Gatifloxacin Induced Dysglycemic Behaviour and Its Impact on Worldwide Patients

Yogesh Joshi

Assistant Professor, Department of Pharmacology, Himalayan Institute of Pharmacy & Research, Rajawala, Dehradun, Uttarakhand (India)

ABSTRACT:

Gatifloxacin, a synthetic, novel fluoroquinolone, broad-spectrum antimicrobial agent, is primarily indicated for the treatment of upper respiratory tract infections, urinary tract infections and many more infectious disorders. It acts by inhibiting DNA gyrase and also by inhibiting topoisomerase IV for bacterial infections. Its absolute bioavailability is approximately 96%, extensively distributed into many tissues and body fluids, elimination half-life is approximately 8 hours and major route of elimination is urinary excretion of unchanged drug, with renal clearance accounting for >70%. Approximately 82-88% was recovered in urine as unchanged drug and 6% was recovered in feces. Gatifloxacin was reported to be associated with many serious glycemic abnormalities mostly observed in diabetic as well as in non-diabetic patients. Hypoglycemia usually occurs immediately after the administration while hyperglycemia often takes several days to develop and discontinuation of gatifloxacin treatment markedly improves glucose homeostasis in many cases. It was observed that dysglycemia occurs more frequently in elderly patients, patients with renal insufficiency, diabetic patients, and patients taking medications for diabetics (mainly hypoglycemic agents). One of the study identified that increased gatifloxacin exposure correlates with age-related decreases in renal function and may be responsible for elderly patients being at an increased risk for hyperglycemia. Failure to adjust the dose of gatifloxacin for renal insufficiency has been commonly associated with gatifloxacin-induced hypoglycemia and hyperglycemia. Some researchers observed high incidence rates of hyperglycemia in patients with diabetes compared to those without diabetes while some found no significant difference. Patients receiving glucose lowering medications were at the greatest risk for gatifloxacin-associated hyperglycemic events and patient’s not receiving glucose-lowering medications also had a significantly increased risk of hyperglycemia. Gatifloxacin is still being used in various parts of the world for treatment of infectious diseases. Therefore, gatifloxacin should be used with caution while undergoing treatment with gatifloxacin.

KEYWORDS: Dysglycemia, gatifloxacin, hyperglycemia, hypoglycemia, elderly patients

INTRODUCTION:

Gatifloxacin is a synthetically derived, novel fluoroquinolone antimicrobial agent used to treat a variety of infections and was approved by the United States Food and Drug Administration in December 1999 along with the approval in various countries. It has broad-spectrum of activity against gram-positive, gram-negative, anaerobic and atypical microorganisms^{1, 2, 3}. It is commonly indicated for the treatment of community-acquired pneumonia, acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, complicated and uncomplicated urinary tract infections, and gonorrhea⁴. Adverse effects associated with it mainly include seizures, headache, dizziness, prolongation of the QT interval, tendon rupture, rash, nausea, diarrhea, vaginitis and peripheral neuropathy^5-7.

However, after clinical introduction in 1999, many serious glycemic abnormalities associated with use of gatifloxacin were reported. Most of these adverse reactions were observed in diabetic patients, and is now contraindicated for diabetic patients in Japan and the United States¹.

1. Chemical & Physical Nature:

Chemically, it is (±)-1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid sesquihydrate (Figure 1) having empirical formula C₁₉H₂₂FN₃O₄ 1.5 H₂O and molecular weight of 402.42. It is a sesquihydrate crystalline powder and is white to pale yellow in color. Solubility of gatifloxacin is pH dependent, with maximum aqueous solubility (40-60 mg/ml) occurring in a pH range of 2-5. It is designed for both oral and intravenous administration. It is available as 200 and 400 mg white, film-coated tablets. The intravenous formulation is available in both single-use vials and ready-to-use flexible bags. Both vials and bags are sterile, preservative-free aqueous solutions with pH of 3.5-5.5^{2, 3, 5}.

Figure 1: Structure of Gatifloxacin

2. Pharmacodynamics & Pharmacokinetics:

Gatifloxacin exerts its antimicrobial activity by inhibiting DNA gyrase, a tetrameric enzyme consisting of two A and two B subunits, as a primary target in Escherichia coli and also by inhibiting topoisomerase IV as a primary target in gram-positive bacteria such as Staphylococcus aureus and Streptococcus pneumoniae. It is well absorbed from the gastrointestinal tract after oral administration and its absolute bioavailability is approximately 96%. Its binding by serum proteins is approximately 20% and is independent of concentrations. It is extensively distributed into many tissues and body fluids. The mean plasma terminal elimination half-life of the drug is approximately 8 hours in individuals with normal renal function. Its major route of elimination is urinary excretion of unchanged drug, with renal clearance accounting for >70%. Less than 1% of orally administered gatifloxacin was excreted in urine as ethylenediamine and methylethylenediamine metabolites; approximately 82-88% was recovered in urine as unchanged drug within 72 hours and 6% was recovered in feces^{2, 8, 9}.

