Nicholas AuPharm.D. Candidate 2009

Excellent safety and tolerability Popular alternative to penicillin allergic

patients Ciprofloxacin and Levofloxacin were listed

in the top 200 drugs by sales in 2007◦ www.pharmacytimes.com

Inhibit topoisomerase II (DNA Gyrase) and IV, an enzyme needed in bacterial DNA replication

Bactericidal, concentration-dependent killing

Blondeau JM. 2004. Surv Ophthalmol. 2004

2nd generation: good gram (-) coverage◦ Infections of the urinary tract, bone and joint,

skin, sinus, etc.

Substrate of: SLC22A8, SLCO1A2, ABCG2, UGT1A1, ABCC1, ABCB1 (P-gp)

Inhibitor of: CYP1A2, CYP3A4, SLC22A8

3nd generation: Both gram (-) and gram (+) coverage as well as atypical pathogens◦ Very similar indications to ciprofloxacin, but also

covers community acquired pneumonia

Substrate of: SLCO1A2, SLC22A2, ABCB1

Inhibitor of: SLC22A2, SLC22A4

Ciprofloxacin listed 36 different drug interactions

Levofloxacin listed 11 drug interactions 12 new interactions were added to the

GenMedRx database with these drugs found from PubMed, Stockley’s, and BNF◦ Ciprofloxacin: levothyroxine, duloxetine, zolmitriptan◦ Levofloxacin: cimetidine, lithium, amiodarone◦ Fluoroquinolones: antidiabetics, NSAIDs, probenecid,

magnesium containing drugs, sucrafate, didanosine

Mechanism Drug

CYP1A2 inhibition

caffeine, clozapine, mexiletine, olanzapine, R-warfarin, rasagiline,

ropinirole, ropivacaine, theophylline, tizanidine, duloxetine, zolmitriptan

CYP3A4 inhibition cyclophosphamide, sildenafil, glyburide, cyclosporine

Inhibition of organic ion transporters

methotrexate, probenecid, procainamide, cimetidine

Reduced enterohepatic recycling

Ethinyl estradiol

Lack of interaction Diazepam, ethanol

Unknown isoniazid

Mechanism Drug

Induction of ABCB1 (P-gp) Doxorubicin, rifampin

Inhibition of organic ion transporters

Probenecid

Unknown Methadone, morphine, omeprazole, foscarnet

Mechanism Drug

Inhibition of organic ion transporters

cimetidine, procainamide

Lack of interaction digoxin, oxycodone, theophylline, AZT

Unknown Cyclosporine, tacrolimus

Mechanism Drug

Inhibition of organic ion transporters

cimetidine

A clinical study showed that cimetidine decreased the renal clearance and increased the half-life of levofloxacin in the body.  However, the interaction was not clinically significant and does not warrant a dose adjustment of levofloxacin

Fish DN, Chow AT. Clin Pharmacokient. 1997.

Mechanism Drug

Complexation of drug to fluoroquinolone

antacids, iron salts, calcium salts, magnesium salts, zinc oxide, didanosine

Disruption of normal gut flora warfarin

Unknown Antidiabetics, NSAIDs, probenecid

Online program that predicts the outcomes of the drug-drug interaction even when clinical data is lacking

Computes a score that determines % change in AUC of the victim drug when accounting for factors such as metabolic pathways, inhibitor strength (Ki), level of induction, and the strength of evidence in the literature (if any)

Point Score Change Reported (AUC)

More than -100 -90-100%

-50 to -100 -60-90%

-25 to -50 -25-60%

0 to -24 0 to -25%

0 to +24 0 to +25%

+25 to +50 +25-75%

+50 to +100 75-150%

More than 100 Over 150%

Victim / Culprit Substr. ofInhibitor

Ki (Points)Inducer(Points)

PathSize

ChangePoints

clozapine / ciprofloxacin

CYP1A2 2 (50)   0.25 12.5

clozapine / ciprofloxacin

CYP3A4 3 (50)   0.25 12.5

cyclophosphamide / ciprofloxacin

CYP3A4 3 (50)   0.2 10

Cipro / probenecid Glucuronidation 3 (50)   0.38 19

theophylline / levofloxacin

CYP3A4 3 (50)   0.2 10

digoxin / levofloxacin CYP3A4 3 (50)   0.08 4

Many drugs involved in an interaction with ciprofloxacin or levofloxacin were not fully calculated by the algorithm because the metabolic pathways involved were minor, but still generally predicted the AUC change in the correct direction (increase or decrease)

Thanks to:◦ Jessica Oesterheld for her guidance through

GenMedRx◦ Kristine Ashcraft and Don Rule for answering

questions when needed◦ Bob Patterson in fixing the editor program◦ Howard Coleman for establishing this clerkship

Pharmacy Times. Top 200 prescription drugs of 2007. May 2008. Accessed 28 January 2009. http://www.pharmacytimes.com/issues/articles/2008-05_003.asp

Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokient. 1997;32(2):101-19

Andriole VT. The quinolones: past, present, and future. Clin Infect Dis. 2005;15;41 Suppl 2:S113-9.

Alvarez AI, Pérez M, Prieto JG, Molina AJ, Real R, Merino G. Fluoroquinolone efflux mediated by ABC transporters. J Pharm Sci. 2008;97(9):3483-93

Blondeau JM. Fluoroquinolones: mechanism of action, classification, and development of resistance. Surv Ophthalmol. 2004;49 Suppl 2:S73-8.

Wikipedia. Ciprofloxacin. 2008. 20 January 2009 <http://en.wikipedia.org/wiki/Ciprofloxacin>.

Wikipedia. Levofloxacin. 2008. 20 January 2009 <http://en.wikipedia.org/wiki/Ciprofloxacin>.

British National Formulary. Ciprofloxacin Interactions. 2008. 20 January 2009. <http://www.medicinescomplete.com/mc/bnf/current/41001i195.htm>

British National Formulary. Levofloxacin Interactions. 2008. 20 January 2009. <http://www.medicinescomplete.com/mc/bnf/current/41001i840.htm>

FDA. Ciprofloxacin. 2008. 20 January 2008 <http://www.fda.gov/cder/foi/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf

FDA. Levofloxacin. 2008. 20 January 2008 <http://www.fda.gov/cder/foi/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf