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Levofloxacin (LevaquinŇ): A New Formulary Addition for Community-Acquired Pneumonia
Sean Gorman, Pharm.D. Student, Manjoyt Randhawa, Pharm.D. Student (Reviewed by the members of the Antibiotic Use Subcommittee (G Stiver, PJ Jewesson, B Bowie, E Bryce, A Chow, F Marra, T Nevill)

August 2000 Drug & Therapeutics Newsletter
(C) 2000, CSU-Pharmaceutical Sciences
Vancouver Hospital & Health Sciences Centre

New Canadian Treatment Guidelines for Treatment of Community Acquired Pneumonia (CAP)

New Canadian guidelines for the treatment of CAP have been drafted by a Canadian CAP Working Group and are expected to be published shortly.1 These guidelines represent an update of previously published recommendations2 and reflect new information regarding the best management of this common, yet serious infection.3 As described by the Working Group, these guidelines were derived by the consensus of experts and were not entirely based on evidence from randomized clinical trials. In the creation of the new guidelines, the group considered new mortality risk prediction data, criteria for hospital admission and discharge, and the development of critical pathways for CAP management. Also considered was the need to re-evaluate the choice of empiric first-line agents as a result of changing susceptibility patterns, the availability of newer fluoroquinolones and macrolides, the need to simplify dosing regimens and promote IV-PO sequential therapy, and finally the concern for the development of resistance and toxicity associated with the newer agents.1

Adult patients with CAP may be treated as outpatients, in the nursing home setting or they may require acute care hospitalization. Most patients with CAP who do not require hospitalization may be treated with a macrolide (eg. erythromycin, clarithromycin or azithromycin) or doxycycline to cover for pneumococci and atypical organisms including C. pneumoniae and M. pneumonia. Those patients with chronic obstructive lung disease or macroaspiration should receive a newer macrolide to increase coverage for H. influenzae.

Patients with CAP who require hospitalization can be further categorized into those who can be managed on a general medical unit versus those who require support on an intensive care unit.1 Empiric treatment for general medical unit patients should be aimed at bacteremic pneumococcal pneumonia and therapy should be sufficiently broad to also cover for possible infection with H. influenzae, enteric gram-negative bacilli and Chlamydia or Legionella spp.. Monotherapy with a “respiratory” fluoroquinolone (i.e. a fluoroquinolone such as levofloxacin with good activity against gram-positive cocci, gram-negative bacilli and atypical pathogens), or combination therapy involving a 2nd or 3rd generation cephalosporin plus a macrolide is recommended.1

Patients admitted to an intensive care unit with CAP not known or suspected to involve P. aeruginosa should initially receive combination broad spectrum therapy with a macrolide or a respiratory fluoroquinolone plus a non-pseudomonal 3rd-generation cephalosporin or a beta-lactam/beta-lactamase inhibitor. If P. aeruginosa is suspected, combination therapy with an anti-pseudomonal fluoroquinolone (ie. ciprofloxacin) plus an anti-pseudomonal beta-lactam or an aminoglycoside is recommended. Alternatively, triple therapy with an anti-pseudomonal beta-lactam plus an aminoglycoside plus a macrolide can be considered.1

Whenever possible, initial therapy should be modified to narrower spectrum antibiotics with activity against the identified pathogens. Treatment is generally continued for 7-14 days and IV-PO stepdown therapy should be considered as soon as clinically feasible to facilitate discharge from hospital, reduce costs and improve the patient’s quality of life.

In consideration of the publication of the Canadian guidelines, the VHHSC Antibiotic Use Subcommittee (AUS) considered the addition of a respiratory fluoroquinolone at VHHSC. Levofloxacin was considered an acceptable choice over other available respiratory fluoroquinolones (e.g. trovofloxacin, grepafloxacin) based upon its safety record and the published evidence supporting its use in CAP. The AUS was not convinced that there was a need to relax the current restrictions for clarithromycin use (currently restricted for use in H. pylori--associated peptic ulcer disease and Mycobacterium avium complex infections) nor to add azithromycin to the formulary. Erythromycin and doxycycline are currently on formulary. Doxycycline was considered by the AUS to be a suitable alternative to newer macrolides for outpatient therapy and as an alternative oral antibiotic for patients who cannot tolerate oral erythromycin.

