Optimizing Use of Quinolones in the Critically Ill

ABSTRACT

Fluoroquinolones (FQs) are broad spectrum, concentration dependent, bactericidal antimicrobials that have been commonly utilized to treat severe nosocomial infections. FQ activity is derived from their ability to inhibit DNA gyrase and topoisomerase IV; resistance has been shown to develop in target site mutations, alterations in efflux pump systems, and incorporation of plasmids. The probability of preventing emergence of resistance and achieving maximal rates of kill are best related to the ratio of free-drug in the area under the concentration-time curve (AUC) to minimum inhibitory concentration (AUC:MIC). Major dosage adjustments for FQs are not necessary in hepatic insufficiency, accumulation of extracellular fluids, and burn patients. Appropriate dosage adjustments in renal function should be taken into consideration. FQ optimization in the critically ill is a multifactorial process that should be individualized to each patient and should take into account the MIC of the pathogen, pharmacokinetic/pharmacodynamic profile of the FQ, and the patient's pathophysiological state.

KEYWORDS

Fluoroquinolones - pharmacokinetics - pharmacodynamics - critically ill

REFERENCES

• 1 Vincent J-L, Bihari D J, Suter P M et al.. The prevalence of nosocomial infection in intensive care units in Europe: results of the European Prevalence of Infection in Intensive Care (EPIC) Study.  JAMA. 1995;  274 639-644
• 2 Highet V S, Forrest A, Ballow C H et al.. Antibiotic dosing issues in lower respiratory tract infection: population-derived area under inhibitory curve is predictive of efficacy.  J Antimicrob Chemother. 1999;  43(Suppl A) 55-63
• 3 Zhou J, Dong Y, Zhao X et al.. Selection of antibiotic-resistant bacterial mutants: allelic diversity among fluoroquinolone-resistant mutations.  J Infect Dis. 2000;  182 517-525
• 4 Talbot G H, Bradley J, Edwards Jr J E et al.. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America.  , [see comment][erratum appears in Clin Infect Dis 2006;42:1065] Clin Infect Dis. 2006;  42 657-668
• 5 Robicsek A, Jacoby G A, Hooper D C et al.. The worldwide emergence of plasmid-mediated quinolone resistance.  Lancet Infect Dis. 2006;  6 629-640
• 6 Jacoby G A, Walsh K E, Mills D M et al.. qnrB, another plasmid-mediated gene for quinolone resistance.  Antimicrob Agents Chemother. 2006;  50 1178-1182
• 7 Truong-Bolduc Q C, Strahilevitz J, Hooper D C et al.. A new efflux pump regulated by MgrA of Staphylococcus aureus .  Antimicrob Agents Chemother. 2006;  50 1104-1107
• 8 Ince D, Zhang X, Silver L C et al.. Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T-3811ME), a new desfluoroquinolone.  Antimicrob Agents Chemother. 2002;  46 3370-3380
• 9 Gore J, Bryant Z, Stone M D et al.. Mechanochemical analysis of DNA gyrase using rotor bead tracking.  Nature. 2006;  439 100-104
• 10 Champoux J J, Champoux J J. DNA topoisomerases: structure, function, and mechanism.  Annu Rev Biochem. 2001;  70 369-413
• 11 Wang J C, Wang J C. Cellular roles of DNA topoisomerases: a molecular perspective.  Nat Rev Mol Cell Biol. 2002;  3 430-440
• 12 Clinical and Laboratory Standards Institute .Performance Standards for Antimicrobial Susceptibility Testing: Seventeenth Informational Supplement. Vol 27. Wayne, PA; Clinical and Laboratory Standards Institute 2007
• 13 Jones R N, Beach M L, Pfaller M A et al.. Spectrum and activity of three contemporary fluoroquinolones tested against Pseudomonas aeruginosa isolates from urinary tract infections in the SENTRY Antimicrobial Surveillance Program (Europe and the Americas; 2000): more alike than different!.  Diagn Microbiol Infect Dis. 2001;  41 161-163
• 14 Jones R N, Pfaller M A, Jones R N, Pfaller M A. In vitro activity of newer fluoroquinolones for respiratory tract infections and emerging patterns of antimicrobial resistance: data from the SENTRY antimicrobial surveillance program.  Clin Infect Dis. 2000;  31(Suppl 2) S16-S23
