Cyp3a4

Fig. 1. The relative proportions of clinically used drug metabolized by cytochrome P450 enzymes.

Significant interindividual variability exists in the outcomes of drug interactions. This variability is associated with patient-specific factors such as disease state, other concomitant medications, and genetics. Specifically, there is at least 10-fold interindividual variability in CYP450 content, which is most likely due to a combination of clinical factors and genetics. In addition, certain CYP450 enzymes (eg, CYP2D6, CYP2C9, CYP2C19) exhibit clinically important polymorphisms that contribute to ethnic differences in metabolism as well as drug safety and efficacy. Thus, each interaction in each individual patient must be assessed for clinical relevance.

In addition to pharmacokinetic drug interactions, pharmacodynamic drug interactions may occur. Pharmacodynamic drug interactions are associated with a change in efficacy or safety of the object drug, with or without a change in its pharmacokinetics. Examples of this type of interactions include the additive risk for developing nephrotoxicity with the concurrent administration of aminoglycoside antibiotics and other nephrotoxic agents, such as amphotericin B, cisplatin, cyclosporine, or vancomycin.

Antibacterials b-lactams

The b-lactams are the oldest class of antibiotics in clinical use and are delineated as penicillins, cephalosporins, carbapenems, and monobactams [10]. These agents exhibit an excellent safety profile, with the rare exception of epileptogenic activity in populations such as those with renal insufficiency, the elderly, and patients who have a history of seizure disorders [11]. The drug interaction profiles of these agents are typically associated with the inhibition of their secretion and specific pharmacodynamic interactions. In addition, b-lactams can alter the GI flora, leading to alteration of drugs dependent on enterohepatic recirculation. Metabolic inhibition and induction are not common mechanisms by which b-lactams interact with other drugs. A summary of potential drug interactions based on the mechanism of interaction is provided in this section.

Gastric acid suppression

Oral penicillins, such as penicillin V, amoxicillin, ampicillin, and amoxi-cillin/clavulanate, are generally not affected by the use of H2-antagonists or proton pump inhibitors [7,10]. In contrast, oral cephalosporin prodrugs, such as cefpodoxime proxetil, cefuroxime axetil, and cefditoren pivoxil, have reduced bioavailability (30% to 40% reduction in area under the concentration-time curve [AUC]) when coadministered with H2-antagonists [6,7,10]. Concomitant antacid use has also been shown to reduce the exposure of cefaclor, cefdinir, cefpodoxime, and cefditoren by 20% to 40% [5,7,10]. These oral cephalosporins should be separated by at least 2 hours if concomitant use with H2-antagonists or antacids cannot be avoided.

Inhibition of renal tubular secretion

Probenecid inhibits the renal tubular secretion of most b-lactams eliminated by the kidney [7,10]. The AUCs of amoxicillin, ampicillin, ticarcillin, and nafcillin almost double when used with probenecid [7,10]. A similar effect is noted with the use of ceftizoxime, cefoxitin, cefaclor, and cefdinir with probenecid [10]. This effect, however, is minimal with concomitant use of pipera-cillin/tazobactam, ceftazidime, or ceftriaxone and probenecid. The effect on carbapenems is mixed, with minimal interaction noted with use of either imi-penem or ertapenem with probenecid [10]. By contrast, the AUC of merope-nem increases by 55% when it is coadministered with probenecid [7,10]. Achieving higher concentrations of these agents may be beneficial for the management of patients who have meningitis and endocarditis. However, the use of probenecid to boost b-lactam concentrations should be avoided in patients who are elderly, have renal dysfunction, or have a history of seizure disorder [11]. Other agents with the potential to inhibit tubular secretion of b-lactams include methotrexate, aspirin, and indomethacin [10]. The clinical relevance of interactions associated with these agents has not been well characterized.

Pharmacodynamic interactions

The pharmacodynamic interactions associated with b-lactams include synergy or antagonism with combined antimicrobial use and an increased risk for select toxicities. Synergy and antagonism are well-defined laboratory phenomena that have a limited number of clinical correlates. These limited few clinical correlates include the combination of ampicillin with aminogly-cosides for susceptible Enterococcus spp-related endocarditis. The combination of ampicillin and gentamicin for enterococcal endocarditis is associated with fewer relapses compared with ampicillin monotherapy [6,7,10]. Antagonism has been reported with concomitant use of tetracycline and b-lactams in the setting of Streptococcus (S) pneumoniae-related meningitis [12]. Although better agents (than tetracycline) are available for meningitis, the poor response noted with these agents supports the idea that use of bactericidal agents with bacteriostatic agents may result in antagonistic outcomes.

