Therapeutic Drug Monitoring of Meropenem and Piperacillin in Critical Illness-Experience and Recommendations from One Year in Routine Clinical Practice

Christina Scharf, Michael Paal, Ines Schroeder, Michael Vogeser, Rika Draenert, Michael Irlbeck, Michael Zoller, Uwe Liebchen, Christina Scharf, Michael Paal, Ines Schroeder, Michael Vogeser, Rika Draenert, Michael Irlbeck, Michael Zoller, Uwe Liebchen

Abstract

Various studies have reported insufficient beta-lactam concentrations in critically ill patients. The extent to which therapeutic drug monitoring (TDM) in clinical practice can reduce insufficient antibiotic concentrations is an ongoing matter of investigation. We retrospectively evaluated routine meropenem and piperacillin measurements in critically ill patients who received antibiotics as short infusions in the first year after initiating a beta-lactam TDM program. Total trough concentrations above 8.0 mg/L for meropenem and above 22.5 mg/L for piperacillin were defined as the breakpoints for target attainment. We included 1832 meropenem samples and 636 piperacillin samples. We found that 39.3% of meropenem and 33.6% of piperacillin samples did not reach the target concentrations. We observed a clear correlation between renal function and antibiotic concentration (meropenem, r = 0.53; piperacillin, r = 0.63). Patients with renal replacement therapy or creatinine clearance (CrCl) of <70 mL/min had high rates of target attainment with the standard dosing regimens. There was a low number of patients with a CrCl >100 mL/min that achieved the target concentrations with the maximum recommended dosage. Patients with impaired renal function only required TDM if toxic side effects were noted. In contrast, patients with normal renal function required different dosage regimens and TDM-guided therapy to reach the breakpoints of target attainment.

Keywords: critical illness; experience; meropenem; pharmacokinetic; piperacillin; renal function; therapeutic drug monitoring (TDM).

Conflict of interest statement

Upon manuscript submission, all authors declare they have no competing interests.

Figures

Figure 1
Figure 1
The distribution of meropenem trough level concentrations with the administration of 1 g (q8) and 2 g (q8) in relation to the individual creatinine clearance (CrCl) in patients without renal replacement therapy. The vertical black lines demarcate groups 1–3, and the red horizontal lines denote the breakpoint for target attainment and the toxic breakpoint. Note: log: logarithmic, MER: meropenem, CrCl: creatinine clearance.
Figure 2
Figure 2
The distribution of piperacillin trough level concentrations with the administration of 4.5 g of piperacillin-tazobactam, twice a day (q12), three times a day (q8), and four times a day (q6) in relation to the individual creatinine clearance (CrCl) in patients without renal replacement therapy. The vertical black lines demarcate groups 1–3, and the red horizontal lines denote the breakpoint for target attainment and the toxic breakpoint. Note: log: logarithmic, PIP: piperacillin, CrCl: creatinine clearance.
Figure 3
Figure 3
Dosing algorithm for critically ill patients treated with meropenem and piperacillin based on renal function. Note: RRT: renal replacement therapy, CrCl: creatinine-clearance, MER: meropenem, q8: eight-hourly, SI: short infusion = 30 minutes, TDM: therapeutic drug monitoring, PI: prolonged infusion, CI: continuous infusion, PIP: piperacillin, q12: 12-hourly, q6: six-hourly.