Effective immediately, levofloxacin has been added to the hospital formulary as a reserved antimicrobial drug (RAD). This fluoroquinolone is restricted for use in the management of acute lower respiratory tract infections.

Review of Levofloxacin

Levofloxacin, the l-isomer of ofloxacin, is the first “respiratory” fluoroquinolone to be released in Canada. Compared with the older fluoroquinolones, levofloxacin has enhanced in vitro activity against gram-positive bacteria (including Streptococcus pneumoniae) as well as possessing good activity against atypical pathogens and gram-negative bacilli.

Pharmacokinetics

Levofloxacin demonstrates excellent oral bioavailability (>95%) that is not significantly affected by co-administration with food.4 As with other fluoroquinolones, co-administration with aluminum- and magnesium-containing antacids and ferrous sulfate results in significantly decreased levofloxacin absorption.5 These agents should be administered at least 2 hours before or after levofloxacin administration.

Because the oral absorption of levofloxacin is close to 99%, plasma concentration versus time profiles after either oral or intravenous administration of 500mg are similar. Therefore, both routes of administration can be considered interchangeable in patients with normally functioning gastrointestinal tracts. Maximum serum concentrations (Cmax) achieved with a single levofloxacin 500mg oral dose (5.19mg/L) are considerably higher than those achieved with ciprofloxacin 750mg (3.4mg/L) or ofloxacin 400mg (4.0mg/L).6 Minimum plasma concentrations (Cmin) after repeated oral administration of 500mg once a day are approximately 0.5mg/L.7

Levofloxacin penetrates well into most body tissues and fluids including sputum, achieving concentrations that are generally higher than those in plasma.8 The elimination half-life of levofloxacin (6-8 hours) is comparable to ciprofloxacin and ofloxacin, however the drug is marketed for once daily dosing due to its ability to achieve a high Cmax.7 Levofloxacin is primarily eliminated (~80%) in the urine as unchanged drug. Patients with reduced renal function (i.e. creatinine clearance < 50mL/min) should receive reduced daily doses.5 Neither hemodialysis nor CAPD significantly remove levofloxacin.9 Unlike ciprofloxacin, levofloxacin appears to have only a minor effect on the disposition of theophylline, warfarin, zidovudine, digoxin or cyclosporin. However, patients receiving these drugs concomitantly should be closely monitored for signs of enhanced pharmacological effect or toxicity.

Spectrum of Activity

Gram-positive organisms: When compared to ciprofloxacin, levofloxacin demonstrates enhanced in vitro activity against methicillin-susceptible S. aureus and some strains of methicillin-resistant S. aureus (MRSA).10,11 Levofloxacin is also active against most strains of methicillin-susceptible coagulase-negative staphylococci and is similar in activity to ofloxacin and ciprofloxacin for S. epidermidis.12 However, its use clinically for the treatment of MRSA and coagulase negative staphylococci infections has not been established. The in vitro activity of levofloxacin against streptococci is slightly greater than ofloxacin and ciprofloxacin.7 This agent is active against S. pneumoniae and the MIC90 (1-2mg/L) are similar for strains that are susceptible, intermediate and resistant to penicillin.11,12 Levofloxacin also retains activity against multi-resistant strains of S. pneumoniae, including those that are resistant to third-generation cephalosporins.11,12 Like other fluoroquinolones, levofloxacin has only modest activity against Enterococcus faecalis and Enterococcus faecium. Enterococcal strains that are ampicillin and vancomycin resistant (VanA or Van B) are frequently resistant to levofloxacin.11,12

