Quinolones: Keys to Reducing the Risk of Interactions

Quinolones are commonlyused to treat a widevariety of infectious diseases,such as community-acquired pneumoniaand urinary tract infections. Somequinolones are also given as prophylaxisfor spontaneous bacterial peritonitis.These popular antimicrobial agents areassociated with several clinically significantdrug interactions, which can beclassified into 2 major categories^1-3:

• Concomitant administration of severaldivalent or trivalent cations--especiallymagnesium,^1-3 aluminum (includingsucralfate),^1-3 and iron^1-3--dramaticallyreduces serum quinoloneconcentrations (Table 1).
• Some quinolones (eg, ciprofloxacinand enoxacin) inhibit the metabolismof certain drugs, including warfarin3and theophylline (Table 2).³

EFFECT OF DIVALENTAND TRIVALENT CATIONSON QUINOLONES

Magnesium-aluminumantacids

. Antacids that contain magnesiumhydroxide and aluminum hydroxideare used frequently in hospitalsand at home. If they are givenclose to the time quinolones are administered,these antacids dramaticallyreduce the serum concentrationsof the antimicrobial agents. The complexesthat form between the quinolonesand the divalent and trivalentcations in the antacids are poorly absorbedfrom the GI tract.

Figure 1

shows the results of astudy in which ciprofloxacin wasgiven concomitantly with an antacid.

⁴

The serum concentrations of ciprofloxacinwere markedly reduced.When ciprofloxacin was given 5 to 10minutes after 30 mL of antacid, thebioavailability of the antimicrobial wasreduced by up to 85%. This interactionis best avoided by administering thequinolone 2 hours

before

the antacid.Remember that some productsmay have "hidden" antacid. For example,didanosine chewable tabletscontain magnesium hydroxide andcalcium carbonate, because didanosineis quite labile in acid. A study ofconcomitant administration of didanosineand ciprofloxacin revealed astriking reduction in ciprofloxacinbioavailability.

⁵

Clinically significant reductionsin serum concentrations of otherquinolones (eg, levofloxacin, gatifloxacin, and moxifloxacin) have alsobeen shown when these agents aregiven concurrently with magnesiumaluminumantacids.

^2,6,7

In addition toantacids, other magnesium products(eg, magnesium citrate or milk ofmagnesia) should also be spaced appropriatelyfrom quinolones.

Sucralfate

. This agent containsaluminum, and it has been welldocumented to dramatically reduceserum quinolone concentrations ifdoses are not appropriately spaced.When ciprofloxacin was givenconcomitantly with sucralfate, peakserum concentrations of ciprofloxacinwere reduced by 90%(

Figure 2

).

⁸

Obviously, such a large magnitudeof reduction in peak serum concentrationmay be associated withtherapeutic failure. In studies with levofloxacin,ofloxacin, and norfloxacin,the interaction was circumvented bygiving the quinolone 2 hours

before

sucralfate.

^9,10

If the quinolone is giventwice daily, maximize the interval betweenthe morning sucralfate doseand the evening quinolone dose (eg,give the quinolone at 6 AM, sucralfateat 8 AM, the quinolone at 6 PM, andsucralfate at 8 PM). If sucralfate cannotbe discontinued until quinolonetherapy is completed, schedule dosesof sucralfate every 12 hours--ratherthan every 6 hours--to increase thetime between doses.

Iron

. Products that containiron, including ferrous sulfate andferrous gluconate, have been shownto decrease serum quinolone concentrations.

¹¹

Although the effect isnot as dramatic as that of magnesiumand aluminum, the reduction inbioavailability is significant.

Figure 3

shows the decrease in serum quinoloneconcentrations associated withconcomitant administration of ciprofloxacin and ferrous sulfate.

¹²

Toavoid this interaction, administer thequinolone 2 hours before oral ironproducts are given.

Calcium

. Dairy products andpharmaceutical products that containcalcium have less impressive effectson the bioavailability of quinolones.For some of the newer quinolones(eg, levofloxacin and gatifloxacin),the effect appears to be negligible.

^2,13

GI absorption of moxifloxacin is notsignificantly reduced by dairy products.

⁷

However, the bioavailability ofciprofloxacin is reduced by up to40%; thus, it is important to give thequinolone 2 hours before any calcium-containing product--includingdairy foods--is ingested.