References

    1. Rhodes A., Evans L.E., Alhazzani W., Levy M.M., Antonelli M., Ferrer R., Kumar A., Sevransky J.E., Sprung C.L., Nunnally M.E., et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43:304–377. doi: 10.1007/s00134-017-4683-6.
    1. Angus D.C., Linde-Zwirble W.T., Lidicker J., Clermont G., Carcillo J., Pinsky M.R. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit. Care Med. 2001;29:1303–1310. doi: 10.1097/00003246-200107000-00002.
    1. Felton T.W., Goodwin J., O’Connor L., Sharp A., Gregson L., Livermore J., Howard S.J., Neely M.N., Hope W.W. Impact of Bolus dosing versus continuous infusion of Piperacillin and Tazobactam on the development of antimicrobial resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2013;57:5811–5819. doi: 10.1128/AAC.00867-13.
    1. Kumar A. Early antimicrobial therapy in severe sepsis and septic shock. Curr. Infect. Dis. Rep. 2010;12:336–344. doi: 10.1007/s11908-010-0128-x.
    1. Kumar A., Ellis P., Arabi Y., Roberts D., Light B., Parrillo J.E., Dodek P., Wood G., Kumar A., Simon D. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136:1237–1248. doi: 10.1378/chest.09-0087.
    1. Taccone F.S. Pierre-François, L.; Thierry, D.; Herbert, S.; Isabelle, D.; Xavier, W.; Daniel, D.B.; Brice, L.; Pierre, W.; Jean-Louis, V.; et al. Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit. Care. 2010;14:R126. doi: 10.1186/cc9091.
    1. Zander J., Dobbeler G., Nagel D., Maier B., Scharf C., Huseyn-Zada M., Jung J., Frey L., Vogeser M., Zoller M. Piperacillin concentration in relation to therapeutic range in critically ill patients--a prospective observational study. Crit. Care. 2016;20:79. doi: 10.1186/s13054-016-1255-z.
    1. Dulhunty J.M., Roberts J.A., Davis J.S., Webb S.A., Bellomo R., Gomersall C., Shirwadkar C., Eastwood G.M. Myburgh, J. Paterson, D.L. et al. A Multicenter Randomized Trial of Continuous versus Intermittent beta-Lactam Infusion in Severe Sepsis. Am. J. Respir. Crit. Care Med. 2015;192:1298–1305. doi: 10.1164/rccm.201505-0857OC.
    1. Craig W.A. The pharmacology of meropenem, a new carbapenem antibiotic. Clin. Infect. Dis. 1997;24(Suppl. 2):S266–S275. doi: 10.1093/clinids/24.Supplement_2.S266.
    1. Goncalves-Pereira J., Povoa P. Antibiotics in critically ill patients: A systematic review of the pharmacokinetics of beta-lactams. Crit. Care. 2011;15:R206. doi: 10.1186/cc10441.
    1. Roberts J.A., Abdul-Aziz M.H., Lipman J., Mouton J.W., Vinks A.A., Felton T.W., Hope W.W., Farkas A., Neely M.N., Schentag J.J., et al. Individualised antibiotic dosing for patients who are critically ill: Challenges and potential solutions. Lancet Infect. Dis. 2014;14:498–509. doi: 10.1016/S1473-3099(14)70036-2.
    1. De Waele J.J., Lipman J., Akova M., Bassetti M., Dimopoulos G., Kaukonen M., Koulenti D., Martin C., Montravers P., Rello J. Risk factors for target non-attainment during empirical treatment with beta-lactam antibiotics in critically ill patients. Intensive Care Med. 2014;40:1340–1351. doi: 10.1007/s00134-014-3403-8.
    1. Jamal J.A., Economou C.J., Lipman J., Roberts J.A. Improving antibiotic dosing in special situations in the ICU: Burns, renal replacement therapy and extracorporeal membrane oxygenation. Curr. Opin. Crit. Care. 2012;18:460–471. doi: 10.1097/MCC.0b013e32835685ad.
    1. Roberts J.A., Paul S.K., Akova M., Bassetti M., De Waele J.J., Dimopoulos G., Kaukonen K.M., Koulenti D., Martin C., Montravers P. DALI: Defining antibiotic levels in intensive care unit patients: Are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin. Infect. Dis. 2014;58:1072–1083. doi: 10.1093/cid/ciu027.
    1. Li C., Du X., Kuti J.L., Nicolau D.P. Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob. Agents Chemother. 2007;51:1725–1730. doi: 10.1128/AAC.00294-06.
    1. Guilhaumou R., Benaboud S., Bennis Y., Dahyot-Fizelier C., Dailly E., Gandia P., Goutelle S., Lefeuvre S., Mongardon N., Roger C. Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Societe Francaise de Pharmacologie et Therapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Societe Francaise d’Anesthesie et Reanimation-SFAR) Crit. Care. 2019;23:104. doi: 10.1186/s13054-019-2378-9.