• 14a Yang J C, Bulitta J B, Forrest A F, Tsuji B T. High inocula Pseudomonas aeruginosa attenuates colistin bactericidal activity and alters pharmacodynamics. Paper presented at: 47th Interscience Conference on Antimicrobial Agents and Chemotherapy September 16-20, 2007 Chicago, IL;
• 15 Paterson D L. “Collateral damage” from cephalosporin or quinolone antibiotic therapy.  Clin Infect Dis. 2004;  38(Suppl 4) S341-S345
• 16 Campillo B, Dupeyron C, Richardet J P et al.. Epidemiology of hospital-acquired infections in cirrhotic patients: effect of carriage of methicillin-resistant Staphylococcus aureus and influence of previous antibiotic therapy and norfloxacin prophylaxis.  Epidemiol Infect. 2001;  127 443-450
• 17 Dziekan G, Hahn A, Thune K et al.. Methicillin-resistant Staphylococcus aureus in a teaching hospital: investigation of nosocomial transmission using a matched case-control study.  J Hosp Infect. 2000;  46 263-270
• 18 Graffunder E M, Venezia R A, Graffunder E M, Venezia R A. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials.  J Antimicrob Chemother. 2002;  49 999-1005
• 19 Weber S G, Gold H S, Hooper D C et al.. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients.  Emerg Infect Dis. 2003;  9 1415-1422
• 20 Lautenbach E, Strom B L, Bilker W B et al.. Epidemiological investigation of fluoroquinolone resistance in infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae .  Clin Infect Dis. 2001;  33 1288-1294
• 21 Paterson D L, Mulazimoglu L, Casellas J M et al.. Epidemiology of ciprofloxacin resistance and its relationship to extended-spectrum beta-lactamase production in Klebsiella pneumoniae isolates causing bacteremia.  Clin Infect Dis. 2000;  30 473-478
• 22 Ziha-Zarifi I, Llanes C, Kohler T et al.. In vivo emergence of multidrug-resistant mutants of Pseudomonas aeruginosa overexpressing the active efflux system MexA-MexB-OprM.  Antimicrob Agents Chemother. 1999;  43 287-291
• 23 Le Thomas I, Couetdic G, Clermont O et al.. In vivo selection of a target/efflux double mutant of Pseudomonas aeruginosa by ciprofloxacin therapy.  , [see comment] J Antimicrob Chemother. 2001;  48 553-555
• 24 Drlica K, Zhao X, Drlica K, Zhao X. DNA gyrase, topoisomerase IV, and the 4-quinolones.  Microbiol Mol Biol Rev. 1997;  61 377-392
• 25 Schmitz F J, Hofmann B, Hansen B et al.. Relationship between ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin (BAY 12-8039) MICs and mutations in grlA, grlB, gyrA and gyrB in 116 unrelated clinical isolates of Staphylococcus aureus.  J Antimicrob Chemother. 1998;  41 481-484
• 26 Drlica K, Zhao X, Drlica K, Zhao X. Mutant selection window hypothesis updated.  Clin Infect Dis. 2007;  44 681-688
• 27 Barnard F M, Maxwell A, Barnard F M, Maxwell A. Interaction between DNA gyrase and quinolones: effects of alanine mutations at GyrA subunit residues Ser(83) and Asp(87).  Antimicrob Agents Chemother. 2001;  45 1994-2000
• 28 Bast D J, Low D E, Duncan C L et al.. Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance.  Antimicrob Agents Chemother. 2000;  44 3049-3054
• 29 Jorgensen J H, Weigel L M, Ferraro M J et al.. Activities of newer fluoroquinolones against Streptococcus pneumoniae clinical isolates including those with mutations in the gyrA, parC, and parE loci.  Antimicrob Agents Chemother. 1999;  43 329-334
• 30 Janoir C, Zeller V, Kitzis M D et al.. High-level fluoroquinolone resistance in Streptococcus pneumoniae requires mutations in parC and gyrA.  Antimicrob Agents Chemother. 1996;  40 2760-2764
• 31 Martinez-Martinez L, Pascual A, Jacoby G A et al.. Quinolone resistance from a transferable plasmid.  Lancet. 1998;  351 797-799
• 32 Tran J H, Jacoby G A, Hooper D C et al.. Interaction of the plasmid-encoded quinolone resistance protein QnrA with Escherichia coli topoisomerase IV.  Antimicrob Agents Chemother. 2005;  49 3050-3052
• 33 Thomas J K, Forrest A, Bhavnani S M et al.. Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.  Antimicrob Agents Chemother. 1998;  42 521-527
