Fluoroquinolone Positioning in Hospital Antimicrobial Stewardship Programs

US Pharm. 2007;32(12)HS-10-HS-17.

Antimicrobial stewardship is a marriage of infection control and judicious antimicrobial use whose primary goals are to optimize clinical outcomes and to minimize the emergence of antimicrobial resistance.¹ Effective antimicrobial stewardship requires the selection of specific antimicrobials for inpatient formulary use based not only on efficacy, toxicity, and cost but also on the consideration of important collateral damage issues. These issues include the agent's ability to reduce the incidence of infections caused by resistant bacteria (such as extended-spectrum, beta-lactamase-producing, gram-negative bacteria); its propensity to cause Clostridium difficile–associated diarrhea (CDAD); its selection of stably derepressed isolates of AmpC beta-lactamase-producing gram-negative bacteria (such as Pseudomonas aeruginosa, Acinetobacter species, Citrobacter species, Enterobacter species, and Serratia species); and its ability to select for isolates of vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA).

Only two of the numerous fluoroquinolone agents developed, ciprofloxacin and levofloxacin, have had extensive use for more than 10 years with well-documented efficacy and safety profiles. Two newer fluoroquinolones, moxifloxacin and gemifloxacin, may require several more years of clinical use before their long-term efficacy and safety profiles can be fully established. This may be particularly true for gemifloxacin, which is available only as an oral agent and thus cannot be used in more severely ill patients who require intravenous (IV) administration or who are unable to take oral medication. The fluoroquinolones have been effective in reducing overall health care costs in hospitals that implement critical pathways encouraging IV-to-oral switch and earlier discharge when they are prescribed for community-acquired pneumonia (CAP).^2-4

The fluoroquinolone class has had an expansion of clinical indications, primarily related to improvements in pharmacokinetics and spectrum of activity. Norfloxacin, the first fluoroquinolone available for the treatment of gram-negative urinary tract infections, is not used for systemic infections because of inadequate serum concentrations.⁵ Ciprofloxacin was the first fluoroquinolone that offered improved pharmacokinetics, twice-daily dosing, and a favorable safety profile and was approved for the treatment of both urinary tract and systemic infections.⁶ However, ciprofloxacin exhibits poor activity against Streptococcus pneumoniae, a major cause of community-acquired respiratory tract infections, thus limiting its use for empiric therapy for these indications. Recently, the Clinical Laboratory Standards Institute (CLSI) withdrew the minimum inhibitory concentration (MIC) interpretative standards for ciprofloxacin, so testing of this agent against isolates of S pneumoniae is no longer suggested. Further fluoroquinolone development attempted to identify compounds with additional enhancements, such as improved pharmacokinetics and pharmacodynamics, greater activity against gram-positive bacteria, particularly S pneumoniae, and a more favorable safety and drug interaction profile. Many fluoroquinolones, such as trovafloxacin, sparfloxacin, grepafloxacin, and, more recently, gatifloxacin, were withdrawn from the U.S. market or have severely limited use because of toxicity concerns. ^7,8

Levofloxacin has a long track record for both safety and efficacy.⁹ Importantly, levofloxacin is highly active against S pneumoniae, which enables its use for empiric treatment of community-acquired respiratory tract infections. The more recent respiratory fluoroquinolones moxifloxacin and gemifloxacin are also active against S pneumoniae. For gram-negative organisms, levofloxacin and ciprofloxacin demonstrate similar activity, including activity against P  aeruginosa. The gram-negative activity of moxifloxacin, however, is not well established, and there are no CLSI MIC interpretative standards for either Enterobacteriaceae or for nonfermentative gram-negative bacteria such as P aeruginosa and Acinetobacter species. ^10,11 In addition, because only a limited portion of moxifloxacin undergoes renal excretion as active drug, this agent is not approved for urinary tract infections.¹²