Gram-negative organisms: Similar to other fluoroquinolones, levofloxacin has excellent in vitro activity against b-lactamase positive and negative Haemophilus influenzae and Moraxella catarrhalis.13 Levofloxacin has excellent in vitro activity against most enterobacteriaceae and other enteric pathogens, however, its activity tends to be less than that exhibited by ciprofloxacin.14-16 Levofloxacin has comparable activity to ciprofloxacin against Serratia marcescens and Providencia rettgeri.14,15 The agent has only moderate in vitro activity against P. aeruginosa and this activity is significantly less than that of ciprofloxacin.17 Most strains of S. maltophilia and B. cepacia are resistant to levofloxacin and the other currently available fluoroquinolones.18

Anaerobic and Other Pathogens: Similar to ciprofloxacin, levofloxacin does not appear to possess clinically useful in vitro activity against B. fragilis, C. perfringens, and Peptostreptococcus.12,14,19 Levofloxacin appears to have improved in vitro activity compared to ciprofloxacin and ofloxacin against L. pneumophilia, M. pneumoniae and C. pneumoniae.20,21 Like ciprofloxacin, levofloxacin is also active against M. tuberculosis however it has diminished activity compared to ciprofloxacin against M. avium complex.22,23 Levofloxacin also possesses good in vitro activity against most genital pathogens including N.gonorrhoeae, C. trachomatis, G. vaginalis and U. urealyticum.24

Clinical Studies in CAP

There are two comparative clinical trials evaluating the efficacy of levofloxacin in patients with CAP.25,26 Both studies were of open-label design and involved comparisons with variable regimens of ceftriaxone or cefuroxime (with or without erythromycin or doxycycline).

File et al evaluated 590 adults with CAP in an open-label study comparing levofloxacin with 2nd and 3rd generation cephalosporins.25 Patients were randomly assigned to receive levofloxacin 500mg daily IV or orally versus ceftriaxone 1g or 2g IV once or twice daily or cefuroxime axetil 500 mg orally twice daily for 7-14 days. Intravenous or oral erythromycin (500-1000mg every 6 hours) or doxycycline was added to cephalosporin therapy in circumstances when atypical respiratory pathogens were suspected or proven. Four hundred and fifty-six patients (226 given levofloxacin and 230 administered ceftriaxone and/or cefuroxime axetil) were evaluated for clinical response to therapy at 5-7 days post-antibiotic therapy.

The analysis revealed clinical success rates at 5-7 days post-antibiotic therapy favouring levofloxacin (96%) versus cephalosporin therapy (90%) (95% CI -10.7 to -1.3). The secondary outcome of bacteriologic eradication also favoured levofloxacin (98%) versus cephalosporin (85%) (95% CI -21.6 to -4.8). Both levofloxacin and ceftriaxone-cefuroxime eradicated 100% of Streptococcus pneumoniae. Eradication rates for Haemophilus influenzae were 100% for levofloxacin and 79% for ceftriaxone-cefuroxime axetil. Microbiologic success for the atypical pathogens was 99% for levofloxacin compared to 94% for the cephalosporin arm. It should be noted, however, that only 28% of the comparator group with atypical pathogens received either erythromycin or doxycycline. Clinical response was similar in the cephalosporin-treated patients whether or not they had received erythromycin or doxycycline. Adverse events were reported in 5.8% of patients receiving levofloxacin and 8.5% of patients given the cephalosporins.

The second clinical trial was also an open-label study to evaluate the safety and efficacy of levofloxacin versus ceftriaxone in the treatment of hospitalized patients with either community-acquired or hospital-acquired pneumonia.26 Patients were randomized to levofloxacin 500mg IV twice daily (N=314) versus ceftriaxone 4g IV once daily (N=305). Patients in the levofloxacin arm were switched to oral therapy on day 3-5 of therapy, and if clinical signs and symptoms of pneumonia had improved. The total duration of therapy was left up to the discretion of the physician but the minimum number of days was five. The primary outcome of efficacy was based on the clinical cure rate determined 2-5 days after the end of treatment.