Other noteworthy interactions include an increased risk (threefold higher) for rash with the combined use of allopurinol and amoxicillin or am-picillin. The mechanism of this interaction is not known, although patients who have hyperuricemia are noted to be at higher risk for allergic reactions. An increased risk for seizures is possible with the use of ganciclovir and imi-penem/cilastatin, so concomitant use of these agents is not recommended [4,7]. Similarly, use of imipenem/cilastatin in transplant recipients receiving cyclosporine has been associated with an increased risk for central nervous system toxicity. An increased risk for seizures has also been noted with use of valproic acid and carbapenems. This interaction is associated with a rapid reduction in valproic acid concentrations, so therapeutic drug monitoring and dosage increment of valproic acid should be performed when concomitant use of a carbapenem is necessary [7,13].

Alteration in gastrointestinal flora

Oral estrogens undergo phase II hepatic metabolism to form glucuronide and sulfate conjugates that are excreted in bile. GI flora hydrolyze these conjugates, allowing for reabsorption of estrogens and maintenance of their pharmacologic effect. Consequently, breakthrough bleeding and pregnancies have been reported with use of oral contraceptives and antibiotics [14]. The estimated likelihood of this interaction is rare (approximately 1%), and the recommendation to counsel patients about the potential for oral contraceptive failure remains controversial [14]. Alteration in gut flora that synthesize vitamin K is also thought to be one of the mechanisms by which b-lactams interact with warfarin. Warfarin exerts its anticoagulant effect by inhibiting the synthesis of vitamin K-dependent clotting factors and has a high potential for drug and food interactions [15]. Reducing endogenous vitamin K production can augment the effect of warfarin. In addition, semisynthetic cephalosporins such as cefamandole, cefoperazone, and cefotetan (which contain an N-methylthiotetrazole side chain) can prolong the prothrombin time [6,7,10]. Use of these agents may increase the risk for bleeding in patients who are receiving warfarin, so patients receiving the combination should be monitored for signs and symptoms of bleeding.

Macrolides, azalides, and ketolides

The macrolides (erythromycin and clarithromycin) and ketolides (teli-thromycin), with the exception of the azalides (azithromycin), are associated with numerous drug interactions [16,17]. The most common mechanism for these interactions involves inhibition of the CYP450 system and PGP. Erythromycin inhibits CYP450 noncompetitively by forming iron-nitrosoal-kane complexes, so onset of its potential drug interaction is rapid [18]. In contrast, telithromycin does not form stable CYP-iron-nitrosoalkane complexes but rather competitively inhibits CYP450 isoenzyme systems [18]. Azithromycin also does not form CYP450 complexes and is considered to have the lowest drug interaction potential of this group of agents [18]. The interaction profile is greatest against orally administered CYP3A substrates, because erythromycin, clarithromycin, and telithromycin can inhibit both intestinal and hepatic CYP3A isoenzymes [16-18]. A profile of clinically relevant drug interactions based on CYP450 isoenzyme and other mechanistic systems is provided in this section.

Inhibition of CYP3A4

Increased concentrations of key CYP3A4 substrates can have harmful effects; these substrates include midazolam, cyclosporine, tacrolimus, lovastatin, simvastatin, and calcium channel blockers, to name a few. A twofold to sixfold increase in the AUC of oral midazolam can occur when it is used with erythromycin, clarithromycin, or telithromycin [5-7,16,17].

Benzodiazepines not metabolized by CYP3A4, such as lorazepam or oxaz-epam, should be considered as alternatives, especially in the elderly and those sensitive to the effects of benzodiazepines. A twofold to fivefold increase in serum concentrations of cyclosporine and tacrolimus can occur within 2 days of concomitant clarithromycin or erythromycin use [5-7,16]. Although this interaction has not been characterized with telithromycin, a similar interaction profile is expected. Therapeutic drug monitoring is vital for these immunosuppressants, given that nephrotoxicity has been associated with this interaction.

