Increasing evidence suggests that antibiotic dosing in critically ill patients with acute kidney injury (AKI) often does not achieve pharmacodynamic goals, and the continued high mortality rate due to infectious causes appears to confirm these findings. Although there are compelling reasons why clinicians should use more aggressive antibiotic dosing, particularly in patients receiving aggressive renal replacement therapies, concerns for toxicity associated with higher doses are real. The presence of multisystem organ failure and polypharmacy predispose these patients to drug toxicity. This article examines the pharmacokinetic and pharmacodynamic consequences of critical illness, AKI, and renal replacement therapy and describes potential solutions to help clinicians give “enough but not too much” in these very complicated patients.
DellingerRPLevyMMRhodesA. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228.
2.
UchinoSKellumJABellomoR. Acute renal failure in critically ill patients. JAMA. 2005;294(7):813–818.
3.
SilvesterWBellomoRColeL. Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med. 2001;29(10):1910–1915.
4.
HosteEAClermontGKerstenA. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10(3):R73.
5.
WaikarSSLiuKDChertowGM. The incidence and prognostic significance of acute kidney injury. Curr Opin Nephrol Hypertens. 2007;16(3):227–236.
6.
BagshawSMUchinoSKellumJA. Association between renal replacement therapy in critically ill patients with severe acute kidney injury and mortality. J Crit Care. 2013;28(6):1011–1018.
7.
AronoffGRAronoffJR. Drug prescribing in kidney disease: can’t we do better?Am J Kidney Dis. 2014;63(3):382–383.
8.
FaragAGargAXLiLJainAK. Dosing errors in prescribed antibiotics for older persons with CKD: a retrospective time series analysis. Am J Kidney Dis. 2014;63(3):422–428.
9.
MicekSTWelchECKhanJ. Resistance to empiric antimicrobial treatment predicts outcome in severe sepsis associated with gram-negative bacteremia. J Hosp Med. 2011;6(7):405–410.
10.
AngusDCLinde-ZwirbleWTLidickerJClermontGCarcilloJPinskyMR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–1310.
11.
MartinGSManninoDMEatonSMossM. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med. 2003;348(16):1546–1554.
12.
AngusDCPereiraCASilvaE. Epidemiology of severe sepsis around the world. Endocr Metab Immune Disord Drug Targets. 2006;6(2):207–212.
13.
VincentJLRelloJMarshallJ. International study of the prevalence and outcomes of infection in intensive care units(EPIC II study). JAMA. 2009;302(21):2323–2329.
14.
QuenotJPBinquetCKaraO. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit Care. 2013;17(2):R65.
15.
KollefMHShermanGWardSFraserVJ. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Chest. 1999;115(2):462–474.
16.
IbrahimEHShermanGWardSFraserVJKollefMH. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146–155.
17.
HarbarthSGarbinoJPuginJRomandJALewDPittetD. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115(7):529–535.
18.
ShorrAFMicekSTWelchECDohertyJAReichleyRMKollefMH. Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med. 2011;39(1):46–51.
19.
TacconeFSLaterrePFDugernierT. Insufficient B-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care. 2010;14(4):R126.
20.
SeylerLCottonFTacconeFS. Recommended B-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy. Crit Care. 2011;15(3):R137.
BinderLSchwörerHHoppeS. Pharmacokinetics of meropenem in critically ill patients with severe infections. Ther Drug Monit. 2013;35(1):63–70.
23.
StechmillerJKTreloarDAllenN. Gut dysfunction in critically ill patients: a review of the literature. Am J Crit Care. 1997;6(3):204–209.
24.
BoucherBAWoodGCSwansonJM. Pharmacokinetic changes in critically illness. Crit Care Clin. 2006;22(2):255–271.
25.
SmithBSYogaratnamDLevasseur-FranklinKEForniAFongJ. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012;141(5):1327–1336.
26.
RobertsDJ. Drug absorption, distribution, metabolism and excretion considerations in critically ill adults. Expert Opin Drug Metab Toxicol. 2013;9(9):1067–1084.
