Theophylline with quinolones

Carbapenems (imipenem more than meropenem) are believed to increase central nervous system excitation by inhibition of GABA binding to receptors. Combinations with other GABA-inhibiting drugs, such as theophylline or quinolones, have been reported to provoke seizures (59,60). 

The quinolones have been found to cause erosion of cartilage in the joints of immature animals [56]. This observation, which has been seen in several studies, has resulted in the contraindication of quinolones for the treatment of children. A study analyzing the risk-benefit situation for the use of pefloxacin in children (clinically, several adverse athralgic effects have been attributed to this agent) has appeared [57]. The underlying mechanism responsible for these effects has yet to be established, and the development of an agent which is safe for paediatric use would be a major advance in quinolone therapy. Some of the quinolones, such as enoxacin, have been shown to interfere with theophylline metabolism [58], and side-effects associated with this agent may be related to this property. 

In summary, the adverse effects associated with the quinolones appear presently to be mild to moderate in severity and reversible upon discontinuation of therapy. Severe systemic adverse reactions are rare [62], It is suggested that the use of these agents should be avoided, as far as possible, in children and pregnant women and that caution be used in their administration to patients with a seizure disorder or those taking theophylline or warfarin [62]. Articles suggesting the appropriate clinical usage for these important antibacterials have appeared [64],... 

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

The quinolones are contraindicated in patients with a history of hypersensitivity to any drug in this family. Absorption of the fluoroquinolones is reduced by antacids, iron, and zinc salts, and thus they should not be taken concurrently. Oral ciprofloxacin and enoxacin inhibit the metabolism of theophylline, and toxicity can occur when these two drugs are administered concurrently. Oral administration of the fluoroquinolones can cause convulsions and should therefore be done with caution in patients with central nervous system disorders. These drugs are not recommended for systemic administration in children, adolescents younger than age 18 years, or pregnant women. Topical administration is contraindicated for use in patients younger than 1 year of age. 

Appropriate dose reductions and serum concentration monitoring should be performed if theophylline is concomitantly used with interacting quinolones. 

Other quinolones vary in the extent to which they inhibit CYP1A2 (see Theophylline + Quinolones , p.ll92), so that any interaction with other quinolones would be expected to reflect this variation. 

Gaffuri-Riva V, Crippa F, Guf nti EE. Theophylline interacticn with new quinolones and macrolides in COPD patients. AmRevRespirDis (1991) 143, A498. 

Staib AH, Harder S, Fuhr U, Wack C. Interaction of quinolones with the theophylline metabolism in man investigations with lomefloxadn and pipemidic acid. IntJ Clin Pharmacol Ther Toxicol 27, 289-93. 

Segev S,RehaviM, Rubinstein E. Quinolones, theophylline, and diclofenac interactions with die Y-aminobutyric acid receptor. Antimicrob Agents Chemother 9ZZ) 32,1624-6. 

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