P&T News: April 1997

Levofloxacin to Become UIHC's Pri mary Flurorquinolone Antimicrobial

Douglas E. Morgan, M.S., R.Ph. Clinical Pharmacist, Pharmacotherapy Evaluation and Consultation Service, Department of Pharmaceutical Care
Peer Review Status: Bradley E. Britigan, M.D ., Professor and Director, Infectious Diseases Division, Department of Internal Medicine and Ronald N. Jones, M.D., Professor and Director, Medical Microbiology Division, Department of Pathology

a) Levofloxacin demonstrates comparable or superior in vitro antibacterial activity;

b) Levofloxacin demonstrates generally equivalent clinical utility;

c) Levofloxacin can be dosed once daily (versus BID dosing for ofloxacin); and

d) At therapeutically equivalent doses, levofloxacin is less xpensi ve than ofloxacin.

Antibacterial Spectrum of Activity
The fluoroquinolones have a wide spectrum of activity against both Gram-positive and Gram-negative pathogens.7 They are bactericidal against most bacteria at a concentration appro ximately twice that of the minimum inhibitory concentration (MIC).2 3 Levofloxacin is the l-isomer of ofloxacin. Tables 1 and 2 illustrate typical activity of ofloxacin and levofloxacin against commonly encountered pathogens.2-4 The breakpoint for susc eptibility to levofloxacin is an MIC 2 or less mcg/ml, while organisms with an MIC 8 or more than mcg/ml are considered resistant.2,3 These breakpoints are identical to those defined for ofloxacin.

Levofloxacin demonstrates modestly improved ( two-fold) in vitro activity against most Gram-positive aerobic bacteria, when compared to ofloxacin.2-4 Levofloxacin resistance is encountered for methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, and multi-resistant enterococci. 2,3 Based on in vitro susceptibility data, levofloxacin is likely to be no more efficacious than ofloxacin for vancomycin- susceptible enterococci, and is unlikely to be active against ciprofloxacin-resistant enterococci.2 Levofloxacin activity against Gram-negative aerobic organisms is up to four-fold greater than ofloxacin for many pathogens.2,3 In general, the in vitro MICs fall well under the levofloxacin resistance breakpoint of 8 mcg/ml for most Gram-negative pathoge ns except Pseudomonas species.3,4 Pseudomonas aeruginosa continues to demonstrate growing resistance to fluoroquinolones.2

Table 1. Activity of Fluoroquinolones Against Gram-positive Pathogens2-4

Organism	MIC90 (mcg/ml)
	Levofloxacin	Ofloxacin
Staphylococcus aureus (MR)	8	16
Staphylococcus aureus (MS)	0.5	1
Coagulase-negative staphylococci (MR)	8	16
Coagulase-negative staphylococci (MS)	0.25	1
Streptococcus pneumoniae (penicillin-resistant)	2	2
Streptococcus, group A or B < /TD>	0.5	1
Viridans streptococci (penicillin-resistant)	2	2
Enterococcus faecalis ("standard")	2	4
Enterococ cus faecalis (HLGR)	32	64
Enterococcus faecium (HLGR, ampicillin-resistant)	16	32
Abbreviations: MIC90 = minimum inhibitory concentration for 90% of tested isolates, HLGR = high level gentamicin resistance, MR = methicillin-resistant, MS = methicillin-susceptible.

Table 2. Activity of Fluoroquinolones Against Gram-negative Pathogens2-4

Organism	MIC90 (mcg/ml)
	Levofloxacin	Ofloxacin
Neisseria gonorrhoeae	0.015	0.06
Escherichia coli	0.06	0.12
Haemophilus influenzae	0.015	0.06
Klebsiella pneumoniae	0.25	0.5
Proteus mirabilis	0.25	0.5
Enterobacter cloacae	0.12	0.25
Citrobacter species	0.12	0.25
Serratia marcescens	0.5	1.0
Salmonella species	0.12	0.12
Pseudomonas aeruginosa	8	8
Pseudomonas cepacia	2	4
Xanthomonas maltophilia	2	4
Abbreviations: MIC90 = Minimum inhibitory concentration for 90% of tested isolates.

