Special Feature

Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, and Stability of Continuous or Extended Infusion Regimens of Carbapenems

By Andy Chan, PharmD Candidate, University of the Pacific

and Jessica C. Song, MA, PharmD, Assistant Professor, Pharmacy Practice, University of the Pacific, Stockton, CA; Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.

Both Andy Chan and Jessica C. Song report no financial relationships relevant to this field of study.

In intensive-care units, death attributable to infections caused by multidrug-resistant bacteria, especially Pseudomonas aeruginosa and Acinetobacter baumannii species, is a common occurrence.1 Given their broad spectrum of activity, carbapenems are frequently prescribed for empirical treatment of hospital-acquired infections.2 Furthermore, this class of antimicrobial drugs has been shown to be consistently effective against difficult-to-treat pathogens, including extended-spectrum beta-lactamase producing Gram-negative bacilli and Acinetobacter species.3

In theory, the clinical efficacy of time-dependent antibiotics, such as carbapenems, could be maximized with increased exposure times that the antimicrobial concentrations remain above the minimum inhibitory concentration (MIC) (T > MIC).4-5 In-vitro and in-vivo animal studies have suggested that a T > MIC in excess of 40% is required for optimal activity of carbapenems.6 However, Li et al recently questioned the validity of this pharmacodynamic target.7 Their study of meropenem-treated patients with lower respiratory tract infections revealed that a 54% T > MIC predicted microbiological success.

Extended- or continuous-infusion dosing schemes have been explored to improve bactericidal exposure β-lactam antibiotics require for bacterial eradication. At present, pharmaceutical manufacturers recommend intermittent administration of carbapenems. However, intermittent administration could potentially lead to high peaks and troughs that fall below the MIC during the dosing interval. In contrast, continuous infusion of carbapenem antibiotics results in constant serum levels above the MIC.6

The intent of this review is to discuss the pharmacokinetic and pharmacodynamic properties of continuous- and extended-infusion carbapenems in critically ill patients. In addition, carbapenem stability is addressed due to concerns about decreased potency in extended- and continuous-infusion regimens. A summary of recently published clinical studies of extended- and continuous-infusion carbapenem regimens used in critically ill patients will be highlighted in this article.

Pharmacokinetics/Pharmacodynamics

Critically ill patients pose a significant challenge with regard to antimicrobial dosing, given the wide array of pathophysiological changes that can occur in this population. Increases in volume of distribution (Vd) and clearance of antimicrobials can result in reduced plasma concentrations of drug in critically ill patients with septic shock.6 Roberts and associates conducted a pharmacokinetic/pharmacodynamic study that enrolled 10 septic, ventilator-dependent patients with normal renal function.8 Five patients received intermittent bolus (IB) meropenem (MP), and the other patients received continuous infusion (CI) MP. Monte Carlo simulation was performed using three IB, three CI, and three extended-infusion (EI) dosing regimens. Table 1 summarizes demographic data, inclusion criteria, and doses reported in this study and the other pharmacodynamic/pharmacokinetic studies discussed in this section.

Table 1: Pharmacokinetic/Pharmacodynamics of Continuous Infusion/Extended Infusion Carbapenems in Critically Ill patients

Author (Year)

Design/ Study Outcomes

Inclusion Criteria

Dosing Regimens

Patient Population

Results

Comments

Roberts (2009)8

Prospective, randomized

Outcomes

1.To determine differences in plasma and subcutaneous tissue concentration–time profiles of meropenem (MP) administered by intermittent bolus dosing (IB) or continuous infusion (CI) to critically ill patients with sepsis and normal renal function.

2. Utilization of population pharmacokinetic modeling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens

Known or suspected sepsis of a critically ill patient; normal renal functiona

IB MP (n = 5): 1.5 g first dose (infused over 5 min.), then 1 g q8h (infused over 3 min.)

CI MP (n = 5): loading dose 500 mg (infused over 3 min.), followed by 1 g q8h (administered as three separate doses of 1,000 mg over 8 h in 250 mL of 0.9% sodium chloride)

Ten critically ill ventilated patients with sepsis

IB: mean age, 55 years; mean day 1 cSOFA score 3; mean CrCI, 106 mL/min.

CI: mean age, 57 years; mean day 1 SOFA score, 5; mean CrCI, 93 mL/min.

PTA (Probability of Target Attainment) for P. aeruginosa: CFR for CI: MP 1,500 mg/day, 43.8%; MP 3,000 mg/d, 100%; MP 6,000 mg/d, 100%. CFR for extended infusion (infused over 4 h): 500 mg q8h, 50%; 1,000mg q8h, 68.8%; 2,000 mg q8h, 96.9. CFR for IB: 500 mg q8h, 12.5%; 1,000 mg q8h, 40.6%; 2,000 mg q8h, 68.8%.

Pharmacokinetics

Median Vd, 22.7 L;
mean CL, 13.6 L/h; Subcutaneous Tissue

Day 1 and 2 Cmin (mg/L): 0 for IBMP; 4 for CIMP (p = 0.02-0.03) .

Plasma
Day 1 and 2 Cmin (mg/L): 0 for IBMP; 7-8 for CIMP (p = 0.01-0.02).