Fluoroquinolones are indicated for treating community-acquired respiratory tract infections (such as CAP, acute bacterial exacerbation of chronic bronchitis, and acute bacterial sinusitis); nosocomial pneumonia; genitourinary infections (such as uncomplicated and complicated urinary tract infections, acute pyelonephritis, and chronic bacterial prostatitis); skin and skin structure infections; and intra-abdominal infections.¹³ Consequently, there appear to be only two reasonable options for hospital formulary fluoroquinolone choices: either the bundling of fluoroquinolones to provide effective coverage or the use of a single broad-spectrum fluoroquinolone. Ciprofloxacin cannot be considered as a single-fluoroquinolone formulary option because it lacks activity against S pneumoniae. Moxifloxacin cannot be considered either because it lacks important clinical indications as well as CLSI susceptibility breakpoints for gram-negative bacteria. Therefore, one possible formulary choice would be to combine or bundle ciprofloxacin and moxifloxacin as the fluoroquinolones for a given hospital. However, levofloxacin as a single-fluoroquinolone formulary choice offers the hospital equivalent activity to ciprofloxacin for gram-negative infections and clinical equivalency to moxifloxacin for gram-positive infections. While the availability of ciprofloxacin as a generic antimicrobial may lead hospital pharmacy and therapeutics (P&T) committees to reconsider their current fluoroquinolone use policy in an attempt to reduce drug-acquisition costs, issues beyond drug-acquisition costs should also be considered by P&T committees. These issues include a drug's spectrum of activity, its pharmacokinetic/pharmacodynamic properties, dosing considerations, and potential for collateral damage.

In Vitro Activity
The most common cause of respiratory tract infections in the United States is S pneumoniae . Ciprofloxacin has limited in vitro activity against S pneumoniae and is not recommended in the joint guidelines issued by the Infectious Diseases Society of America and the American Thoracic Society (IDSA/ATS) as empiric therapy for respiratory tract infections or for infections known to be caused by this pathogen.¹⁴ However, the respiratory fluoroquinolones (levofloxacin, moxifloxacin, and gemifloxacin) each achieve the pharmacokinetic/pharmacodynamic targets needed for effective treatment and eradication of this organism.¹⁵ Resistance of S pneumoniae to respiratory fluoroquinolones has remained at 1% or less.^16,17 All respiratory fluoroquinolones are effective against other respiratory tract pathogens, such as Haemophilus influenzae, Moraxella  catarrhalis, and atypical respiratory pathogens.¹⁵ As such, if ciprofloxacin is maintained on formulary, a second fluoroquinolone will be required to ensure S pneumoniae coverage for empiric treatment of community-acquired respiratory tract infections. Similarly, with moxifloxacin, which does not have clinical experience against important gram-negative pathogens such as Escherichia coli and Klebsiella pneumoniae, a second fluoroquinolone will be required to ensure effective coverage of gram-negative bacteria. Levofloxacin offers effective coverage against both gram-negative and gram-positive pathogens.¹⁸

As in other antimicrobial classes, development of resistance is a major concern with fluoroquinolones. Resistance can arise through mutations in defined regions of DNA gyrase or topoisomerase IV (the quinolone resistance–determining regions [QRDRs]), through increased efflux that pumps drugs out of the cell, or through plasmid-mediated resistance.¹⁹ For S pneumoniae, one or more mutations in the QRDRs is required to confer resistance to the fluoroquinolones, while overexpression of efflux mechanisms can lead to low-level resistance. In E coli, ciprofloxacin and moxifloxacin have been shown to be more susceptible than other fluoroquinolones to efflux mechanisms, increasing the risk of developing resistance to these two agents. ²⁰ Ciprofloxacin is also susceptible to efflux mechanisms in S pneumoniae and may help to select for fluoroquinolone-resistant strains. Susceptibility to levofloxacin is less affected by efflux pump overexpression. ²¹

Pharmacokinetics/Pharmacodynamics
The metabolism and elimination of the fluoroquinolones vary considerably among the agents. While ciprofloxacin is primarily excreted through the urine (40% renally excreted), approximately 15% of an IV dose (and 20%–35% of an oral dose) is excreted as unchanged drug through the gastrointestinal (GI) system. Moxifloxacin is predominantly metabolized by the liver, with approximately 25% of each dose passing through the GI system as unchanged drug.¹² With only 20% of each dose excreted in the urine, moxifloxacin is not approved for treatment of urinary tract infections. In contrast, levofloxacin is predominantly excreted as unchanged drug in the urine, with less than 5% passing through the gut. ¹³