27.
NguyenNQNgMPChapmanMFraserRJHollowayRH. The impact of admission diagnosis on gastric emptying in critically ill patients. Crit Care. 2007;11(1):R16.
28.
MuellerBABriertonDGAbelSRBowmanL. Effect of enteral feeding with Ensure on oral bioavailabilities of ofloxacin and ciprofloxacin. Antimicrob Agents Chemother. 1994;38(9):2101–2105.
29.
MimozOBinterVJacolotA. Pharmacokinetics and absolute bioavailability of ciprofloxacin administered through a nasogastric tube with continuous enteral feeding to critically ill patients. Intensive Care Med. 1998;24(10):1047–1051.
30.
BlumRAD’AndreaDTFlorentinoBM. Increased gastric pH and the bioavailability of fluconazole and ketoconazole. Ann Intern Med. 1991;114(9):755–757.
31.
PiscitelliSCGossTFWiltonJD’AndreaDTGoldsteinHSchentagJJ. Effects of ranitidine and sucralfate on ketoconazole bioavailability. Antimicrob Agents Chemother. 1991;35(9):1765–1771.
32.
ChinTWFLoebMFongIW. Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole. Antimicrob Agents Chemother. 1995;39(8):1671–1675.
33.
Dörffler-MellyJde JongeEPontAC. Bioavailability of subcutaneous low-molecular- weight heparin to patients on vasopressors. Lancet. 2002;359(9309):849–850.
34.
HaasCENelsenJLRaghavendranK. Pharmacokinetics and pharmacodynamics of enoxaparin in multiple trauma patients. J Trauma. 2005;59(6):1336–1343.
35.
ParrilloJE. Pathogenetic mechanisms of septic shock. N Engl J Med. 1993;328(20):1471–1477.
36.
TriginerCIzquierdoIFernandezR. Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med. 1990;16(5):303–306.
37.
GousAGDanceMDLipmanJLuytDKMathivhaRScribanteJ. Changes in vancomycin pharmacokinetics in critically ill infants. Anaesth Intensive Care. 1995;23(6):678–682.
BuijkSEMoutonJWGyssensICVerbrughHABruiningHA. Experience with a once- daily dosing program of aminoglycosides in critically ill patients. Intensive Care Med. 2002;28(7):936–942.
40.
Del Mar Fernandez de Gatta GarciaMRevillaNCalvoMVDominquez-GilASanchez NavarroA. Pharmacokinetic/pharmacodynamics analysis of vancomycin in ICU patients. Intensive Care Med. 2007;33(2):279–285.
41.
TacconeFSHitesMBeumierMScollettaSJacobsF. Appropriate antibiotic dosage levels in the treatment of severe sepsis and septic shock. Curr Infect Dis Rep. 2011;13(
5):406–415.
42.
VilayAMGrioMDePestelDD. Daptomycin pharmacokinetics in critically ill patients receiving continuous venovenous hemodialysis. Crit Care Med. 2011;39(1):19–25.
43.
WenischJMMeyerBFuhrmannV. Multiple-dose pharmacokinetics of daptomycin during continuous venovenous haemodiafiltration. J Antimicrob Chemother. 2012;67(4):977–983.
44.
BauerSRSalemCConnorMJJr. Pharmacokinetics and pharmacodynamics of piperacillin-tazobactam in 42 patients treated with concomitant CRRT. Clin J Am Soc Nephrol. 2012;7(3):452–457.
45.
KhadzhynovDSlowinskiTLiekerI. Plasma pharmacokinetics of daptomycin in critically ill patients with renal failure and undergoing CVVHD. Int J Clin Pharmacol Ther. 2011;49(11):656–665.
46.
DvorchikBArbeitRDChungJLiuSKnebelWKastrissiosH. Population pharmacokinetics of daptomycin. Antimicrob Agents Chemother. 2004;48(8):2799–2807.
47.
BothaFJvan derBijl PSeifartHIParkinDP. Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient. Intensive Care Med. 1996;22(5):443–446.