    1. Ehmann L., Zoller M., Minichmayr I.K., Scharf C., Maier B., Schmitt M.V., Hartung N., Huisinga W., Vogeser M., Frey L., et al. Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: A prospective observational study. Crit. Care. 2017;21:263. doi: 10.1186/s13054-017-1829-4.
    1. Weber N., Jackson K., McWhinney B., Ungerer J., Kennedy G., Lipman J., Roberts J.A. Evaluation of pharmacokinetic/pharmacodynamic and clinical outcomes with 6-hourly empiric piperacillin-tazobactam dosing in hematological malignancy patients with febrile neutropenia. J. Infect. Chemother. 2019 doi: 10.1016/j.jiac.2019.02.014.
    1. Delattre I.K., Taccone F.S., Jacobs F., Hites M., Dugernier T., Spapen H., Laterre P.F., Wallemacq P.E., Van Bambeke F., Tulkens P.M. Optimizing beta-lactams treatment in critically-ill patients using pharmacokinetics/pharmacodynamics targets: Are first conventional doses effective? Expert Rev. Anti-Infect. Ther. 2017;15:677–688. doi: 10.1080/14787210.2017.1338139.
    1. Carrie C., Legeron R., Petit L., Ollivier J., Cottenceau V., d’Houdain N., Boyer P., Lafitte. F., Xuereb F., Sztark F. Higher than standard dosing regimen are needed to achieve optimal antibiotic exposure in critically ill patients with augmented renal clearance receiving piperacillin-tazobactam administered by continuous infusion. J. Crit. Care. 2018;48:66–71. doi: 10.1016/j.jcrc.2018.08.026.
    1. Jacobs A., Taccone F.S., Roberts J.A., Jacobs F., Cotton F., Wolff F., Creteur J., Vincent J.-L., Hites M. beta-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance. Antimicrob. Agents Chemother. 2018;62 doi: 10.1128/AAC.02534-17.
    1. Tamatsukuri T., Ohbayashi M., Kohyama N., Kobayashi Y., Yamamoto T., Fukuda K., Nakamura S., Miyake Y., Dohi K., Kogo M. The exploration of population pharmacokinetic model for meropenem in augmented renal clearance and investigation of optimum setting of dose. J. Infect. Chemother. 2018;24:834–840. doi: 10.1016/j.jiac.2018.07.007.
    1. Mahmoud S.H., Shen C. Augmented Renal Clearance in Critical Illness: An Important Consideration in Drug Dosing. Pharmaceutics. 2017;9:36. doi: 10.3390/pharmaceutics9030036.
    1. Leroy A., Fillastre J.P., Borsa-Lebas F., Etienne I., Humbert G. Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment. Antimicrob. Agents Chemother. 1992;36:2794–2798. doi: 10.1128/AAC.36.12.2794.
    1. Paul-Ehrlich-Gesellschaft für Chemotherapie e.V [(accessed on 20 March 2020)];Kalkulierte parenterale Initialtherapie bakterieller Erkrankungen bei Erwachsenen - Update 2018. 2018 Available online: .
    1. de With K., Allerberger F., Amann S., Apfalter P., Brodt H.R., Eckmanns T., Fellhauer M., Geiss H.K., Janata O., Krause R. Strategies to enhance rational use of antibiotics in hospital: A guideline by the German Society for Infectious Diseases. Infection. 2016;44:395–439. doi: 10.1007/s15010-016-0885-z.
    1. Wong G., Briscoe S., McWhinney B., Ally M., Ungerer J., Lipman J., Roberts J.A. Therapeutic drug monitoring of beta-lactam antibiotics in the critically ill: Direct measurement of unbound drug concentrations to achieve appropriate drug exposures. J. Antimicrob. Chemother. 2018;73:3087–3094. doi: 10.1093/jac/dky314.
    1. Imani S., Buscher H., Day R., Gentili S., Jones G.R.D., Marriott D., Norris R., Sandaradura I. An evaluation of risk factors to predict target concentration non-attainment in critically ill patients prior to empiric beta-lactam therapy. Eur. J. Clin. Microbiol. Infect. Dis. 2018;37:2171–2175. doi: 10.1007/s10096-018-3357-9.
    1. Fournier A., Eggimann P., Pagani J.L., Revelly J.P., Decosterd L.A., Marchetti O., Pannatier A., Voirol P., Que Y.A. Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients. Burns. 2015;41:956–968. doi: 10.1016/j.burns.2015.01.001.
    1. Muller A.E., Huttner B., Huttner A. Therapeutic Drug Monitoring of Beta-Lactams and Other Antibiotics in the Intensive Care Unit: Which Agents, Which Patients and Which Infections? Drugs. 2018;78:439–451. doi: 10.1007/s40265-018-0880-z.