In concentration-dependent antimicrobials such as the fluoroquinolones, bacterial killing and prevention of resistance are associated with the ratio between area under the curve (AUC) and MIC (AUC/MIC) and between peak concentration (C_max) and MIC (C _max/MIC). An AUC/MIC free drug ratio of 30 has been suggested for successful treatment of S pneumoniae infections, and levofloxacin has been shown to achieve greater than 99% eradication of S pneumoniae at an AUC/MIC free drug ratio of 32. This eradication rate is similar to that of moxifloxacin, which has higher AUC/MIC ratios against S pneumoniae. ^15,23

AUC/MIC ratios of 90 to 125 are sometimes required for effective eradication of gram-negative pathogens. ²⁴ Ciprofloxacin has an approximately twofold lower MIC for gram-negative pathogens compared to levofloxacin. However, the 500-mg and 750-mg doses of levofloxacin achieve at least twofold higher plasma C_max and AUC values compared to ciprofloxacin.^13,22,25 Thus, the probability of reaching AUC/MIC targets for several gram-negative pathogens, including P aeruginosa, has been shown to be comparable for these two agents.^24,26

To optimize the pharmacokinetic/pharmacodynamic parameters for levofloxacin, a high-dose, 750-mg regimen has been approved for several indications. This 50% increase in dosage has resulted in a doubling of AUC and C_max values.^13,25 In vitro studies have shown enhanced bacterial eradication and a lower risk of resistance emergence with the 750-mg dosage, including against ciprofloxacin-resistant S pneumoniae.²⁷ Clinical studies have shown that the 750-mg levofloxacin dosage was well tolerated, including in the elderly and the severely ill, and resulted in a rapid reduction in CAP symptoms.^28-30 The levofloxacin 750-mg dosage is recommended for treatment of CAP in the IDSA/ATS guidelines.¹⁴

Dosing and Convenience

Levofloxacin and moxifloxacin demonstrate high bioavailability and long half-lives, allowing for same-dose IV-to-oral switch and once-daily dosing (gemifloxacin is only available as an oral agent). Ciprofloxacin must be dosed twice daily for most indications, and every 8 hours for more severe/complicated infections of the respiratory tract, skin and skin structure, and bones and joints. Ciprofloxacin's lower bioavailability also necessitates dosage adjustment when switching from IV to oral dosing.^12,13,22

Efficacy and Tolerability
The respiratory fluoroquinolones have shown similar rates of efficacy for community-acquired respiratory tract infections, although only a few clinical studies have compared two fluoroquinolone agents directly.¹⁸ In a clinical study with nosocomial pneumonia patients, a 750-mg levofloxacin regimen was noninferior to imipenem-cilastatin followed by ciprofloxacin.³¹ Levofloxacin has also been shown to be noninferior to ciprofloxacin for a variety of genitourinary infections.^32-34

The fluoroquinolones are well tolerated, with the most common adverse reactions related either to the central nervous system (headaches, insomnia) or to the GI system (nausea, diarrhea).¹³ However, all fluoroquinolones, at dosages greater than those approved by the FDA, are associated with rare but serious adverse reactions, including disruption of glucose homeostasis, QT interval prolongation, and systemic rash.⁷

Collateral Damage from Antimicrobial Use
Antibiotic use is a major risk factor in the development of nosocomial infectious diarrhea, particularly cases caused by C difficile. Two aspects of antimicrobials that affect their impact on the anaerobic population in the gut are their antianaerobic activity and the amount of active drug that passes through the intestines.³⁵ Moxifloxacin and ciprofloxacin are excreted unchanged into the gut in relatively large amounts (15%–35% of each dose), while less than 5% of each dose of levofloxacin is excreted unchanged in the gut. Moxifloxacin exhibits the greatest anaerobic activity, particularly against Bacteroides fragilis, while ciprofloxacin and levofloxacin have only minimal activity against this organism.^18,35 Given the hospitalization costs and mortality related to CDAD cases (estimated at nearly $3,700 of additional costs per CDAD case), reducing the incidence of CDAD will be an important factor in improving clinical outcomes in hospitals and reducing overall health care expenditure.³⁶