48.
TormoCAbadFJRonchera-OmsCLParraVJimenezNV. Critically-ill patients receiving total parenteral nutrition show altered amikacin pharmacokinetics. Clinical Nutrition. 1995;14(4):254–259.
49.
Ronchera-OmsCLTormoCOrdovasJPAbadJJimenezNV. Expanded gentamicin volume of distribution in critically ill adult patients receiving total parenteral nutrition. J Clin Pharm Ther. 1995;20(5):253–258.
50.
PayenDde PontACSakrY. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care. 2008;12(3):R74.
51.
BouchardJSorokoSBChertowGM. Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. Kidney Int. 2009;76(4):422–427.
52.
GramsMEEstrellaMMCoreshJBrowerRGLiuKD; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network. Fluid balance, diuretic use, and mortality in acute kidney injury. Clin J Am Soc Nephrol. 2011;6(5):966–973.
53.
TeixeiraCGarzottoFPiccinniP. Fluid balance and urine volume are independent predictors of mortality in acute kidney injury. Crit Care. 2013;17(1):R14.
54.
SAFE Study Investigators. FinferSBellomoRMcEvoyS. Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: analysis of data from the Saline versus Albumin Fluid Evaluation (SAFE) study. BMJ. 2006;333(7577):1044.
55.
RobertsJAFedericoPLipmanJ. The clinical relevance of plasma protein binding changes. Clin Pharmacokinet. 2013;52(1):1–8.
56.
BurkhardtOKumarVKatterweD. Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration. J Antimicrob Chemother. 2007;59(
2):277–284.
57.
EylerRFVilayAMNaderAM. Pharmacokinetics of ertapenem in critically ill patients receiving continuous venovenous hemodialysis or hemodiafiltration. Antimicrob Agents Chemother. 2014;58(3):1320–1326.
58.
AndreasenF. The effect of dialysis on the protein binding of drugs in the plasma of patients with acute renal failure. Acta Pharmacol Toxicol. 1974;34(4):284–294.
59.
MusscheMMBelpaireFMBogaertMG. Plasma protein binding of phenylbutazone during recovery from acute renal failure. Eur J Clin Pharmacol. 1975;9(1):69–71.
60.
VilayAMChurchwellMDMuellerBA. Clinical review: drug metabolism and nonrenal clearance in acute kidney injury. Crit Care. 2008;12(6):235.
61.
LalandeLCharpiatBLeboucherGTodM. Consequences of renal failure on non-renal clearance of drugs. Clin Pharmacokinet. 2014;53(6):521–532.
62.
KirwanCJMacPheeIALeeTHoltDWPhilipsBJ. Acute kidney injury reduces the hepatic metabolism of midazolam in critically ill patients. Intensive Care Med. 2012;38(1):76–84.
63.
SunHFrassettoLBenetLZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109(1-2):1–11.
64.
JonesEMMcMullinCMHedgesAJ. 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(1):121–124.
65.
MaciasWLMuellerBAScarimSK. Vancomycin pharmacokinetics in acute renal failure: preservation of nonrenal clearance. Clin Pharmacol Ther. 1991;18(4):451–458.
66.
MuellerBAScarimSKMaciasWL. Comparison of imipenem pharmacokinetics in patients with acute or chronic renal failure treated with continuous hemofiltration. Am J Kidney Dis. 1993;21(2):172–179.
67.
TegederIBremerFOelkersR. Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration. Antimicrob Agents Chemother. 1997;41(12):2540–2545.
68.
GolperTANoonanHMElzingaL. Vancomycin pharmacokinetics, renal handling, and nonrenal clearances in normal human patients. Clin Pharmacol Ther. 1988;43(5):565–570.
69.
BrunetSLeblancMGeadahDParentDCourteauSCardinalJ. Diffusive and convective solute clearances during continuous renal replacement therapy at various dialysate and ultrafiltration flow rates. Am J Kidney Dis. 1999;34(3):886–892.
70.
