Clinical Drug Utilization Of Fluoquinones Antibacterials And Transporter Polymorphism-related Urinary Excretion Study Of Levofloxacin

OBJECTIVE:To learn the changes in rationality of fluoroquinolones use during the national program of antibiotics stewardship and Joint Commission International accreditation, explore the relationship of levofloxacin pharmacokinetics with pharmacogenomics in transporters in renal excretion, and provide references for rational and personalized use of fluoquinolones.METHODS:A retrospective analysis was performed on antibacterial use and bacterial resistance rate of A. Baumannii (Ab), P. Aeruginosa (Pa), Klebsiella pneumonia (Kp) and E. coli (Ec) in this hospital during 2009-2013. Correlation of use intensity of antibacterials with bacterial resistance rate were analyzed. The appropriateness of levofloxacin use in inpatients and fluoroquinolones-related medication errors were evaluated. The effect of single nucleotide polymorphism (MDR1 C3435T and MRP2 C3972T) on urine excretion of levofloxacin was investigated. Lastly, the progress in personalized therapy of levofloxacin from perspective of pharmacokinetics was reviewed.RESULTS:(1) Decreasing trend was observed in the use intensity of anti-Gram-negative bacteria agents and resistance of the four Gram-negative bacteria. The largest absolute value of reduced resistance rate was observed with Ab against levofloxacin. A continuous decrease in resistance rate was observed with Ab, Kp and Ec against ciprofloxacin and levofloxacin, and Pa against levofloxacin. Levofloxacin experienced the biggest reduction in use intensity. The use intensity of fluoroquinolones decreased year by year and it was positively correlated with resistance rate of four bacterial against ciprofloxacin, levofloxacin, piperacillin sodium/tazobactam sodium, Pa against ceftazidime, cefepime, imipenem and meropenem. The use intensity of levofloxacin and moxifloxacin was positively correlated with resistance rate of bacterial against some antibacterials. There was little correlation of ciprofloxacin's use intensity with bacterial resistance rate. The use intensity of piperacillin sodium/tazobactam sodium, imipenem and compound beta-lactamase inhibitors were negatively correlated with resistance rate of four bacterial against ciprofloxacin and levofloxacin, however, the use intensity of aminoglycosides, third generation of cephalosporins were positively correlated with resistance rate of four bacterial against ciprofloxacin and levofloxacin (r>0.71,P<0.05). The ratio of intravenous route to oral route of levofloxacin decreased significantly (P?0.05); the relative percentage of consumption of fluoroquinolones in gastroenterology wards and urinary surgery wards, dose adjustment based on creatinine clearance rate and intravenous drip time longer than 60 min regarding administering levofloxacin infusion (0.5g/100ml) increased significantly (P<0.05). There were 147 cases of fluoroquinolones-related medication errors,97.2% of which were near misses efficiently intercepted by auditing pharmacists. (2) In volunteer study, the accumulation urinary excretion amount was 313.79±43.58mg. The effect of single nucleotide polymorphism (MDR1 C3435T and MRP2 C3972T) on urine excretion of levofloxacin was minimal (P>0.05). The accumulation urinary excretion amount in volunteers with MRP2c.3972 TC was 300.78±57.20mg (n=6) whereas the value in volunteers with MRP2c.3972 CC was 319.37±37.51mg (w=14), with no statistically significant inter-group difference (P=0.5112); The accumulation urinary excretion amount in volunteers with MDRlc.3435 CC was 322.76±37.81mg (n=8) whereas the value in volunteers with MDRlc.3435 TT+CT was 316.62±54.04mg ( n=12), with no statistically significant inter-group difference (P=0.4467); The accumulation urinary excretion amount in volunteers with MRP2/MDR1c.3972 CC/c.3435 CC was 321.74±40.72mg(n=7) whereas the value in volunteers with MRP2/MDR1 Non-c.3972 CC/c.3435 CC was 316.89±41.29mg (n=13), with no statistically significant inter-group difference (P=0.5508). (3) The update review indicates that the awareness of personalized therapy of levofloxacin is poor. PK/PD mode could guide the prevention of bacterial resistance against levofloxacin. Pharmacokinetic alternations may appear in special population and thus dosage should be tailored. Medication regimen and drug interaction issue exhibit new progress.CONCLUSIONS:After the initiation of national program and JCI accreditation, the rationality of fluoroquinolones clinical use improves significantly. Fluoroquinolones have complicated relationships with other antibacterials with respect to bacterial resistance. Suitable use of compound beta-lactamase inhibitors may decrease the antimicrobial resistance of ciprofloxacin and levofloxacin. Control of overusing fluoroquinolones may positively affect the bacterial resistance of other antibacterials. Interpatient variation in pharmacokinetics of levofloxacin observed in clinical practice may be due to miscellaneous factors other than MDR1 and MRP2 polymorophism. Different fluoroquinolones may have different influences on the bacterial resistance. Personalized levofloxacin therapeutics is necessary for the sake of better safety, clinical success, and avoidance of resistance. New findings regarding individual dosing of levofloxacin in special patient populations in vivo are opening up new horizons in clinical practice.