Preface

Since the introduction of ciprofloxacin in 1987 fluoroquinolones have expanded far beyond their early role in the treatment of urinary tract infections. It is their ease of administration, favourable pharmacokinetic profile, excellent tolerability and clinical efficacy which makes them excellent chemotherapeutic agents in clinical practice. Moreover, while possessing many of the favourable properties of intravenous agents, most fluoroquinolones offer the convenience of oral administration, thus contributing to decreased healthcare costs through increased outpatient therapy and shortened hospital stay. Fluoroquinolones currently approved by the US FDA include norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, levofloxacin , sparfloxacin, gatifloxacin, trovafloxacin and moxifloxacin. Here we review the profile of levofloxacin , a fluoroquinolone which has aroused considerable interest amongst physicians globally because of its unmatched safety profile .

Levofloxacin, the L-isoform of ofloxacin, is a third generation fluoroquinolone with broad spectrum of activity against Gram-positive and Gram-negative bacteria, atypical pathogens and anaerobes. In comparison with other fluoroquinolones like gatifloxacin and ciprofloxacin, levofloxacin when given orally achieves significantly higher C max (Fig. 1) and AUC values with a longer elimination half-life. These properties permit once daily dosing while maintaining drug concentrations in serum above the MICs for susceptible pathogens. Since the activity of fluoroquinolones is concentration-dependent, the high concentration achieved with levofloxacin contributes to its clinical efficacy. Moreover, when compared with other fluoroquinolones like ciprofloxacin, sparfloxacin and gatifloxacin, levofloxacin has an excellent tolerability profile. Gatifloxacin has been associated with potentially life-threatening hepatotoxicity and is known to prolong the QTc interval in humans. Current recommendation is to avoid use of gatifloxacin in patients with known prolongation of the QTc interval. Sparfloxacin is known to cause significant photosensitivity reactions. In contrast extensive clinical usage of levofloxacin has not resulted in hepatic toxicity or adverse cardiac events and the drug has a low phototoxic potential. Levofloxacin therefore offers a unique combination of documented efficacy and safety and provides an important option for treatment of moderate to severe bacterial infections.

Table 1: Superior pharmacokinetics
Parameter	Levofloxacin	Gatifloxacin	Benefits of Levofloxacin
Oral bioavailability	100%	96%	i) I.V. power in oral form ii) Drug of choice for I.V. to oral switch
C max	6.21	3.42	Faster bactericidal action
Renal Excretion	90%	83%	Drug of choice in UTI

 

LEVOFLOXACIN VS GATIFLOXACIN

Both levofloxacin and gatifloxacin are third generation fluoroquinolones offering much broader spectrum of activity as compared to older fluoroquinolones and are used for similar indications. These include exacerbations of chronic bronchitis, acute sinusitis, community-acquired pneumonia, uncomplicated and complicated cystitis, pyelonephritis and gonococcal infections due to susceptible organisms. However, levofloxacin scores over gatifloxacin in terms of efficacy, tolerability and safety.

Superior pharmacokinetic profile

The oral bioavailability of levofloxacin is 100% as compared to 96% with gatifloxacin. This makes it an ideal drug for switch over from intravenous to oral therapy. Moreover, it has faster bactericidal action and is a drug of choice in urinary tract infections (Table 1).

Better clinical efficacy

In pneumonia, levofloxacin has a 100% success rate while with gatifloxacin it is only 80%. The MIC 90 against Salmonella spp. is 0.09 for levofloxacin while it is 0.17 for gatifloxacin. Thus levofloxacin is twice more potent than gatifloxacin against typhoid fever. In urinary tract infections levofloxacin has a superior bactericidal activity and antibactericidal spectrum especially for pseudomonas (Table 2 and 3).

Unmatched safety profile

Compared to gatifloxacin, levofloxacin has no cardiotoxic or hypotoxic effects (Tables 4, 5 & 6).

Table 2: Urinary tract infections Superior bactericidal activity
MIC 90 (mg/ml)	Levofloxacin	Gatifloxacin
Proteus mirabilis	0.1	0.5
Klebsiella spp.	0.06	0.5

 

Table 3:  Superior spectrum for pseudomonas
	Gram-positive	Gram-negative	Pseudomonas species	Anaerobic	Atypical
Levofloxacin	++	+++	+++	+	+++
Gatifloxacin	++	+++	++	+	+++

 

Table 4: Comparison of cardiotoxicity
Prolongation of QT c interval
Levofloxacin	No adverse effects
Gatifloxacin	Potential to prolong QT c interval contraindicated in patients with risk factors

 

Table 5: Comparison of hepatotoxicity
Hepatotoxicity
Levofloxacin	No hepatotoxicity
Gatifloxacin	Fulminant hepatic failure reported

 

Table 6: Interaction with anti-diabetics
Levofloxacin	No reports of hypoglycaemia
Gatifloxacin	Report of serious hyper and hypoglycaemia episodes. Should be used with caution in those with diabetes as well as elderly