ChurchwellMDMuellerBA. Drug dosing during continuous renal replacement therapy. Semin Dial. 2009;22(2):185–188.
ChoiGGomersallCDTianQJoyntGMFreebairnRLipmanJ. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med. 2009;37(7):2268–2282.
73.
HeintzBHMatzkeGRDagerWE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29(5):562–577.
74.
EylerRFMuellerBA. Antibiotic dosing in critically ill patients with acute kidney injury. Nat Rev Nephrol. 2011;7(4):226–235.
75.
KielsteinJTBurkhardtO. Dosing of antibiotics in critically ill patients undergoing renal replacement therapy. Curr Pharm Biotechnol. 2011;12(12):2015–2019.
76.
BogardKNPetersonNTPlumbTJErwinMWFullerPDOlsenKM. Antibiotic dosing during sustained low-efficiency dialysis: special consideration in adult critically ill patients. Crit Care Med. 2011;39(3):560–570.
77.
ScovilleBAMuellerBA. Medication dosing in critically ill patients with acute kidney injury with renal replacement therapy. Am J Kideny Dis. 2013;61(3):490–500.
78.
MuellerBASmoyerWE. Challenges in developing evidence-based drug dosing guidelines for adults and children receiving renal replacement therapy. Clin Pharmacol Ther. 2009;86(5):479–482.
79.
VesconiSCruzDNFumagalliR. DOse REsponse Multicentre International collaborative Initiative (DO-RE-MI Study Group): delivered dose of renal replacement therapy and mortality in critically ill patients with acute kidney injury. Crit Care. 2009;13(2):R57.
80.
VA/NIH Acute Renal Failure Trial Network, PalevskyPMZhangJHO’ConnorTZ. Intensity of renal support in critically ill patients with acute kidney injury. N Engl J Med. 2008;359(1):7–20.
81.
RENAL Replacement Therapy Study Investigators, BellomoRCassAColeL. Intensity of continuous renal replacement therapy in critically ill patients. N Eng J Med. 2009;361(17):1627–1638.
CovajesCScollettaSPenacciniL. Continuous infusion of vancomycin in septic patients receiving continuous renal replacement therapy. Int J Antimicrob Agents. 2013;41(3):261–266.
84.
RobertsJAMehtaRLLipmanJ. Sustained low efficiency dialysis allows rational renal replacement therapy, but dose it allow rational drug dosing?Crit Care Med. 2011;39(3):602–603.
85.
FiaccadoriEMaggioreURotelliC. Removal of linezolid by conventional intermittent hemodialysis, sustained low-efficiency dialysis, or continuous venovenous hemofiltration in patients with acute renal failure. Crit Care Med. 2004;32(12):2437–2442.
86.
ArzuagaAMaynarJGascónAR. Influence of renal function on the pharmacokinetics of piperacillin/tazobactam in intensive care unit patients during continuous venovenous hemofiltration. J Clin Pharmacol. 2005;45(2):168–176.
87.
KielsteinJTCzockDSchopkeT. Pharmacokinetics and total elimination of meropenem and vancomycin in intensive care unit patients undergoing extended daily dialysis. Crit Care Med. 2006;34(1):51–56.
88.
BurkhardtOJoukhadarCTraunmullerFHademJWelteTKielsteinJT. Elimination of daptomycin in a patient with acute renal failure undergoing extended daily dialysis. J Antimicrob Chemother. 2008;61(1):224–225.
89.
WilsonFPBernsJS. Vancomycin levels are frequently subtherapeutic during continuous venovenous hemodialysis (CVVHD). Clin Nephrol. 2012;77(4):329–331.
90.
ZollerMMaierBHornussC. Variability of linezolid concentrations after standard dosing in critically ill patients: a prospective observational study. Crit Care. 2014;18(4):R148.
91.
OwensRCShorrAF. Rational dosing of antimicrobial agents: pharmacokinetic and pharmacodynamics strategies. Am J Health-Sys Pharm. 2009;66(4):S23–S30.
92.
MariatCVenetCJehlF. Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation. Crit Care. 2006;10(1):R26.
