Drug Interactions in Infectious Diseases || Quinolones

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  • 277S.C. Piscitelli et al. (eds.), Drug Interactions in Infectious Diseases, Infectious Disease,DOI 10.1007/978-1-61779-213-7_9, Springer Science+Business Media, LLC 2011

    Abstract Fluoroquinolone (FQ) antimicrobials are among the most commonly used agents in the outpatient and institutional patient care environments. Due to this high frequency of utilization, the potential for deleterious drug-drug interactions with non-antimicrobials is also high. The majority of interactions with the FQs involve deleteri-ous effects on the FQ component. These are also the most clinically-important interactions with these agents. Multivalent cations such as Mg2+, Ca2+, Fe2+, Zn2+, Al3+, and other minerals as well as drugs such as sucralfate, lanthanum, sevelamer, and didanosine (the cation-supplemented version of the latter) can substantially reduce FQ bioavailability, leading the subtherapeutic drug concentrations at the infection site and clinical failure. Separation of dose administrations may or may not reduce the magnitude of these interactions. Ciprofloxacin, norfloxacin, and two experimental FQs in clinical trials (pazufloxacin and prulifloxacin) act as moderate cytochrome P450 enzyme inhibitors and may increase serum concentrations of theophylline and caffeine. Warfarin pharmacodynamics are variably affected by the FQs. The pharma-codynamic interactions between NSAIDs and FQs are only relevant if fenbufen is used concurrently with enoxacin or, possibly, prulifloxacin. Caution is warranted if sparfloxacin or moxifloxacin is used concurrently with other medications prolonging the QTc interval or if patients have other risk factors for prolongation of the QTc interval (e.g. abnormal QTc interval pre-treatment, electrolyte abnormalities, use of starvation-liquid diets, or history of heart disease). Fluoroquinolone antimicrobials can be used effectively and safely in the vast majority of patients if the clinician remembers those few drug-drug interactions that are clinically-important.

    D.R.P. Guay (*)Department of Experimental & Clinical Pharmacology, College of Pharmacy,University of Minnesota, Weaver-Densford Hall 7-148, 308 Harvard Street SE, Minneapolis, MN 55455, USA

    HealthPartners Geriatrics, HealthPartners Inc., Minneapolis, MN, USAe-mail: guayx001@umn.edu

    Chapter 9Quinolones

    David R.P. Guay

  • 278 D.R.P. Guay

    9.1 Introduction

    Drug-drug interactions can be categorized into those originating from pharmacokinetic mechanisms and those originating from pharmacodynamic mechanisms. Pharma-cokinetic interactions are those that result in alterations of drug absorption, distribu-tion, metabolism and elimination; pharmacodynamic interactions occur when one drug affects the actions of another drug. This chapter deals only with the pharma-cokinetic and pharmacodynamic interactions of fluoroquinolones (hereafter referred to as quinolones) with non-antimicrobial agents. Additive, synergistic or antagonistic antimicrobial activity interactions between quinolones and other antimicrobials are not discussed.

    Some drug interactions can be predicted from the chemical structure of the agent, its pharmacologic activity, its toxicologic profile, and other characteristics determined in its premarketing evaluation. Other interactions cannot be prospectively predicted and can only be detected through intense, large-scale clinical studies or postmarket-ing surveillance. The quinolones exhibit drug-drug interactions of both types.

    There are a number of problems in the prospective clinical evaluation of drug-drug interactions in humans. First, there may be ethical concerns when administer-ing interacting drug combinations to patients or volunteers, depending on the potential consequences of the interaction. Second, because there are an endless number of drug combinations, doses, and timings of administration that could be investigated, it is economically impossible to fund the study of all possibilities. Third, the prospective evaluation of an interaction in a manageable number of patients is unlikely to uncover a rare interaction. Finally, studies that are carried out in normal volunteers and demonstrate a pharmacokinetic interaction, such as slightly decreased absorption of a drug, may be of uncertain clinical relevance.

    Despite these obstacles, delineating the frequencies and types of pharmacokinetic interactions of the quinolones with other drugs is important for several reasons. Since quinolones are often administered orally, absorptive interactions may compro-mise the efficacy of antimicrobial therapy. Due to their breadth of activity, agents of this class find substantial use in the critically ill and elderly, many of whom receive potentially interacting medications [14]. Because the elderly have an increased sensitivity to drug-induced toxicity and experience more adverse drug reactions, they may also exhibit an increased incidence and severity of drug-drug interactions. Finally, the quinolones are such a structurally diverse group that the extrapolation of drug-drug interactions from one to another of these agents may not be appropriate.

    9.2 Pharmacokinetic Interactions

    9.2.1 Absorption Interactions

    The deleterious effect of multivalent cations on the oral bioavailability of quinolones was first reported in 1985 [5]. Since this pivotal report, numerous investigations have duplicated and extended this observation; these are detailed in Table 9.1 [570].