Direct and Indirect Costs
At institutions where ciprofloxacin is already the preferred fluoroquinolone for appropriate indications, there are additional direct and indirect costs beyond drug acquisition costs that should be weighed when considering a switch to ciprofloxacin as a preferred fluoroquinolone. In addition to the factors already discussed, other considerations include health care personnel education and training, which may involve classroom sessions, newsletters, or direct mailings that consume time and resources. Computer software used by the physicians, pharmacists, and nurses would require updating to recognize a switch in the preferred agent. The twice- to three-daily dosing requirement for ciprofloxacin would require additional time and resources by the pharmacy and nursing staff for the preparation and administration of doses. Finally, a policy of two preferred fluoroquinolone agents for specific indications could lead to confusion and inappropriate use of these agents for unapproved indications.

Conclusions

Although use of generic IV ciprofloxacin may provide an opportunity to save on drug-acquisition costs for the fluoroquinolones, this may not necessarily be in the best interests of the patients, hospital, and staff. Respiratory fluoroquinolones provide several advantages over ciprofloxacin, such as improved coverage of gram-positive infections, more convenient dosing, and less risk of resistance development. Indeed, ciprofloxacin is not considered a respiratory fluoroquinolone and should not be substituted for either levofloxacin or moxifloxacin for community-acquired respiratory tract infections. Differences among the respiratory fluoroquinolones should also be considered, such as potency against gram-positive and gram-negative pathogens and adverse events profile, including the potential for collateral damage. Only when all of these factors are considered can a rational decision be made for the optimal positioning of the fluoroquinolones on each hospital formulary.

References
1. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44:159-177.
2. Marrie TJ, Lau CY, Wheeler SL, et al. A controlled trial of a critical pathway for treatment of community-acquired pneumonia. JAMA. 2000;283:749-755.
3. Marrie TJ. Experience with levofloxacin in a critical pathway for the treatment of community-acquired pneumonia. Chemotherapy. 2004;50(suppl 1):11-15.
4. Feagan BG. A controlled trial of a critical pathway for treating community-acquired pneumonia: the CAPITAL study. Pharmacotherapy. 2001;21:89S-94S.
5. Blondeau JM. A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new respiratory quinolones. J Antimicrob Chemother. 1999;43(suppl B):1-11.
6. Davis R, Markham A, Balfour JA. Ciprofloxacin: an updated review of its pharmacology, therapeutic efficacy and tolerability. Drugs. 1996;51:1019-1074.
7. Bertino J Jr, Fish D. The safety profile of the fluoroquinolones. Clin Ther. 2000;22:798-817.