3. Indications with reference to dysglycemia:

Fluoroquinolones are among the most widely prescribed antibiotics especially for respiratory and urinary tract infections. Four quinolones have been withdrawn from the market: temafloxacin, as a result of hemolysis, renal failure and hypoglycemia; trovafloxacin, as a result of hepatotoxicity; grepafloxacin, as a result of torsades de pointes; and sparfloxacin (still in the market of developing countries) as a result of phototoxicity and torsades de pointes. The latest safety concern regarding the use of quinolones includes dysglycemic effects associated with it^10,
11. Dysglycemia (hypo or hyperglycemia) has been reported rarely with many of the fluoroquinolones^{10, 12}. Hypoglycemia induced by quinolones usually occurs immediately after the first administration of the drug as categorized under the acute effects of gatifloxacin while gatifloxacin-induced hyperglycemia often takes several days to develop high glucose levels and discontinuation of gatifloxacin treatment markedly improves glucose homeostasis in most cases^13-17.

Even though it is not yet confirmed that how fluoroquinolones cause hyperglycemia. Investigations have identified a possible mechanism of fluoroquinolone induced hypoglycemia and in vitro experiments have revealed that fluoroquinolones can stimulate insulin release and subsequently hypoglycemia by blocking the ATP-sensitive potassium channels of pancreatic cells. It can trigger the vacuolation of pancreatic beta cells and subsequently lead to reduced insulin levels and hyperglycemia^1,13,18-21. Based on the case reports and studies conducted, it was observed that dysglycemia occurred more frequently in elderly patients and diabetic patients (however the same has been reported in case of non-diabetic patients)^{10, 11}.

Published case reports and certain studies from various parts of world suggest that dysglycemia is more common with gatifloxacin than with other fluoroquinolones and was associated with 80 per cent of all glucose homeostasis abnormality reports among the various antibiotics evaluated (Table 1). The authors reported that the rate of glucose homeostasis abnormalities with gatifloxacin was at least ten-fold higher than the rate associated with any of quinolone comparators. Evidence that proved gatifloxacin causes dysglycemia effects in humans includes case reports and studies in healthy volunteers or hospital inpatients^{10, 13, 22}. In the published reports, hypoglycemia occurred in the first two days after administration of gatifloxacin and hyperglycemia occurred on days 2-6^{10, 11}. Even though dysglycemia does not appear to be a common manifestation, it is quite significant. Although the risk seems to be significantly high with gatifloxacin compared to other fluoroquinolone antibiotics, it is worthwhile to note that dysglycemia has been reported rarely with other fluoroquinolones especially levofloxacin and ciprofloxacin^{11, 12}.

Table 1: Summary of Case Reports from Various Parts of World Related to Gatifloxacin-Induced Dysglycemia

S.N.	Study conducted by	Status of Glycemic Level	Number of Patients	Patient Details (Age, Gender)	Place with Country Name
1.	Yip and Lee, 2006	Hyperglycemia	01	86 Yrs, Male	California, US
2.	Happe et al, 2004	Hyperglycemia	02	60 Yrs, Male 47 Yrs, Male	Washington, US
3.	Khovidhunkit and Sunthornyothin, 2004	Hypoglycemia Hyperglycemia	01 01	87 Yrs, Female 69 Yrs, Female	Bangkok, Thailand
4.	Donaldson et al²⁹, 2004	Hyperglycemia	01	64 Yrs, Female	Auburn, US
5.	Biggs, 2003	Hypoglycemia Hyperglycemia	02 02	82 Yrs, Male 68 Yrs, Female 82 Yrs, Female 91 Yrs, Female	Texas, US
6.	Blommel and Lutes³⁰, 2005	Hyperglycemia	02	91 Yrs, Female 65 Yrs, Female	Monongahela, US
7.	Beste and Mersfelder, 2005	Hyperglycemia	01	71 Yrs, Male	Rhode Island, US
8.	Stading et al³¹, 2005	Hyperglycemia	01	57 Yrs, Male	Omaha, US
9.	Kesavadev and Rasheed, 2006	Both Hypo- & Hyperglycemia	01	55 Yrs, Female	Thiruvanantha-puram, Kerala
10.	Aspinall et al, 2009	Hypoglycemia Hyperglycemia	76 99	Mean Age of overall patients - 62.9 Yrs	Pennsylvania, US
11.	Mohr et al, 2005	Hypoglycemia Hyperglycemia	04 11	Mean Age - 67 Yrs Mean Age - 72 Yrs	Texas, US
12.	Mohr III et al, 2008	Hyperglycemia	69	Mean Age – 67.3 Yrs	Texas, US
13.	Zvonar, 2006	Hyperglycemia Hypoglycemia	01 02	93 Yrs, Female 81 Yrs, Male 73 Yrs, Male	Canada, US
14.	Park-Wyllie et al, 2006	Hyperglycemia Hypoglycemia	86 61	Mean Age - 77.8Yrs Mean Age - 78.4 Yrs	Canada, US
15.	Edwards et al, 2007	Hyperglycemia	04	74 Yrs, Male 76 Yrs, Male 57 Yrs, Male 61 Yrs, Female	Texas, US
16.	Baker and Hangii³², 2002	Hypoglycemia	01	73 Yrs, Male	Virginia, US
17.	LaPlante et al³³, 2008	Hypoglycemia Hyperglycemia	08 05	Mean Age - 79.6Yrs Mean Age - 75.8 Yrs	Rhode Island, US