Similarly, elevation in concentrations of statins, such as lovastatin and simvastatin, and development of rhabdomyolysis secondary to CYP3A4 inhibition have occurred. A fourfold to eightfold increase in the AUC of simvas-tatin occurs when it is coadministered with erythromycin, clarithromycin, or telithromycin [5-7,16,17]. Azithromycin appears to be the safest choice when coadministered with lovastatin or simvastatin [16]. Atorvastatin is less extensively metabolized by CYP3A4; only a 30% increase in AUC is noted when it is administered with erythromycin [5-7,16]. Pravastatin and rovustatin are not metabolized by CYP3A4, and fluvastatin is metabolized by CYP2C9, so these agents are less likely to be affected when used with macrolides and ketolides [17]. Similarly, calcium channel blockers such as nifedipine, felodi-pine, diltiazem, and verapamil have similar interactions with these CYP3A inhibitors [5-7,16,18]. Patients should be monitored for hypotension, tachycardia, edema, flushing, and dizziness when using calcium channel blockers with erythromycin, clarithromycin, or telithromycin.

Inhibition of CYP3A4 by erythromycin and clarithromycin can lead to fatal drug interactions. The primary causes of these fatalities include QTc prolongation, leading to torsades de pointes and death. Erythromycin can directly increase the QTc interval and also increase concentrations of antiar-rhythmics such as quinidine, ibulitide, sotalol, dofetilide, amiodarone, and bretylium, to name a few. Tricyclic antidepressants such as amitryptilline and antipsychotic agents such as haloperidol, respiridone, and quetapine can all become elevated and augment the risk for development of torsades de pointes. Key agents, such as cisapride, terfenadine, and astemizole, have been removed from the United States market because of this adverse event. Furthermore, use of CYP3A4 inhibitors such as diltiazem, verapamil, and itraconazole can increase the risk for sudden cardiac death fivefold in patients receiving erythromycin [19]. Similarly, elevation of other CYP3A4 substrates can have serious consequences: priapism (sildenafil), disorientation (clozapine), neutropenia (vinblastine), delirium (fluoxetine), and uveitis (rifabutin) are prime examples [16,20]. The inordinate number of substrates metabolized through the CYP3A4 isoenzyme system requires that one perform a thorough review of potential drug interactions when choosing to use erythromycin, clarithromycin, or telithromycin. Alternative agents should be considered before use of erythromycin in patients who are receiving concomitant CYP3A4 inhibitors [19].

Inhibition of CYP2C9, CYP2C19

Both CYP2C9 and CYP2C19 are encoded by genes associated with significant polymorphisms [18]. Consequently, the pharmacokinetics of drugs metabolized through these enzyme systems exhibits significant population-based variability. Key substrates of these isoenzyme systems include warfarin, phenytoin, and sulfonylureas. Bruising, hematuria, and a rise in the prothrombin time are associated with the use of erythromycin and warfarin [5-7,16]. The potential for this interaction is considerably reduced with the combination of warfarin and clarithromycin or telithromycin [5-7,16,17]. A 10% to 20% increase in the AUC of warfarin is noted when used with telithromycin [17]. Despite this low potential, patients should be advised of the signs and symptoms of hypoprothrombinemia when using the agents together. Therapeutic drug monitoring of phenytoin and counseling of patients on recognizing signs and symptoms of hypogly-cemia (with sulfonylureas) are necessary safety measures with concomitant use of macrolides.

Inhibition of CYP1A2

Theophylline is a key CYP1A2 substrate associated with significant car-diotoxicity when coadministered with erythromycin [5-7,16]. The reported consequences have ranged from GI adverse events to more serious effects such as ventricular fibrillation [16,18]. In contrast, a modest elevation (20%) in theophylline concentrations may be expected when used with clar-ithromycin or telithromycin [6,7,16,17]. Consequently, the significance of this interaction may be more relevant for patients who are maintained on the upper end of the therapeutic range. Caffeine, a methylxanthine like the-ophylline, is also metabolized by CYP1A2, and increased jitteriness may be noted in some patients who use macrolides and ketolides.

Inhibition of P-glycoprotein

Erythromycin and clarithromycin are also PGP inhibitors [8]. Digoxin is primarily eliminated by the kidneys as unchanged drug by means of PGPmediated tubular secretion. The combination of digoxin with erythromycin or clarithromycin has resulted in increased oral bioavailability, decreased renal clearance, and increased serum concentrations of digoxin [5-7,21]. Di-goxin toxicity has developed in patients simultaneously treated with these macrolides. A recent drug-drug interaction study identified that hospital admissions due to digoxin toxicity were 13 times more likely to occur in elderly patients who had received clarithromycin therapy within the past week [22]. Patients receiving digoxin and macrolide therapy, alone or in combination, should have their renal function monitored and digoxin dosage regimens adjusted based on lean body weight, creatinine clearance estimation, and serum drug concentrations.