    1. Kim Y.J., Kim S.I., Lee Y.D., Choi H.J., Choi J.Y., Yoon S.K., You Y.K., Kim D.G. Carbapenem-resistant Acinetobacter baumannii Bacteremia in Liver Transplant Recipients. Transplant. Proc. 2018;50:1132–1135. doi: 10.1016/j.transproceed.2018.01.043.
    1. Raviv Y., Shitrit D., Amital A., Fox B., Bakal I., Tauber R., Bishara J., Kramer M.R. Multidrug-resistant Klebsiella pneumoniae acquisition in lung transplant recipients. Clin. Transplant. 2012;26:E388–E394. doi: 10.1111/j.1399-0012.2012.01671.x.
    1. Kothekar A.T., Divatia J.V., Myatra S.N., Patil A., Nookala Krishnamurthy M., Maheshwarappa H.M., Siddiqui S.S., Gurjar M., Biswas S., Gota V. Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: Implications for empirical therapy against Gram-negative bacteria. Ann. Intensive Care. 2020;10:4. doi: 10.1186/s13613-019-0622-8.
    1. Zhao H.Y., Gu J., Lyu J., Liu D., Wang Y.T., Liu F., Zhu F.X., An Y.Z. Pharmacokinetic and Pharmacodynamic Efficacies of Continuous versus Intermittent Administration of Meropenem in Patients with Severe Sepsis and Septic Shock: A Prospective Randomized Pilot Study. Chin. Med. J. 2017;130:1139–1145. doi: 10.4103/0366-6999.205859.
    1. Wu C.C., Tai C.H., Liao W.Y., Wang C.C., Kuo C.H., Lin S.W., Ku S.C. Augmented renal clearance is associated with inadequate antibiotic pharmacokinetic/pharmacodynamic target in Asian ICU population: A prospective observational study. Infect. Drug Resist. 2019;12:2531–2541. doi: 10.2147/IDR.S213183.
    1. De Waele J.J., Carrette S., Carlier M., Stove V., Boelens J., Claeys G., Leroux-Roels I., Hoste E., Depuydt P., Decruyenaere J. Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: A randomised controlled trial. Intensive Care Med. 2014;40:380–387. doi: 10.1007/s00134-013-3187-2.
    1. Carlier M., Taccone F.S., Beumier M., Seyler L., Cotton F., Jacobs F., Roberts J.A. Population pharmacokinetics and dosing simulations of cefepime in septic shock patients receiving continuous renal replacement therapy. Int. J. Antimicrob. Agents. 2015;46:413–419. doi: 10.1016/j.ijantimicag.2015.05.020.
    1. Leegwater E., Kraaijenbrink B.V.C., Moes D., Purmer I.M., Wilms E.B. Population pharmacokinetics of ceftriaxone administered as continuous or intermittent infusion in critically ill patients. J. Antimicrob. Chemother. 2020 doi: 10.1093/jac/dkaa067.
    1. Fachinformation Meronem® 2019. [(accessed on 20 March 2020)]; Available online: .
    1. Fachinformation Piperacillin-Tazobactam-Teva® 4 g/ 0,5 g Pulver zur Herstellung einer Infusionslösung 2017. [(accessed on 20 March 2020)]; Available online: .
    1. Usman M., Frey O.R., Hempel G. Population pharmacokinetics of meropenem in elderly patients: Dosing simulations based on renal function. Eur. J. Clin. Pharmacol. 2017;73:333–342. doi: 10.1007/s00228-016-2172-4.
    1. Sukarnjanaset W., Jaruratanasirikul S., Wattanavijitkul T. Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis. J. Pharmacokinet. Pharmacodyn. 2019;46:251–261. doi: 10.1007/s10928-019-09633-8.
    1. Imani S., Buscher H., Marriott D., Gentili S., Sandaradura I. Too much of a good thing: A retrospective study of beta-lactam concentration-toxicity relationships. J. Antimicrob. Chemother. 2017;72:2891–2897. doi: 10.1093/jac/dkx209.
    1. Beumier M., Casu G.S., Hites M., Wolff F., Cotton F., Vincent J.L., Jacobs F., Taccone F.S. Elevated beta-lactam concentrations associated with neurological deterioration in ICU septic patients. Minerva Anestesiol. 2015;81:497–506.
    1. Udy A.A., Varghese J.M., Altukroni M., Briscoe S., McWhinney B.C., Ungerer J.P., Lipman J., Roberts J.A. Subtherapeutic initial beta-lactam concentrations in select critically ill patients: Association between augmented renal clearance and low trough drug concentrations. Chest. 2012;142:30–39. doi: 10.1378/chest.11-1671.
    1. Abdul-Aziz M.H., Lipman J., Akova M., Bassetti M., De Waele J.J., Dimopoulos G., Dulhunty J., Kaukonen K.M., Koulenti D., Martin C., et al. Is prolonged infusion of piperacillin/tazobactam and meropenem in critically ill patients associated with improved pharmacokinetic/pharmacodynamic and patient outcomes? An observation from the Defining Antibiotic Levels in Intensive care unit patients (DALI) cohort. J. Antimicrob. Chemother. 2016;71:196–207. doi: 10.1093/jac/dkv288.