Interaction of gatifloxacin with oral hypoglycaemic agents

1. Most antibiotics do not markedly affect blood glucose levels 1,2 and drug interactions between antibiotics and oral hypoglycaemic agents are unusual. 2,3 Among the quinolones, ciprofloxacin may cause slight fluctuations in blood glucose levels in patients treated with oral hypoglycaemic agents. 4,5 Severe hypoglycaemia has not been reported to be a quinolone class effect. However, a recent study discussed three case reports of severe and persistent hypoglycaemia in patients with type 2 diabetes receiving concomitant gatifloxacin plus an oral anti-hyperglycaemic agent . 6 In the three cases presented, serum glucose levels decreased rapidly after the first dose of gatifloxacin, and hypoglycaemia persisted until gatifloxacin was discontinued. Hypoglycaemic reactions ranged from asymptomatic hypoglycaemia to severe symptomatic hypoglycaemia with a seizure. An interaction between gatifloxacin and different oral hypoglycaemic agents (repaglinide, glyburide, pioglitazone and glimepiride) was seen in the patients. After gatifloxacin was discontinued, severe hypoglycaemia did not recur after the original hypoglycaemic agents were restarted. As a result of these and other case reports of serious hyper- and hypoglycaemic episodes associated with the concomitant administration of gatifloxacin plus oral antihyperglycaemic agents, gatifloxacin should be used with caution in those with diabetes or those at risk for hyperglycaemia, such as the elderly. 6

   In fact, in Japan gatifloxacin use in diabetic patients has been forbidden by the Ministry of Health, Labour and Welfare (MHLW) . This followed continuing reports of unusual blood glucose levels during use of the product. The MHLW received reports of seriously lowered blood glucose levels in 75 patients since the product's launch in Japan last June until February, of whom 58 were diabetics. 14 cases of elevated blood sugar levels were reported, including 11 patients with diabetes. New statements on the possible blood glucose problems and the contraindication in patients with diabetes have now been added to the precautions of its use, together with a requirement to check for diabetes or a history of the disorder before initiating gatifloxacin treatment.

   As quinolones are commonly prescribed antibiotics in adults with diabetes mellitus, clinicians should be aware of gatifloxacin's potential for hypoglycaemia which may occur with several hypoglycaemic agents.

   Notably unlike gatifloxacin, there have been no reports of hypoglycaemia in patients with diabetes receiving concomitant levofloxacin and an antihyperglycaemic agent. 7

Role in community-acquired pneumonia

In November 2002, US FDA approved levofloxacin injection/tablets for the treatment of community-acquired pneumonia due to methicillin-susceptible Staphylococcus aureus , P. aeruginosa, E. coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae.

Levofloxacin in community-acquired pneumonia

Position of levofloxacin in American Thoracic Guidelines 8 for community-acquired pneumonia in different settings is summarised below:

Outpatient with cardiopulmonary disease and/or other modifying factors

Beta-lactam (oral cefpodoxime, cefuroxime, high-dose amoxycillin, amoxycillin/clavulanate or parenteral ceftriaxone followed by cefpodoxime) PLUS Macrolide or doxycycline
OR
Antipneumococcal fluoroquinolone (Levofloxacin) (used alone)

Inpatients, not in ICU
Cardiopulmonary disease and/or modifying factors (including being from a nursing home)

IV beta-lactam (cefotaxime, ceftriaxone, ampicillin/sulbactam or high-dose ampicillin) PLUS
IV or oral macrolide or doxycycline
OR
IV antipneumococcal fluoroquinolone (Levofloxacin) (alone)

No cardiopulmonary disease, no modifying factors

IV azithromycin alone, if macrolide allergic or intolerant: doxycycline and a beta-lactam
OR
Monotherapy with an antipneumococcal fluoroquinolone (Levofloxacin)

ICU-Admitted Patients
No risks for Pseudomonas aeruginosa

IV beta-lactam (cefotaxime or ceftriaxone),
PLUS
EITHER IV macrolide (azithromycin)
OR
IV fluoroquinolone (Levofloxacin)

Risks for Pseudomonas aeruginosa

Selected IV antipseudomonal beta-lactam (cefepime, imipenem, meropenem or piperacillin/tazobactam)
PLUS
IV antipseudomonal quinolone
OR
Selected IV antipseudomonal beta-lactam (cefepime, imipenem, meropenem or piperacillin/tazobactam)
PLUS
IV aminoglycoside
PLUS
EITHER IV macrolide (azithromycin)
OR
IV fluoroquinolone (Levofloxacin)

References

1. Cunha BA. Antibiotic side effects. Med Clin North Am 2001; 85 :149-185.
2. Cunha BA. Antibiotic essentials. Birmingham . Michigan ; Physicians Press 2002.
3. Piscitelli SC. Rodvold KA eds. Drug interaction in infectious disease. Totowa , New Jersey ; Human Press 2001.
4. Ciprofloxacin (package insert) West Haven , CT ; Bayer Pharmaceuticals 2000.
5. Roberge RJ, Kaplan R, Frank R, Fore C. Glyburide ciprofloxacin interaction with resistant hypoglycaemia. Ann Emerg Med 2000; 36 :160-163.
6. Menzies DJ, Dorsainvil PA, Cunha BA et al . Severe and persistent hypoglycaemia due to gatifloxacin interaction with oral hypoglycaemic agents. Am J Med 2002; 113 :232-234.
7. Brissol-Myers. Squibb Company. Tequin facts. http://www.tequin.com [accessed online 2002 Sep 2].
8. American Thoracic Society Guidelines. www.thoracic.org/statements.