The oral bioavailability, metabolism, and excretion of colchicine are altered by clarithromycin and erythromycin [5-7]. The most likely mechanisms of this interaction are macrolide-mediated inhibition of PGP and CY3A4. In a retrospective study of 116 patients, death occurred in nine (10.2%) of the 88 patients who received concurrent colchicine and clarithromycin therapy, compared with one (3.6%) of the 28 patients who received the two agents sequentially [23]. The independent variables associated with death among the 88 patients who had concomitant therapy included the duration of overlapping therapy, renal impairment, and the development of pancytopenia. Extreme caution must be exercised when inhibitors of PGP and CY3A4 are used with colchicine.

Alteration in gastrointestinal flora

The potential drug interaction of oral contraceptive agents with macro-lides, azalides, and ketolides is minimal [7,14]. Telithromycin, for example, has not been shown to affect the antiovulatory effects of ethinyl estradiol and levonorgestrel [17]. Pregnancy as a consequence of oral contraceptive failure has not been causally linked to a macrolide, azalide, or ketolide [14]. Conversely, inhibition of Eubacterium lentum (normal gut flora) by these agents is the proposed mechanism by which elevated digoxin concentrations are noted to occur in patients managed with macrolides [24]. Approximately 10% of patients who receive digoxin have significant gut metabolism of digoxin performed by E lentium [16]. Consequently, elevated digoxin concentrations may be noted with concomitant use of the macro-lides and ketolides, as well as of azithromycin.

Fluoroquinolones

Fluoroquinolones are used routinely in outpatients, given their excellent oral bioavailability and safety profile. The oral bioavailability of fluoroqui-nolones such as ciprofloxacin, levofloxacin, ofloxacin, norfloxacin, gatiflox-acin, moxifloxacin, and gemifloxacin can be significantly reduced by cations [5-7,25]. The degree of this interaction is dependent on the cation in question and the relative timing of oral administration. in general, multivalent cations, such as aluminum, magnesium, iron, and zinc, have been noted to have more serious interactions than does calcium [5-7,25]. These interactions are clinically relevant, given that fluoroquinolones have concentration-dependent pharmacodynamics, implying that reductions in maxi-mium concentration (Cmax) and AUC values can lead to therapeutic failure [25]. The recommended administration schemes for fluoroquinolones and cation-containing products, such as antacids and supplements, have been based on the manufacturer-dependent study designs. Patient populations with delayed gastric emptying time, such as those who have cystic fi-brosis, may require additional studies to assess the optimal separation time of fluoroquinolones and cations [26]. Fluoroquinolones have also been associated with fatalities secondary to hypoglycemia in patients receiving medications to manage diabetes [25]. Fluoroquinolones can cause a drug- and dose-dependent prolongation of the QTc interval by inhibiting outward flow of potassium in myocytes. The relative potency for inhibiting these channels (human ether-a-go-go-related gene, HERG) in animal models is as follows: moxifloxacin equals gatifloxacin, which is greater than levofloxacin, which equals gemifloxacin and ciprofloxacin, which are greater than ofloxacin [25]. As a general rule, patients who have a history of QTc prolongation or uncorrected electrolyte abnormalities or those receiving antiarrhythmic agents may be at higher risk for developing torsade de pointes. Use of fluoroquinolones in these patient groups should be closely monitored. Other interactions with fluoroquinolones are minimal, with the exception of those with ciprofloxacin and norfloxacin, which can inhibit CYP1A2 [25]. The specific drug interaction profile for each individual systemic fluoroquinolone is provided as follows.