Pharmacokinetic Properties
Levofloxacin oral absorption approaches 100%.4 In contrast to some quinolones whose absorption is reduced with simultaneous administration of milk or cheeses, food does not alter the extent of oral absorption and there are no contraindications to taking levofloxacin with dairy products.4 Unless the g astrointestinal tract is not functioning, oral levofloxacin is preferred over IV levofloxacin, since serum levels are comparable and oral therapy is more convenient and far less costly.

Like ofloxacin, levofloxacin is renally cleared, with 80 to 90% of a dose excreted unchanged in the urine.1,4 As a result, dose modification is required in moderate to severe renal dysfunction (CrCI less than 50 ml/min). As with other fluoroquinolones, levofloxacin is not removed to any significant extent by hemodialysis or peritoneal dialysis; this is due in large part to its wide-spread distribution to a variety of tissues, with an effective volume of distribution of approximately 1.25 L/kg.4 There is little enterohepatic recycling of IV or oral doses of l evofloxacin.4

Urinary concentrations are quite high and may exceed the MIC of some urinary pathogens (e.g., E. coli) for as long as three days following a single dose. Fluoroquinolones have excellent penetration into almost all tissues and body fluids, including lung tissue, gallbladder tissue and bile, bone, and prostate tissue.1 As a class, fluoroquinolones do not cross the blood-brain barrier with consistency.1 Penetration into cerebral spinal fluid (CSF) may vary widely (e.g., 15 to 90 % of serum concentrations).1,4,5 Levofloxacin was reported to have limited CSF penetration in a single study.5 Accordingly, levofloxacin, like other fluoroquinolones, should not be used to treat meningitis.1 Human macrophages and neutrophils accumulate fl uoroquinolones to intracellular levels ten-fold greater than serum concentrations, possibly explaining efficacy against some intracellular pathogens (e.g., Brucella, Legionella, Mycobacteria, and Salmonella).1 Table 3 summarizes pharmacokine tic parameters for levofloxacin and ofloxacin.

Table 3. Pharmacokinetic Properties of Fluoroquinolones1,4,7-9

Quinolone	Dose (mg)	Oral Absorption (% of dose)	Cmax (mcg/ml)	Cmin (mcg/ml)	Breakpoint for Susceptibility	Breakpoint for Resistance
Ofloxacin	400 PO	80 to 95%	5.5	2.0	2 or less than mcg/ml	8 or more mcg/ml	5.0	73%
	400 IV	---	7.0	2.0			4.9
Levofloxacin	500 PO	more than 95%	5.7	0.8 (est)	2 or less th an mcg/ml	8 or more mcg/ml	7.6	80%
	500 IV	---	6.4	0.8 (est)			7.0
Cmax = Maximum steady-state serum concentration for ofloxacin (q 12 hrs) or levofloxacin (q 24 hrs) at stated dose. Cmin = Minimum steady-state serum concentration (trough) for ofloxacin (q 12 hrs) or levofloxacin (q 24 hrs) at stated dose.

Clinical Applications
Due to increasing microbial resistance associated with indiscriminate fluoroquinolone use, more narrow spectrum antimicrobials should be used whenever possible. In addition, non-quinolone antimicrobials are often far less expensive.

FDA-labeled indications for levofloxacin include: acute bacterial exacerbations of chronic bronchitis, community- acquired pneumonia, skin and skin -structure infections, complicated urinary tract infections and pyelonephritis, and acute maxillary sinusitis caused by susceptible organisms.7

Levofloxacin may be useful in community-acquired pneumonia or acute bacterial exacerbations of chronic bronchitis, as an alternative to cefotaxime or ceftriaxone in hospitalized patients, and as an alternative to oral erythromycin, azithromycin, clarithromycin, or selected oral cephalosporins in ambulatory settings.10,11 Highly resistant S. pneumoniae may respond to levofloxacin.7

Fluoroquinolones, including levofloxacin, are generally inappropriate for initial use in uncomplicated urinary tract infections (UTIs), which respond well to a three-day course of trimethoprim-sulfamethoxazole (TMP -SMX).1 However, their use may be appropriate for patients with recurrent UTIs, for UTIs caused by resistant pathogens, or for patients with an intolerance to TMP-SMX or cephalosporins.1 Fluoroquinolones may also be useful for complicated UTIs caused by P seudomonas aeruginosa or other multi-resistant bacteria.12