The diagnosis of CAP was made in 93% of patients, and the median duration of treatment was 9 days for levofloxacin and 8 days for ceftriaxone. At the clinical endpoint, the cure rates for both levofloxacin (76%) and ceftriaxone (75%) were similar (95% CI –5.7 to +7.8). In addition, levofloxacin (83%) was equivalent to ceftriaxone (83%) for bacterial eradication of the organism (95% CI –12.8 to +11.0). However, the eradication rate for levofloxacin was better than ceftriaxone for gram-negative pathogens (96% vs. 88%) but lower for gram-positive pathogens (76% vs. 85%). Adverse events were reported in 22% of patients receiving levofloxacin and 26% of patients on ceftriaxone.

Adverse Effects

Although direct comparisons are lacking, levofloxacin appears to be better tolerated than older fluoroquinolones.5,27 Gastrointestinal symptoms (nausea, vomiting, abdominal pain, diarrhea, constipation, dyspepsia, taste alteration, and flatulence) are the most commonly observed adverse reactions.5,27 Reports of central nervous system (CNS) toxicities have been generally limited to headache, dizziness and insomnia. The lower incidence of CNS side effects is thought to be related to a decreased affinity for binding of the drug to GABA receptors. Phototoxicity has also been a concern with several fluoroquinolones, however the incidence of phototoxicity in patients taking levofloxacin has been <0.5%, similar to that of ofloxacin and ciprofloxacin.5,27 Other adverse events reported in over 3,460 patients are transient elevation in liver function tests <2%, vaginitis 0.8%, rash 0.3% and pruritus 0.3%.5,27

Table 1. Cost Comparison of Various CAP Regimens:

Drug Regimen

Daily Cost*

Ceftriaxone 1g IV daily PLUS (Erythromycin 500mg po q6h OR Doxycycline 100mg po bid)

$34.00

Ceftriaxone 2g IV daily PLUS Erythromycin 500mg IV q6h

$80.00**

Cefuroxime 750mg IV q8h PLUS (Erythromycin 500mg po q6h or Doxycycline 100mg po bid)

$10.00

Cefuroxime 1.5g IV q8h PLUS Erythromycin 500mg IV q6h

$32.00**

Levofloxacin 500mg po daily

$5.00

Levofloxacin 500mg IV daily

$44.00

*based on VHHSC acquisition costs only
** acquisition cost of erythromycin 500mg IV q6h is $13.00/day

Recommended Dosage and Cost

The recommended dosage for the empiric treatment of CAP in adults is 500 mg once daily for 7-14 days depending upon clinical response. This can be given orally or by slow IV infusion (over 60 minutes). The excellent bioavailability of levofloxacin should permit oral administration for the initial management of CAP in select patients. The cost of oral and IV levofloxacin is comparable to the cost of other antibiotics used for CAP (Table 1). The dosage of levofloxacin should be reduced to 250mg daily for patients with a creatinine clearance of less than 50mL/min and 250mg every 48 hours for clearances less than 20mL/min.

Formulary Status

Levofloxacin, a new “respiratory” fluoroquinolone, has been added to the VHHSC formulary as a reserved antimicrobial drug. A select antimicrobial information notice will be sent with each treatment course and each course will also be monitored by a clinical pharmacist. This agent provides another alternative for the treatment of CAP.

References

  1. Mandell L et al. Canadian guidelines for the initial management of community-acquired pneumonia: An evidence-based update. Can Infect Dis 2000;Oct (In Press).

  2. Mandell LA et al. The Canadian Community-acquired Pneumonia Consensus Group. Antimicrobial treatment of community-acquired pneumonia in adults: A conference report. Can J Infect Dis 1993;4:25-28.

  3. Marrie TJ et al. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. CAPITAL Study Investigators. JAMA 2000;283:749-755.

  4. Chien SC et al. Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses. Antimicrob Agent Chemother 1997;41:2256-2260.

  5. North DS et al. Levofloxacin, a second-generation fluoroquinolone. Pharmacotherapy 1998;18:915-935.

  6. Holland ML et al. The pharmacokinetic profile of levofloxacin following once- or twice-daily 500 mg oral administration of levofloxacin hemihydrate (abstract). In: Selected Posters Presented at the Fifth International Symposium on New Quinolones, Singapore, 1994:38-9.