Ciprofloxacin

Chelation-related drug interactions have been evaluated with concomitant use of ciprofloxacin and iron glucanoate, iron sulfate, magnesium/ aluminum-containing antacids, sucralafate, zinc, calcium carbonate, calcium acetate, bismuth subsalicylate, and sevelamer. Simultaneous administration of iron, magnesium, aluminum, and zinc can result in 50% to 90% reduction in both the Cmax and AUC of oral ciprofloxacin [5-7,25]. In contrast, a 30% to 40% reduction in Cmax and AUC can occur with coadministration of ciprofloxacin and calcium or sevelamer [6,25]. Bismuth interacts minimally (10% reduction in AUC) with ciprofloxacin [25]. Coadministration of these agents 2 hours prior to or 6 hours after the administration of ciprofloxacin reduces this interaction and is the manufacturer-recommended approach [26].

Hypoglycemia requiring urgent management with use of ciprofloxacin in a previously stable patient receiving glyburide has been reported [6,7,25]. To date, the mechanism for this interaction has not been elucidated but does not appear to be pharmacokinetic.

An increase (of approximately 30%) in theophylline concentrations has been reported with use of concomitant ciprofloxacin, leading to symptoms of theophylline toxicity [5-7]. Therapeutic drug monitoring and a dosage reduction in theophylline may be necessary when using ciprofloxacin in these patients. Other CYP1A2 substrates, such as tizanadine, have been noted to exhibit a 10-fold increase in AUC and resultant hypotensive effects in healthy volunteers receiving concomitant ciprofloxacin [5,27].

Levofloxacin/ofloxacin

Levofloxacin and ofloxacin have been studied against a similar range of cations [25]. Simultaneous administration of these agents with iron, magnesium, and aluminum compounds results in a 20% to 40% reduction in the Cmax and AUC of levofloxacin [5-7,25]. The interaction of levofloxacin with calcium-containing compounds is also considerably lower compared with ciprofloxacin (10% to 20% reduction in AUC). Administration of levoflox-acin 2 hours before or 2 hours after these multivalent cation-containing products is recommended to limit this interaction [28]. The risk for hypoglycemia with use of levofloxacin in patients receiving antidiabetic medications is lower than with gatifloxacin. Ofloxacin does not significantly alter the clearance of theophylline [25].

Norfloxacin

Norfloxacin appears to have a greater potential to interact with cations compared with ciprofloxacin. Combined use of norfloxacin with sucralfate, magnesium/aluminum antacids, and iron sulfate results in a greater than 90% reduction in AUC values [5-7,25]. A 60% reduction in exposure is noted with concomitant use of calcium carbonate. Even administration of sucralfate 2 hours before norfloxacin results in a 40% reduction in norflox-acin exposure [5-7,25]. The manufacturer-recommended schedule is to space metal cations and norfloxacin by at least 2 hours. However, use of alternative agents, such as H2-antagonists (eg, famotidine) or proton pump inhibitors (eg, omeprazole) may be prudent, given the likelihood of a sustained interaction. Theophylline toxicity has been reported in patients receiving norfloxa-cin therapy, so patients should be monitored for this interaction [5-7].

Gatifloxacin

Gatifloxacin has a similar metal chelate interaction profile to that of levofloxacin during simultaneous administration of these agents. However, the manufacturer-recommended dosing sequence is to administer gatifloxa-cin 4 hours before the administration of these cation-containing medications [29]. No alteration in the metabolic disposition of concomitantly used medications has been reported with the use of gatifloxacin [29].

The vast majority of reports of fluoroquinolone-associated alteration in glucose homeostasis involve use of gatifloxacin [25]. These have included cases where release of insulin and a resultant drop in glucose concentrations were noted during initiation of therapy. Elderly patients, patients with renal impairment, and patients who are on concomitant glucose-altering medications are at an increased risk for this adverse event [29]. Two population-based case-control studies from Canada [30] and data reported to the FDA indicate that gatifloxacin is most commonly associated with drug interactions leading to dysglycemia [25]. A ''Dear Health care Professional" letter was issued on February 15, 2006 concerning labeling changes to the product package insert of gatifloxacin. The update included additions to the existing warning section on hypoglycemia and hyperglycemia and a contraindication to the use of gatifloxacin in diabetic patients.

Moxifloxacin

Moxifloxacin also has a similar cation-interaction profile to levofloxacin and is minimally affected by coadministration with calcium-containing agents. However, the manufacturer recommends administering moxifloxa-cin 4 hours before or 8 hours after these cation-containing agents [31]. The potential for alteration in glucose homeostasis exists with the use of moxifloxacin as well [25]. Moxifloxacin is unique among fluoroquinolones in that it has minimal renal elimination and is almost entirely removed in feces as sulfate and glucuronide conjugates [31]. Despite this disposition profile, it does not alter the CYP system and is not associated with this category of drug interactions.