The role of levofloxacin in sexually-transmitted diseases (STDs) has not been specifically addressed by the Centers for Disease Control.13 Unlike ofloxacin, levofloxacin is not yet FDA-lab eled for use in gonococcal or nongonococcal urethritis or cervicitis,9 although clinical data support levofloxacin efficacy.4 Ceftriaxone continues to be a first-line choice for gonococcal infections, while doxycycline or azithromycin is first-line therap y for chlamydial cervicitis.13 Doxycycline or erythromycin is the recommended regimen for nongonococcal urethritis.13

Prescribing criteria for intravenous levofloxacin are unchanged from those used previously for ofloxacin therapy and include:

1. Serious gram-negative infection with organisms documented to be resistant to aminoglycosides, third or fourth generation cephalosporins, and extended-spectrum penicillins.

2. Serious gram-negative infection in which there is an intolerance and/or a contraindication to aminoglycosides, third or fourth generation cephalosporins, and extended-spectrum penicillins.

Adverse Reactions
Fluoroquinolones are well tolerated and typically are not associa ted with life-threatening adverse reactions.1,4 Table 4 summarizes the more common adverse reactions encountered with fluoroquinolones.1,17 Levofloxacin, like other fluoroquinolones, is not recommended for use in children due to concerns of arthropathy fo und in animal studies.18 Levofloxacin and other fluoroquinolones are classified by the FDA as Pregnancy Category C.19 Tendonitis and tendon rupture are adverse events detected through post-marketing surveillance of fluoroquinolone use.18 While these event s are infrequent, they carry important morbidity.17, 18

Table 4. Adverse Reactions Associated with Fluoroquinolones13

Adverse Reaction	All Fluoroquinolones	Ofloxacin	Levofloxacin
Gastrointestinal Toxicity (diarrhea, nausea)	0.5 to 11%	2.6%	0.5 to 1.8%
Central Nervous System Toxicity (irritability, insomnia, drowsiness, dizziness)	0.3% to 9%	0.89%	0.3 to 0.5%
Rashes/Skin Toxicity (all types)	0.2 to%	0.53%	0.3 to 0.5%
Phototoxicity or Photosen sitivity	0.01 to 7.9%	less than 0.1% (estimate)	less than 0.1% (estimate)
< P>All Adverse Effects	1.3 to 32% a	2.6 to 4.27%	0.2 to 1.3%
aIncludes adverse reactions associated with fluroroquinolones not currently marketed in the U.S., but does not include adverse reaction rates found with temafloxacin, a fluoroquinolone recently withdrawn from the U.S. market due to fatal adverse events.

Drug Interactions
Drug-drug interactions between levofloxacin and other medications are described in Table 5. Extrapolations from ofloxacin drug-drug int eraction reports suggest limited drug-drug interaction risks directly attributed to an impact on Cytochrome P450 enzyme pathways, since both drugs are characterized by very little hepatic metabolism. Inadequate data are present to fully elucidate the risk s associated with levofloxacin drug-drug interactions, and it is likely that post-marking surveillance may play an important role in this area.

Table 5. Drug Interactions with Levofloxacin and Ofloxacin1,4

Interacting Drugs	Mechanism of Drug Interaction Effect	Magnitude of Drug Interaction Effect	Recommendation to Minimize Effect
Antacids containing aluminum or magnesium	Chelation with cation prevents absorption	Bioavailability decr eases 19 to 44% Peak levels decreases 35 to 60%	Separate doses by 2 to 4 hrs Use calcium-based antacids
Sucralfate (contains al uminum)	Chelation reduces absorption	Assumed similar to aluminum-based antacids	Separate doses by 2 to 4 hrs. Consider alternative GI med.
Iron or zinc containing products or supplements	Chelation reduces absorption	Bioavailability reduced19%	Separate doses by 2 to 4 hrs.
Theophylline/caffeine	Inhibition of metabolism? Seizure risk increases, possibly additive stimulant effect?	Lit tle effect in volunteer studies (less than 11% increases in Cmax)	Monitor for toxicity; if increases HR, H/A, N/V, consider theophylline level.
Warfarin	Potentiation of anticoagulant effect, mechanism unclear	Potentially life-threatening	Monitor PT/INR and follow for signs of bleeding
< P>Urinary alkalinizers (e.g., NaHCO3, citrates)	Alkaline urine enhances risk of crystalluria	Unclear, possible risk of obstructive nephropathy	Ensure liberal fluid intake. Monitor for hematuria and crystalluria.
GI = gastrointestinal, HR = heart rate, H/A = headache, N/V = nausea and/or vomiting, PT = Prothrombin Time, INR = International Normalized Ratio, NaHCO3 = sodium bicarbonate.