¹⁴

Zinc

. Studies of multivitaminsthat contained zinc revealed a slightdecrease in the bioavailability ofquinolones (see

Figure 3

).

¹²

Althoughthis reduction in serum antimicrobialconcentrations may notbe clinically significant, administrationof a quinolone 2 hours before azinc-containing product (eg, zinc sulfate,cold lozenges, and multivitamins)does enhance bioavailability.

Enteral feeding

. Because enteralfeeding formulas contain divalentcations, the bioavailability of quinolonesmay be reduced when they areadministered with tube feeding.

¹⁵

Ifthe quinolone requires once-dailydosing, withholding tube feeding for2 hours before and after administrationof the antimicrobial agent is reasonable.If the quinolone is givenevery 12 hours, withholding tubefeeding for 1 hour before and aftermay allow for adequate quinolonebioavailability (withholding feedingfor 2 hours before and after twicedailydosing would mean 8 hours perday without enteral feeding).

QUINOLONE INHIBITIONOF DRUG METABOLISM

Theophylline

. This agent is associatedwith numerous drug interactions(see "Theophylline: Tips for Safeand Effective Use," CONSULTANT,May 2002, page 717). Although somequinolones do not inhibit theophyllinemetabolism, several of these antimicrobialagents--including ciprofloxacin,norfloxacin, and enoxacin--cause serum theophylline concentrations(STCs) to increase.

^16-18

If quinolones that are associatedwith increased STCs must be used becauseof their antimicrobial spectrum,monitor the STC and anticipate thatthe dosage of theophylline may needto be adjusted. Newer quinolones,such as levofloxacin, gatifloxacin, andmoxifloxacin, have no effect or clinicallyunimportant effects on theophyllinemetabolism.

^2,18

Therefore, incertain settings, this interaction canbe circumvented by using a differentquinolone (or an agent in a differentclass of antimicrobials that does notinteract with theophylline).Theophylline and caffeine areboth xanthines, and it has been reportedthat some quinolones increaseserum concentrations of caffeine(see

Table 2

).

¹⁹

Warfarin

. Numerous well-documentedcase reports strongly suggestthat at least some patients will havean increased response to warfarinwhen quinolones are prescribed concurrently.

^3,20-23

Enoxacin decreasesthe elimination of R-warfarin.

²⁴

AlthoughR-warfarin is less active thanS-warfarin (commercially availablewarfarin is a racemic mixture of RandS-warfarin), reduced clearance ofR-warfarin in some patients is sufficientto cause a rise in prothrombintime (PT)/international normalizedratio (INR).A few studies have shown thatquinolones do not increase the responseto warfarin in most patients.

^25,26

However, it is prudent to monitorPT/INR carefully when quinolonesare given with warfarin.

APPROACHES TOMANAGING QUINOLONEDRUG INTERACTIONS

Inpatient setting

. Although theeffects of agents such as antacids onquinolone bioavailability are wellknown,vigilance is still required toavoid interactions. For example, in ourhospital, an automatic note to givequinolones 2 hours before antacids,sucralfate, iron, and other interactingagents was printed on the nurses'medication activity report; however,the note was frequently ignored. Consequently,quinolones were scheduledat 6 AM (or 6 AM and 6 PM)

by default

in the hospital computer system.As a result, the quinolone is administered2 hours before scheduled morningdoses of products that contain interactingcations. For 6 PM doses,proper spacing is ensured by enteringappropriate times for dosing of interactingagents in the computer system.For "prn" doses of antacids and milkof magnesia, education and remindersabout not giving those agents withquinolones are necessary.

Outpatient setting

. Communitypharmacists usually put a label on thequinolone prescription bottle that remindsthe patient to space doses. Further,the patient often receives a medicationinformation sheet. Becausemany patients do not pay attention tothese reminders to avoid taking interactingagents with quinolones, it ishelpful to stress this point when youhand the prescription to the patient.

Tips for minimizing inhibitionof drug metabolism

. Interactions canfrequently be circumvented by use ofa quinolone that has either no effector minimal effect on the metabolismof drugs such as theophylline andwarfarin. Alternatively, an antimicrobialagent from another class can beprescribed. If a quinolone that inhibitsthe metabolism of other drugsmust be used, appropriate monitoring(eg, of the STC or PT/INR) usuallypermits safe, effective therapy.

References:

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