    1. Ahmed N., Jen S.P., Altshuler D., Papadopoulos J., Pham V.P., Dubrovskaya Y. Evaluation of Meropenem Extended Versus Intermittent Infusion Dosing Protocol in Critically Ill Patients. J. Intensive Care Med. 2018:885066618784264. doi: 10.1177/0885066618784264.
    1. Carlier M., Carrette S., Roberts J.A., Stove V., Verstraete A., Hoste E., Depuydt P., Decruyenaere J., Lipman J., Wallis S.C. Meropenem and piperacillin/tazobactam prescribing in critically ill patients: Does augmented renal clearance affect pharmacokinetic/pharmacodynamic target attainment when extended infusions are used? Crit. Care. 2013;17:R84. doi: 10.1186/cc12705.
    1. Carrie C., Petit L., d’Houdain N., Sauvage N., Cottenceau V., Lafitte M., Foumenteze C., Hisz Q., Menu D., Legeron R. Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of beta-lactams administered by continuous infusion: A prospective observational study. Int. J. Antimicrob. Agents. 2018;51:443–449. doi: 10.1016/j.ijantimicag.2017.11.013.
    1. Rhodes N.J., Liu J., O’Donnell J.N., Dulhunty J.M., Abdul-Aziz M.H., Berko P.Y., Nadler B., Lipman J., Roberts J.A. Prolonged Infusion Piperacillin-Tazobactam Decreases Mortality and Improves Outcomes in Severely Ill Patients: Results of a Systematic Review and Meta-Analysis. Crit. Care Med. 2018;46:236–243. doi: 10.1097/CCM.0000000000002836.
    1. Richter D.C., Frey O., Röhr A., Roberts J.A., Köberer A., Fuchs T., Papadimas N., Heinzel-Gutenbrunner M., Brenner T., Lichtenstern C. Therapeutic drug monitoring-guided continuous infusion of piperacillin/tazobactam significantly improves pharmacokinetic target attainment in critically ill patients: A retrospective analysis of four years of clinical experience. Infection. 2019;47:1001–1011. doi: 10.1007/s15010-019-01352-z.
    1. Taubert M., Zoller M., Maier B., Frechen S., Scharf C., Holdt L.M., Frey L., Vogeser M., Fuhr U., Zander J. Predictors of Inadequate Linezolid Concentrations after Standard Dosing in Critically Ill Patients. Antimicrob. Agents Chemother. 2016;60:5254–5261. doi: 10.1128/AAC.00356-16.
    1. Khachman D., Conil J.M., Georges B., Saivin S., Houin G., Toutain P.L., Laffont C.M. Optimizing ciprofloxacin dosing in intensive care unit patients through the use of population pharmacokinetic-pharmacodynamic analysis and Monte Carlo simulations. J. Antimicrob. Chemother. 2011;66:1798–1809. doi: 10.1093/jac/dkr220.
    1. Paal M., Zoller M., Schuster C., Vogeser M., Schutze G. Simultaneous quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin in human serum using an isotope-dilution HPLC-MS/MS method. J. Pharm. Biomed. Anal. 2018;152:102–110. doi: 10.1016/j.jpba.2018.01.031.
    1. Levey A.S., Stevens L.A., Schmid C.H., Zhang Y.L., Castro 3rd A.F., Feldman H.I., Kusek J.W., Eggers P., Van Lente F., Greene T. A new equation to estimate glomerular filtration rate. Ann. Intern Med. 2009;150:604–612. doi: 10.7326/0003-4819-150-9-200905050-00006.
    1. Schuster C., Sterz S., Teupser D., Brügel M., Vogeser M., Paal M. Multiplex Therapeutic Drug Monitoring by Isotope-dilution HPLC-MS/MS of Antibiotics in Critical Illnesses. J. Vis. Exp. 2018 doi: 10.3791/58148.
    1. Minichmayr I.K., Roberts J.A., Frey O.R., Roehr A.C., Kloft C., Brinkmann A. Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model. J. Antimicrob. Chemother. 2018;73:1330–1339. doi: 10.1093/jac/dkx526.
    1. Quinton M.C., Bodeau S., Kontar L., Zerbib Y., Maizel J., Slama M., Masmoudi K., Lemaire-Hurtel A.S., Bennis Y. Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients. Antimicrob. Agents Chemother. 2017;61 doi: 10.1128/AAC.00654-17.
    1. Wong G., Briscoe S., Adnan S., McWhinney B., Ungerer J., Lipman J., Roberts J.A. Protein binding of beta-lactam antibiotics in critically ill patients: Can we successfully predict unbound concentrations? Antimicrob. Agents Chemother. 2013;57:6165–6170. doi: 10.1128/AAC.00951-13.

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