  7. Lee LJ et al. Effects of food and sucralfate on a single oral dose of 500 milligrams of levofloxacin in healthy subjects. Antimicrob Agent Chemother 1997;41:2196-2200.

  8. Andrews JM et al. Concentrations of levofloxacin (HR 355) in the respiratory tract following a single oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 1997;40:573-577.

  9. Gisclon LG et al. The pharmacokinetics of levofloxacin in subjects with renal impairment, and in subjects receiving hemodialysis or continuous ambulatory peritoneal dialysis (abstract). In: Program and Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, LA.

  10. Barry AL, et al. Antistaphylococcal activity of the fluoroquinolones CI-960, PD-131628, sparfloxacin, ofloxacin and ciprofloxacin. Eur J Clin Microbiol Infect Dis 1991;10:168-171.

  11. Montanari MP et al. In vitro activity of levofloxacin against gram-positive bacteria. Chemotherapy 1999;45:411-417.

  12. Eliopoulos GM et al. Comparative in vitro activity of levofloxacin and ofloxacin against gram-positive bacteria. Diagn Microbiol Infect Dis 1996;25:35-41.

  13. Kitzis MD et al. In-vitro activity of levofloxacin, a new fluoroquinolone: evaluation against Haemophilus influenzae and Moraxella catarrhalis. J Antimicrob Chemother 1999;43 (suppl C):21-26.

  14. Fu KP et al. In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin. Antimicrob Agents Chemother 1992;36:860-866.

  15. Fuchs PC et al. Multicenter evaluation of the in vitro activities of three new quinolones, sparfloxacin, CI-960, and PD 131,628, compared with the activity of ciprofloxacin against 5,252 clinical bacterial isolates. Antimicrob Agents Chemother 1991;35:764-766.

  16. Brisse S et al. Comparative in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Enterobacter aerogenes clinical isolates with alterations in GyrA and ParC proteins. Antimicrob Agents Chemother 1999;43:2051-2055.

  17. Blondeau JM et al. Comparative in vitro activity of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin against 4151 Gram-negative and Gram-positive organisms. Int J Antimicrob Agents 2000;14:45-50.

  18. Spangler SK et al. Susceptibilities of non-Pseudomonas aeruginosa gram-negative nonfermentative rods to ciprofloxacin, ofloxacin, levofloxacin, D-ofloxacin, sparfloxacin, ceftazidime, piperacillin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and imipenem. Antimicrob Agents Chemother 1996;40:772-775.

  19. Wexler HM et al. In vitro activity of levofloxacin against a selected group of anaerobic bacteria isolated from skin and soft tissue infections. Antimicrob Agents Chemother 1998;42:984-986.

  20. Stout JE et al. Comparative activity of ciprofloxacin, ofloxacin, levofloxacin, and erythromycin against Legionella species by broth microdilution and intracellular susceptibility testing in HL-60 cells. Diagn Microbiol Infect Dis 1998;30:37-43.

  21. Kenny GE et al. Susceptibility of Mycoplasma pneumoniae to several new quinolones, tetracycline and erythromycin. Antimicrob Agents Chemother 1991;35:587-589.

  22. Tomioka H et al. Comparative antimicrobial activities of the newly synthesized quinolone WQ-3034, levofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis and Mycobacterium avium complex. Antimicrob Agents Chemother. 2000;44:283-286.

  23. Rastogi N et al. In vitro activities of levofloxacin used alone and in combination with first- and second-line antituberculous drugs against Mycobacterium tuberculosis. Antimicrob Agents Chemother 1996;40:1610-1616.

  24. Ullmann U et al. Comparative in-vitro activity of levofloxacin, other fluoroquinolones, doxycycline and erythromycin against Ureaplasma urealyticum and Mycoplasma hominis. J Antimicrob Chemother 1999;43 (suppl C):33-36.

  25. File TM et al. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone with community-acquired pneumonia 1997;41:1965-1972.

  26. Norrby RS et al. A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia 1998;30:397-404.

  27. Martin SJ et al. Levofloxacin and sparfloxacin: new quinolone antibiotics. Ann Pharmacother 1998;32:320-336.