• 34 Hansen G T, Zhao X, Drlica K et al.. Mutant prevention concentration for ciprofloxacin and levofloxacin with Pseudomonas aeruginosa .  Int J Antimicrob Agents. 2006;  27 120-124
• 35 Schentag J J, Nix D E, Adelman M H et al.. Mathematical examination of dual individualization principles, I: Relationships between AUC above MIC and area under the inhibitory curve for cefmenoxime, ciprofloxacin, and tobramycin.  DICP. 1991;  25 1050-1057
• 36 Forrest A, Nix D E, Ballow C H et al.. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients.  Antimicrob Agents Chemother. 1993;  37 1073-1081
• 37 Preston S L, Drusano G L, Berman A L et al.. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials.  , [see comment] JAMA. 1998;  279 125-129
• 38 Ambrose P G, Grasela D M, Grasela T H et al.. Pharmacodynamics of fluoroquinolones against Streptococcus pneumoniae in patients with community-acquired respiratory tract infections.  Antimicrob Agents Chemother. 2001;  45 2793-2797
• 39 Drusano G L, Preston S L, Fowler C et al.. 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 Dis. 2004;  189 1590-1597
• 40 Drusano G L, Weir M, Forrest A et al.. Pharmacokinetics of intravenously administered ciprofloxacin in patients with various degrees of renal function.  Antimicrob Agents Chemother. 1987;  31 860-864
• 41 Gonzalez M A, Moranchel A H, Duran S et al.. Multiple-dose pharmacokinetics of ciprofloxacin administered intravenously to normal volunteers.  Antimicrob Agents Chemother. 1985;  28 235-239
• 42 Overholser B R, Kays M B, Lagvankar S et al.. Pharmacokinetics of intravenously administered levofloxacin in men and women.  Pharmacotherapy. 2005;  25 1310-1318
• 43 Chow A T, Fowler C, Williams R R et al.. Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.  Antimicrob Agents Chemother. 2001;  45 2122-2125
• 44 Stass H, Kubitza D, Halabi A et al.. Pharmacokinetics of moxifloxacin, a novel 8-methoxy-quinolone, in patients with renal dysfunction.  Br J Clin Pharmacol. 2002;  53 232-237
• 45 Ostergaard C, Sorensen T K, Knudsen J D et al.. Evaluation of moxifloxacin, a new 8-methoxyquinolone, for treatment of meningitis caused by a penicillin-resistant pneumococcus in rabbits.  Antimicrob Agents Chemother. 1998;  42 1706-1712
• 46 Stass H, Kubitza D, Moller J G et al.. Influence of activated charcoal on the pharmacokinetics of moxifloxacin following intravenous and oral administration of a 400 mg single dose to healthy males.  Br J Clin Pharmacol. 2005;  59 536-541
• 47 Gajjar D A, LaCreta F P, Uderman H D et al.. A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men.  Pharmacotherapy. 2000;  20(6 Pt 2) 49S-58S
• 48 Olsen K M, Rebuck J A, Weidenbach T et al.. Pharmacokinetics of intravenous trovafloxacin in critically ill adults.  Pharmacotherapy. 2000;  20 400-404
• 49 Noreddin A M, H V L, Zhanel G G. Pharmacokinetics and pharmacodynamics of the new quinolones.  Curr Opin Pharmacol. 2001;  1 459-463
• 50 Soman A, Honeybourne D, Andrews J et al.. Concentrations of moxifloxacin in serum and pulmonary compartments following a single 400 mg oral dose in patients undergoing fibre-optic bronchoscopy.  J Antimicrob Chemother. 1999;  44 835-838
• 51 Birmingham M C, Guarino R, Heller A et al.. Ciprofloxacin concentrations in lung tissue following a single 400 mg intravenous dose.  J Antimicrob Chemother. 1999;  43(Suppl A) 43-48
• 52 Drusano G L, Plaisance K I, Forrest A et al.. Dose ranging study and constant infusion evaluation of ciprofloxacin.  Antimicrob Agents Chemother. 1986;  30 440-443
• 53 Capitano B, Mattoes H M, Shore E et al.. Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults.  Chest. 2004;  125 965-973
• 54 Rodvold K A, Danziger L H, Gotfried M H et al.. Steady-state plasma and bronchopulmonary concentrations of intravenous levofloxacin and azithromycin in healthy adults.  Antimicrob Agents Chemother. 2003;  47 2450-2457
• 55 Bellmann R, Egger P, Gritsch W et al.. Elimination of levofloxacin in critically ill patients with renal failure: influence of continuous veno-venous hemofiltration.  Int J Clin Pharmacol Ther. 2002;  40 142-149