Dosing of Levofloxacin
In contrast to other currently marketed fluoroquinolones, levofloxacin is labeled for once daily dosing (see Table 6).8 Once daily dosing is supported by levofloxacin s long half-life (typically 6 to 7 hours),8 a potentially significant postantibiotic effect against both Gram-negative and Gram-positive pathogens,20 and efficacy demonstrated with once daily dosing in clinical trials.7 The dose requires modification for substantial renal impairment (see Table 6).7

Table 6. Levofloxacin Dosing in Renal Impairment8

Routine Dosing (CrCl 50 o r more ml/min)	Dose Reduction for Impaired Renal Function
	(CrCl: 20 to 49 ml/min)	(CrCl: 19 or less than ml/min)
500 mg q 24 hoursa	500 mg, then 250 mg q 24 hours	500 mg, then 250 mg q 48 hours
250 mg q 24 hoursb	No Change	250 mg q 48 hours
a Dose for infections not involving the u rinary tract (e.g., pneumonia, sinusitis, skin infections). b FDA-labeled dose for complicated urinary tract infections or pyelonephritis.

Conversion of Ofloxacin to Levofloxacin at UIHC
Levofloxacin (oral or IV) doses are 250 mg q 24 hours for 10 days for complicated urinary tract infections and pyelonephritis, and 500 mg q 24 hours for 7 to 14 days for all other indications. Table 7 outlines the doses for conversion of ofloxacin to levofloxacin.

Table 7. Conversion of Floxacin to Levofloxacin

Ofloxacin Dose	Equivalent Levofloxa cin Dose
200 mg PO q 12 hrs	250 mg PO q 24 hrs
300 mg PO q 12 hrs	500 mg PO q 24 hrs
400 mg PO q 12 hrs	500 mg PO q 24 hrs
200 mg IV q 12 hrs	250 mg IV q 24 hrs
400 mg IV q 12 hrs	500 mg IV q 24 hrs
a UIHC drug acquisition costs

Summary
Levofloxacin IV is available as a pro tocol antibiotic; ofloxacin IV will no longer be available at UIHC. Oral levofloxacin has replaced oral ofloxacin as the primary oral fluoroquinolone; it is not restricted by protocol and does not require completion of a protocol drug order form. Oral ofloxacin will be deleted from the UIHC formulary on May 15, 1997.

Levofloxacin offers a modest improvement in antimicrobial activity over ofloxacin. The once daily dosing regimen enhances convenience and has a favorable impact on hospital resour ces. Drug costs are reduced by using levofloxacin rather than ofloxacin. The drug has exceptional bioavailability, and the use of oral therapy whenever possible will offer additional cost savings and convenience, as well as reducing the risks of bacter emia associated with the use of IV lines. Adverse reactions associated with levofloxacin are similar to those found with other fluoroquinolones, although the frequency may be lower with levofloxacin. Drug drug interaction risks are similar to those fo und with ofloxacin.