Gemifloxacin

Gemifloxacin is available as an oral product only and has been studied against calcium carbonate, iron sulfate, magnesium- and aluminum-containing antacids, and sucralfate. These studies indicate that these cations should not be taken within a period 3 hours before or 2 hours after the dose of gemifloxacin [6,7,25]. The exception is sucralfate: administration of this agent 3 hours prior resulted in a 50% reduction in the gemifloxacin AUC [25]. However, administration of sucralfate 2 hours after gemifloxacin only resulted in a 10% reduction in AUC. Consequently, the manufacturer recommended the 3-hour before or 2-hour after use of cations with gemifloxacin, with the exception of sucralfate, which should be administered 2 hours after gem-ifloxacin [32]. The specific risk for gemifloxacin alteration of glucose homeo-stasis is not known, but no specific cases have been reported in the literature to date. Gemifloxacin is not known to alter the clearance of other concom-itantly used medications.

Aminoglycosides

The parenteral aminoglycosides (eg, gentamicin, tobramycin, amikacin) have remained important antibacterial agents for the treatment of serious gram-negative infections. These agents are excreted almost completely by the kidneys, primarily by glomerular filtration. The significant adverse events associated with aminoglycoside therapy are nephrotoxicity, ototoxicity, and neuromuscular blockade. As a result, the drug interaction profile for these agents is usually an additive or synergistic risk for these major toxicities.

Numerous reports have documented the increased risk for developing nephrotoxicity with the concurrent administration of aminoglycosides and amphotericin B, cisplatin, cyclosporine, vancomycin, or indomethacin (in neonates with patent ductus arteriosus) [5-7,33-35]. The mechanism appears to be either direct or additive injury to the renal tubule. Patients receiving aminoglycoside therapy should have their renal function monitored and dosage regimens adjusted based on body weight, creatinine clearance estimation, or serum drug concentrations. In addition, aminogly-cosides should be avoided or used with caution with the aforementioned agents, as well as with other known nephrotoxic agents, such as foscarnet, intravenous pentamidine, cidofovir, polymyxin B, and colistin.

An increased risk for ototoxicity has been reported with the coadministration of aminoglycosides and loop diuretics [5-7,33]. Ethacrynic acid has been reported to cause hearing loss when administered alone and in conjunction with aminoglycosides such as kanamycin and streptomycin. Furo-semide has also been identified as an additive risk factor for the increased rates of nephrotoxicity and ototoxicity with aminoglycosides. Ethacrynic acid, furosemide, urea, and mannitol should be used cautiously at the lowest possible doses in patients receiving concurrent aminoglycoside therapy.

Aminoglycosides may potentiate the effects of neuromuscular blocking agents [5-7,33]. Concurrent administration of these agents has been associated with prolonged respiratory depression and weakness of skeletal muscles. patients who have myasthenia gravis or severe hypocalcemia or hypomagnesium are particularly susceptible to these adverse effects. The interaction may occur when an aminoglycoside is administered either before or after a neuromuscular blocking agent. patients should be monitored for prolonged signs of respiratory depression and paralysis during the perioperative and postoperative periods.

Aminoglycosides and b-lactam agents are commonly used in combination for additive or synergistic activity in the treatment of disease caused by grampositive and gram-negative pathogens [5-7,33]. However, concomitant use of extended-spectrum penicillins (eg, piperacillin, ticarcillin) may produce in vivo inactivation of the aminoglycoside in patients who have severe renal impairment. Administration times of the aminoglycoside should be adjusted to the end of the penicillin dosing interval, and monitoring of aminoglycoside serum concentrations may be warranted in this clinical situation.