93.
LanggartnerJVasoldAGlückTRengMKeesF. Pharmacokinetics of meropenem during intermittent and continuous intravenous application in patients treated by continuous renal replacement therapy. Intensive Care Med. 2008;34(6):1091–1096.
94.
SaugelBNowackMCHapfelmeierA. Continuous intravenous administration of vancomycin in medical intensive care unit patients. J Crit Care. 2013;28(1):9–13.
95.
BeumierMRobertsJAKabtouriH. A new regimen for continuous infusion of vancomycin during continuous renal replacement therapy. J Antimicrob Chemother. 2013;68(12):2859–2865.
96.
LodiseTPLomaestroBDrusanoG. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended infusion dosing strategy. Clin Infect Dis. 2007;44(3):357–363.
97.
KielsteinJTEngbersCBode-BoegerSM. Dosing of daptomycin in intensive care unit patients with acute kidney injury undergoing extended dialysis-a pharmacokinetic study. Nephrol Dial Transplant. 2010;25(5):1537–1541.
98.
MuellerBAScovilleBA. Adding to the armamentarium: antibiotic dosing in extended dialysis. Clin J Am Soc Nephrol. 2012;7(3):373–375.
99.
TacconeFSde BackerDLaterrePF. Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy. Int J Antimicrob Agents. 2011;37(6):5.
100.
TruongJLEvkovichBJPadiglioneAA. Simple approach to improving vancomycin dosing in intensive care: a standardized loading dose results in earlier therapeutic levels. Intern Med J. 2012;42(1):23–29.
101.
Kamel MohamedOHWahbaIMWatnickS. Administration of tobramycin in the beginning of the hemodialysis session: a novel intradialytic dosing regimen. Clin J Am Soc Nephrol. 2007;2(4):694–699.
102.
SowinskiKMMagnerSJLucksiriAScottMKHamburgerRJMuellerBA. Influence of hemodialysis on gentamicin pharmacokinetics, removal during hemodialysis, and recommended dosing. Clin J Am Soc Nephrol. 2008;3(2):355–361.
103.
VeisteinAVenisseNBadinJPinsardMRobertRDupuisA. Gentamicin in hemodialyzed critical care patients: early dialysis after administration of a high dose should be considered. Antimicrob Agents Chemother. 2013;57(2):977–982.
104.
RobertsJAFieldJVisserA. Using population pharmacokinetics to determine gentamicin dosing during extended daily diafiltration in critically ill patients with acute kidney injury. Antimicrob Agents Chemother. 2010;54(9):3635–3640.
105.
CalboEGarauJ. Application of pharmacokinetics and pharmacodynamics to antimicrobial therapy of community acquired respiratory tract infections. Respiration. 2005;72(6):561–571.
106.
ScaglioneFParaboniL. Influence of pharmacokinetics/pharmacodynamics of antibacterials in their dosing regimen selection. Expert Rev Anti Infect Ther. 2006;4(3):479–490.
107.
McKinnonPSPaladinoJASchentagJJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T > MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents. 2008;31:345–351.
108.
Valtonen MTiulaTakkunenOBackmanJTNeuvonenPJ. Elimination of the piperacillin/tazobactam combination during continuous venovenous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother. 2001;48(6):881–885.
109.
FalagasMETansarliGSIkawaKVardakasKZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infec Dis. 2013;56(2):272–282.
110.
ChantCLeungAFriedrichJO. Optimal dosing of antibiotics in critically ill patients using continuous/extended infusion: a systematic review and meta-analysis. Crit Care. 2013;17(6):R279.
111.
MoriyamaBHenningSANeuhauserMMDannerRLWalshTJ. Continuous-infusion beta-lactam antibiotics during continuous venovenous hemofiltration for the treatment of resistant gram-negative bacteria. Ann Pharmacother. 2009;43(7):1324–1337.
112.
JoyMSMatzkeGRFryeRFPalevskyPM. Determinants of vancomycin clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis. Am J Kidney Dis. 1998;31(6):1019–1027.