  • 2799 Quinolones

    Table 9.1 Effects of multivalent cations on quinolone absorption

    Quinolone Cation/preparation/schedule

    Mean % change in Cmax

    Mean % change in AUC Reference

    Flerox Al OH/0.5,12,24,36 h post-quinolone

    24a 17 [6]

    Levoflox Al OH/simultaneous with quinolone

    65a 44a [7]

    Norflox Al OH/simultaneous with quinolone

    86a,b [8]

    Norflox Al OH/simultaneous with quinolone

    28c 29c [9]

    Oflox Al OH/simultaneous with quinolone

    29a 19 [10]

    Pruli Al OH/1 h prequinolone 93a,d 85a,d [11]Pruli Al OH/3 h prequinolone 40a,d 35a,d [11]

    Al OH/2 h prequinolone 36d 46d

    Al OH/1 h postquinolone +6d 13d

    Al OH/2 h postquinolone 10d 18d

    Tosu Al OH/simultaneous with quinolone 41a 37a [12]Tosu Al OH/simultaneous with quinolone 41a 32a [13]Oflox Al phos/simultaneous

    with quinolone10 3 [14]

    Oflox Al phos/simultaneous with quinolone 7 [8]Norflox Bi subsalicylate/simultaneous

    with quinolone 10b [7]

    Cipro Bi subsalicylate/simultaneous with quinolone

    13 13 [15]

    Cipro Ca carb/simultaneous with quinolone 38a 41a [16]Cipro Ca carb antacid/simultaneous

    with quinolone47a 42a [17]

    Cipro Ca carb antacid/with meals (PO4 binder)

    +13 [18]

    Cipro Ca carb/2 h pre-quinolone +22a 0 [19]Cipro Ca carb/simultaneous with quinolone 29a,b [20]Cipro Ca carb/(TID 11 doses) 2 h

    after dose 1024a 14 [21]

    Gati Ca carb/simultaneous with quinolone 7 8 [22]2 h pre-quinolone 13 82 h post-quinolone +2 0

    Levoflox Ca carb/simultaneous with quinolone 23 3 [7]Levoflox Ca carb/spaced 2 h prequinolone 9 +16 [18]

    and 2 h postquinolone 19a,e 3e

    Lomeflox Ca carb/simultaneous with quinolone 14a 2 [23]Moxi Ca carb/simultaneous with quinolone 15a 2 [24]

    +12 and 24 h post-quinoloneGemi Ca carb/simultaneous with quinolone 21a 17a [25]

    2 h pre-quinolone 11 102 h post-quinolone 0 7

    (continued)

  • 280 D.R.P. Guay

    Table 9.1 (continued)

    Quinolone Cation/preparation/schedule

    Mean % change in Cmax

    Mean % change in AUC Reference

    Norflox Ca carb/simultaneous with quinolone 28c 47a,c [9]Norflox Ca carb antacid/simultaneous

    with quinolone66a 63a [26]

    Norflox Ca carb antacid/simultaneous with quinolone

    66 62 [25]

    Oflox Ca carb/simultaneous with quinolone 0b [20]Oflox Ca carb/simultaneous with quinolone 18 +10 [10]Oflox Ca carb antacid/ [27]

    2 h pre-quinolone +3 424 h pre-quinolone +9 42 h post-quinolone +3 3

    Pruli Ca carb/1 h prequinolone 60a,d 55a,d [11]Tosu Ca carb/simultaneous with quinolone 47a 42a [12]Cipro Ca acetate/simultaneous with quinolone 50a 51a [28]Cipro Ca polycarbophil 1,200 mg

    (5.0 mmol Ca)/[29]

    simultaneous with quinolone 64a 52a

    Cipro Ca-fortified orange juice/ [30]simultaneous with quinolone 41a 38a

    Gati Ca-fortified orange juice/ [31]simultaneous with quinolone 14 12a

    Levo Ca-fortified orange juice/ 23a 14a [32]Ca-fortified orange juice + milk/ 24a 16a

    (both simultaneous with ready- to-eat cereal and quinolone)

    Moxi Ca lact gluc + carb/ [24]immed. before and 12 + 24 h

    after quinolone15a 2

    Cipro Didanosine (+ cations)/3 doses [33](dose 3 simultaneous with quinolone) 93a 98a

    Cipro Didanosine (+ cations)/6 doses [34](quinolone 2 h pre-didanosine) 16 26a

    Cipro Didanosine (cations)/ [35]simultaneous with quinolone 8 9

    Tosu Fe cit/simultaneous with quinolone 31a 16a [12]Cipro Fe gluc/600 mg simultaneous

    with quinolone57a 64a [28]

    Cipro FeSO4/300 mg simultaneous

    with quinolone33a 42a [36]

    Cipro FeSO4/325 mg tid 7 days 75a 63a [37]

    Cipro FeSO4/simultaneous with quinolone 54a 57a [38]

    Gati FeSO4/simultaneous with quinolone 52 28 [39]

    (continued)

  • 2819 Quinolones

    Quinolone Cation/preparation/schedule

    Mean % change in Cmax

    Mean % change in AUC Reference

    Gati FeSO4/simultaneous with quinolone 54a 35a [22]

    2 h pre-quinolone 12 102 h post-quinolone 3 5

    Levoflox FeSO4/simultaneous with quinolone 45a 19a [7]

    Lomeflox FeSO4/simultaneous with quinolone 28a 14 [23]

    Moxi FeSO4/simultaneous with quinolone 59a 39a [40]

    Norflox FeSO4/simultaneous with quinolone 75a 73a [38]

    Norflox FeSO4/simultaneous with quinolone 97a,c 97a,c [