In March 2006, reporting of severe disturbances in glucose homeostasis after treatment with gatifloxacin, the US-FDA revised the prescribing information to include a contraindication to the use of gatifloxacin in patients with diabetes mellitus and to strengthen the warning that use of gatifloxacin should be closely monitored in patients without diabetes mellitus. According to the prescribing information, hyperglycemia usually develops within 2-3 days of the initiation of gatifloxacin treatment; while onset of hyperglycemia occurs from 4 to 10 days after initiation of treatment. Further, the hyperglycemia resolved within 24 hours after discontinuation of gatifloxacin therapy^{6, 7}.

4. Risk factors for dysglycemic behaviour:

The risk factors for dysglycemia have been identified as diabetes mellitus, renal insufficiency, older age, and patients taking medications for diabetics (mainly hypoglycemic agents). Some other independent risk factors especially for hyperglycemia were found to be obesity, pancreatitis, trauma, liver disease and concurrent use of catecholamines or glucocorticoids^{10, 24,
25, 26}.

4.1 Diabetes mellitus:

Some researchers observed high incidence rates of hyperglycemia in patients with diabetes compared to those without diabetes while some found no significant difference in the risk of gatifloxacin associated hyperglycemia in diabetics compared to non-diabetics. A retrospective cohort study showed that the gatifloxacin was independently associated with an approximate two times increase in both hypoglycemia and hyperglycemia as compared to levofloxacin among both diabetic and non-diabetic patients²⁷. Studies signify that the gatifloxacin treated diabetic patients appeared to have a reduced risk of hyperglycemia while non-diabetic gatifloxacin treated patients appeared to have an increased risk of hyperglycemia^{23, 25}.

4.2 Renal insufficiency:

Failure to adjust the dose of gatifloxacin for renal insufficiency has been commonly associated with gatifloxacin-associated hypoglycemia but has not been as well documented with gatifloxacin-associated hyperglycemia. In a case report of patient with impaired renal function, gatifloxacin was associated to develop a severe hyperglycemia and observational data suggest serum glucose should be monitored in renally impaired patients. Further it was concluded that physicians should consider monitoring for hyperglycemia in patients who suffer from or are at risk for renal insufficiency as the dosage of gatifloxacin should not exceed 400 mg/d and should be reduced to 200 mg/d for patients with Creatinine Clearance (CrCl) < 40 mL/min, as recommended in the prescribing information^{23, 25, 28}.

4.3 Age:

A study hypothesized that increased gatifloxacin exposure correlates with age-related decreases in renal function and may be responsible for elderly patients being at an increased risk for gatifloxacin-associated hyperglycemia. A study also showed that the risk of severe hyperglycemia could be lessened with a reduction of the daily gatifloxacin dose from 400 to 200 mg in elderly patients^{7, 23, 25}. Several reports of hyperglycemia in elderly patients (age ≥ 65 years old) who received gatifloxacin therapy with and without diabetes diagnoses have been reported in the literature²⁵.

4.4 Glucose lowering medications:

Although patients receiving glucose lowering medications were at the greatest risk for gatifloxacin-associated hyperglycemic events, patient’s not receiving glucose-lowering medications also had a significantly increased risk of hyperglycemia if they received gatifloxacin therapy²⁵.

CONCLUSION:

Gatifloxacin has been removed from the US market, but it is still being used extensively in various parts of the world for treatment of multi-drug resistant infectious diseases. Therefore, gatifloxacin should be used with caution, especially for patients with predisposed disturbances of glycemic control. Appropriate dosage reduction in patients with renal dysfunction and cautious use in elderly patients needs to be considered while undergoing treatment with gatifloxacin. Further researches based on either dose modification or some other changes in drug therapy related to gatifloxacin may be helpful in overcoming such abnormality associated with its use.

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Received on 13.03.2013

Modified on 11.04.2013

Accepted on 17.04.2013

Research J. Pharmacology and Pharmacodynamics. 5(3): May–June 2013, 187-190