Vancomycin

Vancomycin is a glycopeptide antibacterial that has been available since its discovery in 1956. Despite its long history, there are few reported drug interactions of vancomycin with other therapeutic agents. The most notable drug-drug interaction of vancomycin is the potentially increased incidence of nephrotoxicity with the concurrent administration of aminoglycoside antibiotics [5-7,33-35]. The estimated incidence of vancomycin-induced nephrotoxicity is 5% to 7% when it is used alone and 0% to 35% when it is used concurrently with an aminoglycoside. Data from toxicology animal studies provide evidence that vancomycin alone has mild nephrotoxic potential and that concomitant administration of vancomycin and aminoglycosides results in a significant increase in nephrotoxicity over that of either agent alone. A similar trend toward increased nephrotoxicity in patients with the combined use of vancomycin and an aminoglycoside has been observed in numerous studies. However, not all studies have been able to demonstrate a clear association between increased risk for nephrotoxicity and combination therapy. patients receiving vancomycin and aminoglycoside therapy, alone or in combination, should have their renal function monitored and dosage regimens adjusted based on body weight, creatinine clearance estimation, or serum drug concentrations. Clinicians should attempt to avoid other conditions (hypotension, intravenous contrast media) and risk factors (eg, cumulative doses, other nephrotoxic drugs) that increase the risk for developing nephrotoxicity.

Other drug interactions have included case reports of the possible inactiva-tion of vancomycin by heparin when administered through the same intravenous line, decreased clearance of high-dose methotrexate following recent vancomycin administration, and depression of neuromuscular function after concurrent vecuronium therapy [5-7,33]. Finally, altered disposition (eg, clearance decreased and elimination half-life and apparent volume of distribution increased) of vancomycin has been reported in six neonates who had patent ductus arteriosus and were treated with indomethacin therapy [5,7,33].

Vancomycin may bind to anion-exchange resins such as colestyramine [7].

Daptomycin

Daptomycin is a cyclic lipopeptide that is renally excreted and is not hep-atically metabolized. Metabolic drug interactions are unlikely, because in vitro studies have shown that daptomycin neither induces nor inhibits CYP isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 [36]. In rats, dap-tomycin decreased aminoglycoside-induced nephrotoxicity when both agents were coadministered. In healthy subjects, a single dose of daptomycin 2 mg/kg, tobramycin 1 mg/kg, or the combination was not associated with a significant change in pharmacokinetic parameters or nephrotoxicity [33,36]. Because both daptomycin and hydroxymethyglutaryl-coenzyme A (HMG-CoA) reductase inhibitors may increase creatinine phosphokinase concentrations or cause rhabdomyolysis, the manufacturer recommends that HMG-CoA reductase inhibitors and other drugs associated with rhab-domyolysis be temporarily discontinued during daptomycin therapy [36].

Linezolid

Linezolid is a novel synthetic antibacterial agent from the oxazolidinone class. The drug interaction profile of this antibiotic class is typically associated with the inhibition of monoamine oxidase (MAO), which results in an increase in serotonin concentrations and the development of the serotonin syndrome [7,33]. Metabolic inhibition is an unlikely mechanism for drug interactions, because in vitro studies have demonstrated that linezolid is not metabolized and does not have activity to inhibit common human CYP iso-forms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A4). In addition, studies in rats suggest that linezolid is not an inducer of CYP isoforms [37].

Several case reports have been published regarding the temporal drug interaction relationship between linezolid and selective serotonin reuptake inhibitors such as sertraline, paroxetine, citalopram, and fluoxetine [6,7,33]. In addition, a few case reports have suggested the serotonin noradrenergic reuptake inhibitor venlafaxine [6,7]. Clinicians need to be aware of the possible risk, and, whenever possible, alternative agents should be prescribed. Management of the serotonin syndrome involves discontinuation of the offending agent or agents and, when necessary, administration of the antiserotonin agent cyproheptadine to relieve symptoms.

The reversible MAO inhibitor activity of linezolid also has the potential for drug interactions involving over-the-counter (OTC) cough and cold preparations that contain adrenergic agents such as pseudoephedrine and phenyl-propanolamine [7,33]. A controlled clinical study in healthy subjects demonstrated that significant increases in systolic blood pressure (ie, mean maximum increase from baseline: 32 mm Hg and 38 mm Hg) were observed after the coadministration of linezolid and either pseudoephedrine or phenylpropanolamine [38]. No symptoms of serotonin syndrome or changes in blood pressure, heart rate, or temperature were observed when dextromethor-phan (a known serotonin reuptake inhibitor) was coadministered with linezolid. patients need to be counseled regarding their choice of OTC products and given precautionary information regarding the coadministration of linezolid and products containing pseudoephedrine or phenylpropanolamine.

