theophylline toxic-

ity even with modest increases in the serum theophylline concentration. Also, the reduction in clearance appears to be quite variable, so it may be difficult to predict how much the theophylline will increase following the addition of tetracycline to the medi- cation regimen. All patients should be monitored clinically for signs and symptoms of theophylline toxicity. Serum theophylline concentration should be monitored every 2–3 days in patients at high risk for developing theophylline toxicity.

Oral Contraceptives

Several case reports suggest that tetracycline can reduce the effectiveness of oral contraceptives (67,68). One retrospective study showed that the oral contraceptive fail- ure rate was within the expected range associated with the typical pattern of use (69).

However, prospective trials have failed to document a consistent effect (70,71). These case reports of unintended pregnancies have occurred following the concurrent admin- istration of tetracycline and other antibiotics with oral contraceptives. Two small con- trolled studies evaluated the effect of tetracycline on the serum levels of ingredients contained in commonly prescribed oral contraceptives. Neely et al. compared the serum concentrations of ethinyl estradiol, norethindrone, and endogenous progesterone dur- ing a control period and after a 7-day course of doxycycline starting on day 14 of their cycle (70). There were no statistically significant differences in serum concentrations of ethinyl estradiol, norethindrone, and endogenous progesterone between the control and treatment phases. Murphy et al. studied the effect of tetracycline on ethinyl estra- diol and norethindrone after 24 hours and 5–10 days of therapy with tetracycline (71).

There was no significant decrease in ethinyl estradiol or norethindrone concentrations after 24 hours or after 5–10 days of therapy.

The mechanism for the interaction is unknown but may be because of interference with the enterohepatic circulation of estrogens in the intestines, making this a pharma- cokinetic interaction. Other antibiotics have also been reported to reduce the effective- ness of oral contraceptives when administered concurrently. It is not known if noncompliance played a role in some of these unplanned pregnancies.

Although the evidence of the interaction between tetracycline and oral contracep- tives is limited to case reports, women should be counseled to use other methods of birth control during tetracycline therapy.

Methotrexate

Tortajada-Ituren and colleagues reported an interaction between doxycycline and

high-dose methotrexate (72). A 17-year-old female was receiving high-dose metho-

trexate as part of a chemotherapy regimen. The patient had undergone 10 cycles of the

regimen without complications. Her mean methotrexate pharmacokinetic parameters

following the 10 cycles were a methotrexate clearance of 2.95 L/hour; 2.96-hours half-

life; 4.27-hour mean residence time; and 12.53-L volume of distribution. On admission

to the hospital for the 11th cycle of chemotherapy, the patient was noted to have a

palprebal abscess in her left eye, which was treated with 100 mg doxycycline twice

daily. The high-dose (18 g) methotrexate was administered according to her usual pro-

tocol. During the first 24 hours after the methotrexate infusion, the patient developed

facial erythema, malaise, and vomiting, which had not occurred during the first 10

cycles. The doxycycline was stopped 48 hours after chemotherapy. The pharmacoki-

netic monitoring was prolonged for 168 hours, revealing a significant decrease in meth- otrexate clearance (1.29 L/hour) and significant increase in half-life (6.26 hours) and mean residence time (9.03 hours) compared to the values obtained during the first 10 cycles. Her hospital stay was prolonged to 11 days compared to an average of 7.7 days during the first 10 cycles.

Although the mechanism of the interaction is unknown, one proposed theory sug- gests that tetracyclines may displace methotrexate from plasma protein-binding sites (73). In an attempt to validate this mechanism in their patient, the authors determined the degree of methotrexate plasma protein binding in two plasma samples with similar methotrexate concentrations from the 7th and 11th cycles. The unbound methotrexate concentrations were determined with an ultrafiltration process. The unbound metho- trexate fractions during the 7th and 11th cycles were 53 and 41%, respectively.

Although case reports of a tetracycline–methotrexate interaction are limited, tetra- cyclines should be avoided in patients receiving high-dose methotrexate therapy. If therapy with a tetracycline is required, pharmacokinetic monitoring should be contin- ued until the methotrexate concentrations are below the desired range, and the leucov- orin rescue should be continued, if necessary, until all signs and symptoms of methotrexate toxicity disappear.

