Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: a systematic review and meta-analysis

Abstract

IntroductionThe aim of this study was to determine whether using pharmacodynamic-based dosing of antimicrobials, such as extended/continuous infusions, in critically ill patients is associated with improved outcomes as compared with traditional dosing methods.MethodsWe searched Medline, HealthStar, EMBASE, Cochrane Clinical Trial Registry, and CINAHL from inception to September 2013 without language restrictions for studies comparing the use of extended/continuous infusions with traditional dosing. Two authors independently selected studies, extracted data on methodology and outcomes, and performed quality assessment. Meta-analyses were performed by using random-effects models.ResultsOf 1,319 citations, 13 randomized controlled trials (RCTs) (n = 782 patients) and 13 cohort studies (n = 2,117 patients) met the inclusion criteria. Compared with traditional non-pharmacodynamic-based dosing, RCTs of continuous/extended infusions significantly reduced clinical failure rates (relative risk (RR) 0.68; 95% confidence interval (CI) 0.49 to 0.94, P = 0.02) and intensive care unit length of stay (mean difference, −1.5; 95% CI, −2.8 to −0.2 days, P = 0.02), but not mortality (RR, 0.87; 95% CI, 0.64 to 1.19; P = 0.38). No significant between-trial heterogeneity was found for these analyses (I2 = 0). Reduced mortality rates almost achieved statistical significance when the results of all included studies (RCTs and cohort studies) were pooled (RR, 0.83; 95% CI, 0.69 to 1.00; P = 0.054).ConclusionsPooled results from small RCTs suggest reduced clinical failure rates and intensive care unit length-of-stay when using continuous/extended infusions of antibiotics in critically ill patients. Reduced mortality rates almost achieved statistical significance when the results of RCTs were combined with cohort studies. These results support the conduct of adequately powered RCTs to define better the utility of continuous/extended infusions in the era of antibiotic resistance.

Carbapenem Utilization among Adults Inpatients in One Private Hospital in Surabaya

“…Pemberian secara bolus untuk antibakteri dengan aktivitas bakterisidal yang dipengaruhi oleh waktu (time dependent antibiotics), termasuk carbapenem, merupakan suatu metode administrasi yang kurang tepat, dengan mempertimbangkan parameter farmakokinetik-farmakodinamik yang memiliki korelasi dengan efektivitas bakterisidal golongan β-lactam adalah waktu saat konsentrasi β-lactam berada di atas MIC (T>MIC). [16][17][18][19][20][21] Pemberian secara extended infusion merupakan metode yang diharapkan dapat mengoptimalkan ketercapaian target farmakokinetik dan farmakodinamik dari golongan carbapenem. .…”

“…. 20 Pemilihan pelarut merupakan salah satu hal yang perlu diperhatikan pada pemberian golongan carbapenem secara extended infusion karena akan memengaruhi stabilitas sediaan carbapenem. 21 Total defined daily dose (DDD) meropenem selama periode penelitian lebih tinggi bila dibandingkan imipenem dan doripenem, yaitu: 1433,75 DDD dibandingkan dengan 27,5 DDD dan 1 DDD, secara berturut-turut.…”

Pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient

“…However, patients with severe bacterial infections T >MIC of 100% have shown to display significantly greater cure and bacterial eradication than patients with T <100%. 27 there are theoretical arguments and case reports that support the efficacy and safety of prolonged or continuous infusions. In severe infections caused by less susceptible microorganisms in critical ill patients, where the risk of underdosing is higher, continuous or extended infusions of beta-lactams have proven to be safe, with comparable therapeutic efficacy.…”

Is there a role for continuous infusion of β-lactam antibiotics in severe sepsis?

“…There is an expanding literature examining optimal administration of β-lactam antibiotics in critically ill patients (3,4). The bactericidal and broad spectrum nature of β-lactams make them attractive in patients with sepsis.…”

“…The time-over-MIC dependent killing with β-lactams would suggest benefit with administration as continuous infusion instead of intermittent dosing, particularly given the fluid shifts that occur in critically ill patients (5)(6)(7). Meta-analysis of studies comparing continuous infusions of β-lactams to standard intermittent dosing in acute infections have failed to find a consistent clinical benefit in mortality, infection recurrence, clinical cure, super-infection post-therapy, and safety outcomes in both critically-and non-critically ill patients (3,4,(8)(9)(10). The question remains whether patients with severe sepsis will benefit (11).…”