MooreRDLietmanPSSmithCR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis. 1987;155(1):93–99.
115.
MartinezMNPapichMGDrusanoGL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012;56(6):2795–2805.
116.
JumbeNLouieALearyR. Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy. J Clin Invest. 2003;112(2):275–285.
MatsuoHHayashiJOnoK. Administration of aminoglycosides to hemodialysis patients immediately before dialysis: a new dosing modality. Antimicrob Agents Chemother. 1997;41(12):2597–2601.
119.
TeigenMMDuffullSDangLJohnsonDW. Dosing of gentamicin in patients with end-stage renal disease receiving hemodialysis. J Clin Pharmacol. 2006;46(11):1259–1267.
RyanDMCarsO. A problem in the interpretation of beta-lactam antibiotic levels in tissues. J Antimicrob Chemother. 1983;12(3):281–284.
122.
SchentagJJHellerASHardyBGWelsPB. Antibiotic penetration in liver infection: a case of tobramycin failure responsive to moxalactam. Am J Gastroenterol. 1983;78(10):641–644.
123.
JoukhadarCFrossardMMayerBX. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med. 2001;29(2):385–391.
124.
ZeitlingerMAErovicBMSauermannRGeorgopoulosAMüllerMJoukhadarC. Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis. J Antimicrob Chemother. 2005;56(4):703–708.
125.
KleknerABagyiKBognarLGasparAAndrasiMSzaboJ. Effectiveness of cephalosporins in the sputum of patients with nosocomial bronchopneumonia. J Clin Microbiol. 2006;44(9):3418–3421.
126.
StolleLBPlockNJoukhadarC. Pharmacokinetics of linezolid in bone tissue investigated by in vivo microdialysis. Scand J Infect Dis. 2008;40(1):24–29.
127.
TamVHGamezEAWestonJS. Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: implications on the appropriateness of the resistance breakpoint. Clin Infect Dis. 2008;46(6):862–867.
128.
SorianoAMarcoFMartínezJA. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis. 2008;46(2):193–200.
129.
HidayatLKHsuDIQuistRShrinerKAWong-BeringerA. High-dose vancomycin therapy for methicillin-resistant Staphylococcus aureus infections: efficacy and toxicity. Arch Intern Med. 2006;166(19):2138–2144.
130.
RybakMJLomaestroBMRotschaferJC. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacist. Clin Infect Dis. 2009;49(3):325–327.
131.
KullarRMcClellanIGeriakMSakoulasG. Efficacy and safety of daptomycin in patients with renal impairment: a multicenter retrospective analysis. Pharmacotherapy. 2014;34(6):582–589.
132.
National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32(6):470–485.
133.
KlevensRMEdwardsJRGaynesRP. The impact of antimicrobial-resistant, health care- associated infections on mortality in the United States. Clin Infect Dis. 2008;47(7):927–930.
134.
BoucherHWTalbotGHBradleyJS. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1–12.
135.
PetersNKDixonDMHollandSMFauciAS. The research agenda of the national institute of allergy and infectious diseases for antimicrobial resistance. J Infect Dis. 2008;197(8):1087–1093.
136.
BarthRHDeVincenzoN. Use of vancomycin in high-flux hemodialysis: experience with 130 courses of therapy. Kidney Int. 1996;50(3):929–936.
137.
TaberSSMuellerBA. Drug-associated renal dysfunction. Crit Care Clin. 2006;22(2)357–374.
138.
Kane-GillSLKirisciLVerricoMMRothschildJM. Analysis of risk factors for adverse drug events in critically ill patients. Crit Care Med. 2012;40(3):823–828.
139.
HartzellJDNeffRAkeJ. Nephrotoxicity associated with intravenous colistin (colistin sodium) treatment at a tertiary care medical center. Clin Infect Dis. 2009;48(12):1724–1728.
140.
KwonJALeeJEHuhW. Predictors of acute kidney injury associated with intravenous colistin treatment. Int J Antimicrob Agents. 2010;35(5):473–477.