Rifampin

Colmenero and colleagues studied the possible interaction between rifampin and doxycycline in 20 patients with brucellosis (74). Patients were treated with either doxycyline and streptomycin or doxycyline and rifampin. The doxycycline levels in the patients treated with rifampin were significantly lower than in those patients treated with doxycycline and streptomycin. The doxycycline clearance in patients treated with rifampin was significantly higher than in the patients treated with doxycycline and streptomycin, 3.59 and 1.55 L/hours, respectively. The elimination half-life (4.32 vs 10.59 hours) and AUC were significantly lower in patients in the rifampin-treated patients (30.4 vs 72.6 mg*hours/mL). In addition, there were lower doxycycline levels in the rifampin treatment group, which had rapid acetylaters. There were no treatment failures in the patients receiving doxycyline and streptomycin; there were two treat- ment failures in the doxycyline-rifampin group.

Rifampin is a potent inducer of hepatic microsomal enzymes. Although doxycyline is only partially metabolized, the effect of rifampin may be significant enough to lower doxycyline concentrations to subtherapeutic levels. Caution should be used when treat- ing patients with combined rifampin and doxycycline therapy. If possible, an alterna- tive antibiotic should be prescribed to avoid potential treatment failures.

AMINOGLYCOSIDES

Aminoglycoside antibiotics are involved in a number of drug interactions, many of which result in an increased risk of nephrotoxicity.

Amphotericin B

The concurrent use of aminoglycoside antibiotics Amphotericin B may lead to an

increased risk of developing nephrotoxicity. Churchill and Seely reported four patients

who developed nephrotoxicity when both agents were administered together (75). All

of the patients received amphotericin B at an approximate dose of 0.5 mg/kg/day. Two of the four patients had documented gentamicin trough concentrations of 5 mg/L. All patients developed progressive renal failure during the first several days of combined therapy. In the patients who survived, renal function returned to baseline values after both agents were discontinued.

The mechanism of this is the potential of additive nephrotoxicity from both agents.

Amphotericin B is associated with a predictable rise in creatinine within the first sev- eral days of therapy. Aminoglycoside antibiotics are associated with acute tubular necrosis, especially in the setting of elevated serum concentrations. In the case report, three patients had documented gentamicin concentrations significantly higher than the desired 2 mg/L. This mostly likely contributed to the development of nephrotoxicity in these patients.

Patients receiving aminoglycoside antibiotics and amphotericin B should be closely monitored for the development of renal failure. The aminoglycoside serum concentra- tions should be monitored every 2–3 days and the dosage regimen adjusted to maintain peak and trough concentrations within the desired therapeutic range. Every attempt should be made to avoid other conditions (i.e., hypotension) that might increase the risk of developing renal failure and to avoid administering other medications (i.e., intravenous contrast media, loop diuretics) that might increase the risk of developing renal failure.

Neuromuscular Blocking Agents

Aminoglycoside agents are known to potentiate paralysis from neuromuscular blocking agents (76–79). Often, this has occurred in the setting of the instillation of aminoglycoside-containing irrigation solutions into the intra-abdominal cavity dur- ing surgery. Dupuis et al. evaluated prospectively the interaction between aminoglycosides and atracurium and vecuronium in 44 patients (80). Twenty-two patients had therapeutic concentrations of gentamicin or tobramycin, and 22 patients served as controls. Onset time, clinical duration, and time to spontaneous recovery T

/T

ratio of 0.7 after atracurium or vecuronium injection were measured. Although no statistically significant differences were found in onset time, clinical duration was longer in patients receiving tobramycin or gentamicin and paralyzed with vecuronium than in controls. The neuromuscular blockade produced by atracurium was not sig- nificantly influenced by the presence of therapeutic serum concentrations of tobramycin or gentamicin. The clinical duration of patients receiving atracurium alone or in the presence of an aminoglycoside was approx 40 minutes in each group, and the time to recovery of a T

/T

ratio >0.7 approx 60–70 minutes. The clinical duration was significantly longer in the vecuronium patients receiving aminoglycosides than in the vecuronium control patients, 30 vs 55 minutes, respec- tively. The time to recovery of a T

/T

ratio >0.7 in the patients receiving vecuronium with aminoglycosides also was longer in the patients receiving an aminoglycoside, 55 vs 105 minutes, respectively.

Aminoglycosides have been shown to interfere with acetylcholine release and exert

a postsynaptic curare-like action (81). These agents have membrane-stabilizing prop-

erties and exert their effect on acetylcholine release by interfering with calcium ion

fluxes at the nerve terminal, an action similar to magnesium ions. Aminoglycosides