8. Yip C, Lee AJ. Gatifloxacin-induced hyperglycemia: a case report and summary of the current literature. Clin Ther. 2006;28:1857-1866.
9. Croom KF, Goa KL. Levofloxacin: a review of its use in the treatment of bacterial infections in the United States. Drugs. 2003;63:2769-2802.
10. Karlowsky JA, Jones ME, Thornsberry C, et al. Stable antimicrobial susceptibility rates for clinical isolates of Pseudomonas aeruginosa from the 2001-2003 tracking resistance in the United States today surveillance studies. Clin Infect Dis. 2005;40(suppl 2):S89-S98.
11. Karlowsky JA, Kelly LJ, Thornsberry C, et al. Susceptibility to fluoroquinolones among commonly isolated Gram-negative bacilli in 2000: TRUST and TSN data for the United States. Int J Antimicrob Agents. 2002;19:21-31.
12. Avelox (moxifloxacin hydrochloride) tablets; Avelox I.V. (moxifloxacin hydrochloride in sodium chloride injection. Bayer Pharmaceuticals Corp. June 2004.
13. Levaquin (Levofloxacin) [package insert]. Ortho-McNeil Pharmaceutical; 2007.
14. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(suppl 2):S27-S72.
15. Zhanel GG, Noreddin AM. Pharmacokinetics and pharmacodynamics of the new fluoroquinolones: focus on respiratory infections. Curr Opin Pharmacol. 2001;1:459-463.
16. Karlowsky JA, Thornsberry C, Jones ME, et al. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: Results from the TRUST Surveillance Program (1998-2002). Clin Infect Dis. 2003;36:963-970.
17. Karchmer AW. Increased antibiotic resistance in respiratory tract pathogens: PROTEKT US--An update. Clin Infect Dis. 2004;39(suppl 3):S142-S150.
18. Zhanel GG, Ennis K, Vercaigne L, et al. A critical review of the fluoroquinolones: focus on respiratory infections. Drugs. 2002;62:13-59.
19. Jacoby GA. Mechanisms of resistance to quinolones. Clin Infect Dis. 2005;41(suppl 2):S120-S126.
20. Yang S, Clayton SR, Zechiedrich EL. Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli. J Antimicrob Chemother. 2003;51:545-556.
21. Zhanel GG, Walkty A, Nichol K, Smith H, Noreddin A, Hoban DJ. Molecular characterization of fluoroquinolone resistant Streptococcus pneumoniae clinical isolates obtained from across Canada. Diagn Microbiol Infect Dis. 2003;45:63-67.
22. Bayer Pharmaceuticals Corp. Cipro (ciprofloxacin hydrochloride) tablets; Cipro (ciprofloxacin hydrochloride) oral suspension [prescribing information]. December, 2005.
23. Lister PD, Sanders CC. Pharmacodynamics of moxifloxacin, levofloxacin and sparfloxacin against Streptococcus pneumoniae. J Antimicrob Chemother. 2001;47:811-818.

24. Ebert SC. Application of pharmacokinetics and pharmacodynamics to antibiotic selection. P&T. 2004;29:244-250.
25. Gotfried MH, Danziger LH, Rodvold KA. Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Chest. 2001;119:1114-1122.
26. Drusano GL, Preston SL, Fowler C, Corrado M, Weisinger B, Kahn J. Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia. J Infect Disease. 2004;189:1590-1597.
27. Lister PD. Pharmacodynamics of 750 mg and 500 mg doses of levofloxacin against ciprofloxacin-resistant strains of Streptococcus pneumoniae. Diagn Microbiol Infect Dis. 2002;44:43-49.
28. Dunbar LM, Wunderink RG, Habib MP, et al. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis. 2003;37:752-760.
29. Poole M, Anon J, Paglia M, et al. A trial of high-dose, short-course levofloxacin for the treatment of acute bacterial sinusitis. Otolaryngol Head Neck Surg. 2006;134:10-17.
30. Shorr AF, Khashab MM, Xiang JX, et al. Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients. Respir Med. 2006;100:2129-2136.
31. West M, Boulanger BR, Fogarty C, et al. Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label study. Clin Ther. 2003;25:485-506.
32. Richard GA, Klimberg IN, Fowler CL, et al. Levofloxacin versus ciprofloxacin versus lomefloxacin in acute pyelonephritis. Urology. 1998;52:51-55.
33. Richard GA, Childs SJ, Fowler CL, et al. Safety and efficacy of levofloxacin versus ciprofloxacin in complicated urinary tract infections in adults. Pharm Ther. 1998;23:534-540.
34. Bundrick W, Heron SP, Ray P, et al. Levofloxacin versus ciprofloxacin in the treatment of chronic bacterial prostatitis: a randomized double-blind multicenter study. Urology. 2003;62:537-541.
35. Hoban DJ. Antibiotics and collateral damage. Clin Cornerstone. 2003;(suppl 3):S12-S20.
36. Kyne L, Hamel MB, Polavarm R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis. 2002;34:346-353.

To comment on this article, contact editor@uspharmacist.com.