141.
SchentagJJCerraFBPlautME. Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients. Antimicrob Agents Chemother. 1982;21(5):721–726.
142.
ZagerRA. Endotoxemia, renal hypoperfusion, and fever: interactive risk factors for aminoglycoside and sepsis associated acute renal failure. Am J Kid Dis. 1992;20(3):223–230.
143.
VanHalPatersonDLLodiseTP. Systematic review and meta-analysis of vancomycin- induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734–744.
144.
MooreRDSmithCRLipskyJJMellitsEDLietmanPS. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med. 1984;100(3):352–357.
145.
LodiseTPLomaestroBGravesJDrusanoGL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008;52(4):1330–1336.
146.
LodiseTPPatelNLomaestroBMRodvoldKADrusanoGL. Relationship between initial vancomycin concentration time profile and nephrotoxicity. Clin Infect Dis. 2009;49(4):507–514.
147.
PritchardLBakerCLeggettJSehdevPBrownABayleyKB. Increasing vancomycin serum trough concentrations and incidence of nephrotoxicity. Am J Med. 2010;123(12):1143–1149.
148.
BossoJANappiJRudisillC. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother. 2011;55(12):5475–5479.
149.
CanoELHaqueNZWelchVL. Incidence of Nephrotoxicity and Association With Vancomycin Use in Intensive Care Unit Patients With Pneumonia: Retrospective Analysis of the IMPACT-HAP Database. Clin Ther. 2012;34(1):149–157.
150.
BertinoJSBookerLAFranckPAJenkinsPLFranckKRNafzigerAN. Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring. J Infect Dis. 1993;167(1):173–179.
151.
RybakMJAbateBJKangSLRuffingMJLernerSADrusanoGL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43(7):1549–1555.
152.
DrusanoGLAmbrosePGBhavnaniSMBertinoJSNafzigerANLouieA. Back to the future: using aminoglycosides again and how to dose them optimally. Clin Infect Dis. 2007;45(15):753–760.
153.
CalandraGBBrownKRGradLCAhonkhaiVIWangCAzizMA. Review of adverse experiences and tolerability in the first 2516 patients treated with imipenem/cilastatin. Am J Med. 1985;78(6A):73–78.
154.
HellingerWCBrewerNS. Carbapenems and monobactams: imipenem, meropenem and aztreonam. Mayo Clin Proc. 1999;74(4):420–434.
155.
NorrbySR. Carbapenems in serious infections: a risk benefit assessment. Drug Saf. 2000;22(3):191–194.
156.
NorrbySRNewellPAFauknerKLLeskyW. Safety profile of meropenem international clinical experience based on the first 3125 patients treated with meropenem. J Antimicrob Chemother. 2005;36(suppl A):207–223.
157.
NicolauDP. Carbapenems: a potent class of antibiotics. Expert Opin Pharmacother. 2008;9(1):23–37.
158.
Martinez-RodriguezJEBarrigaFJSantamariaJ. Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med. 2001;111(2):115–119.
159.
GrillMFMagantiR. Cephalosporin-induced neurotoxicity: clinical manifestations, potential pathogenic mechanisms, and the role of electroencephalographic monitoring. Ann Pharmacother. 2008;42(12):1843–1850.
160.
ChapuisTMGiannoniEMajcherczykPA. Prospective monitoring of cefepime in intensive care unit adult patients. Crit Care. 2010;14(2):R51.
161.
FugateJEKalimullahEAHockerSEClarkSLWijdicksEFRabinsteinAA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264.
162.
BagshawSM. Short- and long-term survival after acute kidney injury. Nephrol Dial Transplant. 2008;23(7):2126–2128.
163.
SchifflHFischerR. Five-year outcomes of severe acute kidney injury requiring renal replacement therapy. Nephrol Dial Transplant. 2008;23(7):2235–2241.
164.
EisenbergJMKofferHGlickHA. What is the cost of nephrotoxicity associated with aminoglycosides?Ann Intern Med. 1987;107(6):900–909.