• 56 Jones E M, McMullin C M, Hedges A J et al.. The pharmacokinetics of intravenous ciprofloxacin 400 mg 12 hourly in patients with severe sepsis: the effect of renal function and intra-abdominal disease.  J Antimicrob Chemother. 1997;  40 121-124
• 57 Fuhrmann V, Schenk P, Jaeger W et al.. Pharmacokinetics of moxifloxacin in patients undergoing continuous venovenous haemodiafiltration.  J Antimicrob Chemother. 2004;  54 780-784
• 58 Malone R S, Fish D N, Abraham E et al.. Pharmacokinetics of levofloxacin and ciprofloxacin during continuous renal replacement therapy in critically ill patients.  Antimicrob Agents Chemother. 2001;  45 2949-2954
• 59 Vance-Bryan K, Guay D R, Rotschafer J C et al.. Clinical pharmacokinetics of ciprofloxacin.  Clin Pharmacokinet. 1990;  19 434-461
• 60 Aminimanizani A, Beringer P, Jelliffe R et al.. Comparative pharmacokinetics and pharmacodynamics of the newer fluoroquinolone antibacterials.  Clin Pharmacokinet. 2001;  40 169-187
• 61 Gous A, Lipman J, Scribante J et al.. Fluid shifts have no influence on ciprofloxacin pharmacokinetics in intensive care patients with intra-abdominal sepsis.  Int J Antimicrob Agents. 2005;  26 50-55
• 62 Garrelts J C, Jost G, Kowalsky S F et al.. Ciprofloxacin pharmacokinetics in burn patients.  Antimicrob Agents Chemother. 1996;  40 1153-1156
• 63 Kiser T H, Hoody D W, Obritsch M D et al.. Levofloxacin pharmacokinetics and pharmacodynamics in patients with severe burn injury.  Antimicrob Agents Chemother. 2006;  50 1937-1945
• 64 Lesne-Hulin A, Bourget P, Ravat F et al.. Clinical pharmacokinetics of ciprofloxacin in patients with major burns.  Eur J Clin Pharmacol. 1999;  55 515-519
• 65 Ambrose P G, Bhavnani S M, Owens Jr R C et al.. Clinical pharmacodynamics of quinolones.  Infect Dis Clin North Am. 2003;  17 529-543
• 66 Forrest A, Chodosh S, Amantea M A et al.. Pharmacokinetics and pharmacodynamics of oral grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis.  J Antimicrob Chemother. 1997;  40(Suppl A) 45-57
• 67 Drusano G L, Johnson D E, Rosen M et al.. Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis.  Antimicrob Agents Chemother. 1993;  37 483-490
• 68 Jumbe N, Louie A, Leary R et al.. Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy.  J Clin Invest. 2003;  112 275-285
• 69 Craig W A, Craig W A. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.  Clin Infect Dis. 1998;  26 1-10 , quiz 11-2
• 70 Firsov A A, Zinner S H, Vostrov S N et al.. AUC/MIC relationships to different endpoints of the antimicrobial effect: multiple-dose in vitro simulations with moxifloxacin and levofloxacin.  J Antimicrob Chemother. 2002;  50 533-539
• 71 Madaras-Kelly K J, Ostergaard B E, Hovde L B et al.. Twenty-four-hour area under the concentration-time curve/MIC ratio as a generic predictor of fluoroquinolone antimicrobial effect by using three strains of Pseudomonas aeruginosa and an in vitro pharmacodynamic model.  Antimicrob Agents Chemother. 1996;  40 627-632
• 72 Owens Jr R C, Ambrose P G, Owens Jr R C, Ambrose P G. Antimicrobial safety: focus on fluoroquinolones.  Clin Infect Dis. 2005;  41(Suppl 2) S144-S157
• 73 Ball P, Stahlmann R, Kubin R et al.. Safety profile of oral and intravenous moxifloxacin: cumulative data from clinical trials and postmarketing studies.  Clin Ther. 2004;  26 940-950
• 74 Lipsky B A, Baker C A, Lipsky B A, Baker C A. Fluoroquinolone toxicity profiles: a review focusing on newer agents.  Clin Infect Dis. 1999;  28 352-364
• 75 Lipman J, Allworth A, Wallis S C et al.. Cerebrospinal fluid penetration of high doses of intravenous ciprofloxacin in meningitis.  Clin Infect Dis. 2000;  31 1131-1133
• 76 Akahane K, Sekiguchi M, Une T et al.. Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites.  Antimicrob Agents Chemother. 1989;  33 1704-1708
• 77 Quigley C A, Lederman J R, Quigley C A, Lederman J R. Possible gatifloxacin-induced seizure.  Ann Pharmacother. 2004;  38 235-237
• 78 Owens Jr R C, Owens Jr R C. QT prolongation with antimicrobial agents: understanding the significance.  Drugs. 2004;  64 1091-1124