Quinupristin-dalfopristin

Quinupristin-dalfopristin is a streptogramin antibacterial that is administered intravenously in a fixed 30:70 ratio. Quinupristin-dalfopristin is non-enzymatically metabolized and is primarily excreted in the feces and urine. Although they are not metabolized by CYP or glutathione-transferase enzymes, in vitro studies confirm that quinupristin and dalfopristin are significant inhibitors of CYP 3A4 metabolism of cyclosporine, midazolam, nifedipine, docetaxol, tamoxifen, and terfenadine [5,7,39]. Quinupristin-dalfopristin does not affect other common human CYP isoforms (1A2, 2A6, 2C9, 2C19, 2D6, or 2E1) [39]. In pharmacokinetic studies conducted in healthy subjects, quinupristin-dalfopristin increased the plasma concentrations (AUC and Cmax, respectively) of cyclosporine (63% and 30%), nifedipine (44% and 18%), and midazolam (33% and 14%) [5,39]. A case report also documented a threefold increase in cyclosporine concentrations in a renal transplant patient [7]. Coadministration of quinupristin-dalfopris-tin with drugs that are well-known substrates of CYP 3A4 can result in a pharmacokinetic interaction that markedly increases their plasma drug concentrations. Agents with a narrow therapeutic index should be either avoided or administered with caution, plus close monitoring for adverse effects. Plasma drug concentrations should be carefully monitored for agents such as cyclosporine or tacrolimus and the dose adjusted accordingly.

Tetracyclines

The commonly used agents in the tetracycline class (eg, tetracycline, mino-cycline, doxycycline) differ in their major routes ofelimination. Tetracycline is excreted almost completely by the kidneys, primarily by glomerular filtration. Minocycline is metabolized by the liver, and approximately 10% is excreted in the kidney. Doxycycline is mainly eliminated in the feces, with the remaining 20% to 30% eliminated in the urine by glomerular filtration.

Most drug interactions of tetracyclines are pharmacokinetic and reflect changes in absorption and elimination of this drug class or other agents (Table 2). The plasma concentrations of tetracyclines are markedly reduced (30% to 90%) with the concurrent administration of products containing divalent and trivalent cations, such as aluminium, magnesium, calcium, iron, or zinc [5-7,33]. The potential mechanisms associated with this interaction include chelation, decreased dissolution, and binding to the antacid. This interaction has been reported to occur with the intravenous administration of doxycycline. Common products containing multivalent cations include antacids, laxatives, antidiarrheals, multivitamins, sucralfate, didanosine tablets or powder, molindone, and quinapril tablets. In addition, other products known to decrease the bioavailability of tetracyclines include colestipol, kaolin-pectin, activated charcoal, and sodium bicarbonate [5-7,33]. When a tetracycline is used with one of these products, the administration of each agent should be staggered by at least 2 hours to minimize the impact of this interaction.

As with the b-lactams discussed earlier in this article, drug-drug interactions have been reported between tetracyclines and warfarin, digoxin, and oral contraceptives [5-7,14,33]. In addition, tetracyclines may increase plasma concentrations of theophyllline, although studies have been inconsistent [6,7,33]. Although these interactions do not occur in all patients, it remains best to monitor for their occurrence and, in selected circumstances, consider alternative therapy or additional precautions (eg, other methods of contraception).

Tetracycline may potentiate the toxicities of lithium, methrotrexate, me-thoxyflurane, and ergotamine tartrate [5-7,33]. The combination therapy with retinoids (eg, acitretin, isotretinoin) is not recommended because of the additive effects of pseudotumor cerebri (benign intracranial hypertension) [6,7]. The combination of tetracycline and atovaquone should be avoided, because the plasma concentrations of atovaquone were decreased by approximately 40% [7]. In contrast, a twofold increase in plasma concentrations of quinine has been observed when concomitant tetracycline was administered in patients being treated for Plasmodium falciparum malaria. Barbiturates, phenytoin, carbamazepine, rifampin, and chronic ingestion of ethanol can decrease the elimination half-life and plasma concentrations of doxycycline but do not appear to affect the pharmacokinetics of other tet-racycline products [6,7,33].

Tigecycline

Tigecycline, a semisynthetic derivative of minocycline, is the first agent from the glycylcycline class of antibiotics. The primary routes of tigecycline

Table 2

Drug-drug interactions involving tetracyclines

Table 2

Drug-drug interactions involving tetracyclines

Interacting drug

Effects

Management recommendations

Antacids

Decreased tetracycline

Space administration by at least 2 hours.

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