References

1. Infect Dis Clin North Am 1995; 9:715-30.

2. Diagn Microbiol Infect Dis 1996; 25:3541.

3. Antimicrob Agents Chemother 1992; 36:860-6.

4. Drugs 1994; 47:677- 700.

5. Chemotherapy (Tokyo) 1992; 40:469-73.

6. Rev Infect Dis 1989; 11:S979-84.

7. Ortho Pharmaceutical/McNeil Pharmaceutical. Levaquin Tablets/Injection package inserts. Raritan NJ. 1996 December.

8. Bayer Pharmaceutical. Cipro l.V. and Cipro Tablets package inserts. West Haven, CT 1996 March, 1995 February.

9. McNeil Pharmaceutical. Floxin I.V. and Floxin Tablets package inserts. Raritan, NJ. 1994 June, 1994 April.

10. Med Lett Drug Ther 1996; 38:25-34.

11. Med Lett Drug Ther 1997; 39:31-3.

12. Pharmacotherapy 1993; 13(2 Pt 2):39S-44S.

13. MMWR 1993; 42(RR-14):1-102.

14. Drugs 1995; 49 (Suppl 2):144-51.

15. Clin Infect Dis 1995; 20(Suppl 1):S47-65.

16. Drugs 1995; 49(Suppl. 2):100-11.

17. Drug Safety 1995; 13:343-58.

18. Drug Safety 1995; 13:338-42.

19. Infect Dis Clin North Am 1995; 9:639-51.

20. Diagn Microbiol Infect Dis 1994; 18:57-9.

PHARMACY AND THERAPEUTICS SUBCOMMITTEE ACTIONS

DRUGS ADDED TO STOCK
ATORVASTATIN Tablets: 10 mg, 20 mg, 40 mg Atorvastatin (Lipitor[R] - Parke-Davis) is an HMG-CoA reductase inhibitor indicated as adjunctt o diet for the treatment of primary hypercholesterolemia and mixed dyslipidemia. Note: The prescribing of atorvastatin is restricted to attending clinical faculty physicians.

BRIMONIDINE Ophthalmic Solution: 0.2% Brimonidine (Alphagan[R] - Allerga n) is indicated for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

GLIMEPIRIDE Tablets: 1 mg, 2 mg, 4 mg Glimepiride (Amaryl - HMR) is an oral sulfonylurea indicated as an adjunct to diet and exercise to lower blood glucose in patients with type II diabetes, and for use in combination with insulin in patients with type II diabetes.

INDINAVIR Capsules: 200 mg, 400 mg Indinavir (Crixivan[R] - Merck) is an inhibitor of HIV protease indicated for the treatment of H V infection when antiretroviral activity is warranted.

LEVOFLOXACIN Tablets: 250 mg, 500 mg Injection: 250 mg, 500 mg Levofloxacin (Levaquin[R] - Ortho-McNeil) is a quinolone antibiotic. Note: Levofloxacin injection has been design ated a protocol drug.

NELFINAVIR Tablets: 250 mg Oral Powder: 50 mg per scoop Nelfinavir (Viracept[R] - Agouron) is an inhibitor of HIV protease indicated for the treatment of HIV infection.

TOPIRAMATE Tablets: 25 mg, 100 mg, 200 mg Topir amate (Topamax[R] - Ortho-McNeil) is an antiepileptic agent indicated for the adjunctive treatment of partial onset seizures in adults.

TROGLITAZONE Tablets: 200 mg, 400 mg Troglitazone (Rezulin[R] - Parke-Davis) is an oral antihyperglycemic agent which is indicated for use in patients with type II diabetes whose hyperglycemia is inadequately controlled on insulin therapy. Note: The prescribing of triglitazone is restricted to prescribing by the Division of Endocrinology.

NEW DOSAGE FOR MS ADDED TO STOCK
MICONAZOLE 2% POWDER Indicated for the treatment of superficial fungal infections of the skin.

ONDANSETRON 4 mg per 5 ml ORAL SOLUTION This product provides an easier to swallow dosage form for pediatric patients and adu lt patients with difficulty swallowing.Note: Protocol drug; see criteria for use of ondansetron in the Formulary and Handbook.

ITRACONAZOLE 10 mg per ml ORAL SOLUTION The oral solution is indicated for the treatment of oropharyngeal and sophagealc andidiasis.Note: Itraconazole oral solution has a 60% greater bioavailability than the oral capsules; therefore, it should not be used interchangeably with the oral capsules.

DRUGS DELETED FROM STOCK
APRACLONIDINE OPHTHALMIC SOLUTION D iscontinued due to the availability of brimonidine ophthalmic solution.

CHLORPROPAMIDE TABLETS Discontinued due to low use and the availability of glipizide, glyburide, and glimepiride:

METAPROTERENOL ORAL SOLUTION (ALUPENT[R]) Discontinue d due to low use. Metaproterenol tablets are available.

NYSTATIN TOPICAL POWDER Discontinued due to the availability of miconazole powder.

OFLOXACIN (FLOXIN[R]) - Discontinued due to the availability of levofloxacin.

SULFAPYRIDINE Discontinued due to low use. Alternative sulfonamide antibiotics are available.

TOLBUTAMIDE TABLETS Discontinued due to low use. Glipizide, glyburide and glimepiride are available.

TOLAZAMIDE TABLETS Discontinued due to low use. Glipizide, glyburide and glimepiride are available.

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