Meropenem is stable for at least 8 h at 22°C, thus three 1,000 mg infusions given.
Continuous infusion MP resulted in significantly higher Cmin in subcutaneous tissue and plasma compared with intermittent bolus MP.

Meropenem Vd and clearance were shown to be higher in this cohort of septic patients, compared with values reported in healthy volunteer studies.
Higher doses of CIMP (3 g or 6g) suggested by authors for P. aeruginosa (MIC90 8 mg/L) and Acinetobacter spp. (MIC90 16 mg/L)

Langgarter (2007)4

Prospective, randomized, crossover outcomes to test whether CI of MP achieves effective drug concentrations comparable to IB in patients treated by continuous hemodiafiltration.

1. Suspected infection requiring antibiotic therapy

2. Suspected pathogen susceptible to MP

3. > 18 years

4. I.V. antibiotic treatment of infection anticipated to be necessary for more than 4 days

5. Renal failure requiring CRRT

Patients received MP as 0.5 g IV loading dose followed by 2 g CI over 24 h divided into two 1 g fractions or 1 g IB over 15-20 min given every 12 h.

IB or CI were continued for 48 hours then patients were crossed over to the other treatment for another 48 hours.

Investigators enrolled 11 patients, but 5 were excluded.

Mean age, 53.6 years; pneumonia (n = 1), pneumonia and sepsis (n = 2), acute pancreatitis (n = 1), and sepsis (n = 2)

Pharmacokinetics:
CI median: %(T)> 8mg/L, 100%; CL: 4.40 L/h; Cmax 20 mg/L; Cmin 15.7 mg/L

IB median: %(T) > 8mg/L, 45.9; CL: 4.32 L/h; Cmax 62.8 mg/L; Cmin 8.2 mg/L; t1/2 5.3 h

Meropenem showed stability in the infusion solution at 25 °C for 12 h, with a loss of concentration of 7%.

%T>MIC of CIMP patients surpassed %T>MIC of IBMP patients.

Sakka (2007)2

Prospective, randomized, crossover, controlled.

Outcomes
To study PTA of fT≥MIC of 20%, 30%, and 40% for imipenem/cilastatin (I/C) concentrations

ICU-acquired pneumoniab (length of time of endotracheal intubation and mechanical ventilation > 3 days); normal renal function

CI (n = 10): 7g/7g IC infused over 76 h (83.3/83.3 mg/h started 4h post loading dose of 1g/1g), then received 1 g/1 g I/C q8h

Intermittent infusion (II) (n = 10): 1g/1g I/C (infused over 40 min) TID for 3 days

Patients were randomized to either II or CI

II: mean age, 59 years; mean APACHE II score, 28; CrCl (mL/min), 128; mean ICU length of stay, 12d; mean SOFAc score, 6

CI: mean age, 62 years; mean APACHE II score, 26; CrCl (mL/min), 122; mean ICU-length of stay, 14 d; mean SOFA, 7

PTA:

fT≥MIC of 20%, 30%, 40% for all recovered pathogens was 100% (n = 20)

Pharmacokineticsa
CL 12.3 ± 4.2 L/h;
Vcentral compartment: 12.2 L ± 9.9 L

Antibiotic pretreatment was given in the II and CI groups

Covariates of age, weight, height, and body surface area explained 88.8% of the variance in imipenem clearance

SOFA score of 8 predicted survival using logistic regression where this was entered as a dichotomous variable (p = 0.012)

Thalhammer (1999)5

Prospective, randomized, crossover

Outcomes
1. To determine the differences in pharmacokinetic parameters of CIMP and intermittent administration (IA) MP

2.To determine therapeutic concentrations with 3 g CIMP over 24 h

3.Side effects of IAMP regimen

Predicted duration of treatment required to be at least 4 days & any two of the following: elevated C-reactive protein > 10 mg/dL; ≥ one positive blood culture (Gram-negative or Gram-positive bacteria) or two positive blood cultures showing coagulase-negative staphylococci; clinical signs of infection; respiratory tract infection (new infiltrate on chest X-ray); positive urine culture

All patients received 2g IV loading dose of MP followed by 3 g CI (over 48 hours) or IA 2 g MP IV q8h for 2 days.

After 2 days patients were switched to alternative MP regimen.

Fifteen patients in the intensive care unit: mean age, 55.3 years; hospitalized with pneumonia (n = 7), sepsis (n = 3), systemic inflammatory distress syndrome (n = 5); mean CrCl, 83.7 mL/min; white blood cell count, 16.5 G/L; C-reactive protein level, 19.8

Pharmacokineticsa
IA mean values: AUC mg/L x h, 193.8; Cltot L/h, 9.4 ± 1.2; Cmax mg/L, 110.1; Cmin mg/L 8.5; Vss L, 26.6 ± 3.2; t1/2 2.4 h; kel, 0.32 h-1

CI mean values: AUC mg/Lx h, 117.5; Cltot L/h, 7.7 ± 1.4; Vss L, 25.9 ± 5.7; Css mg/L 11.9

Only AUC and Cltot achieved p ≤ 0.01

2 g MP was diluted in 100 mL of isotonic saline solution, 1 g MP was reconstituted according to the manufacturer's guidelines and then diluted with 50 mL of isotonic saline solution.

No adverse effects were observed during study period.

CIMP yielded cost savings, given that half of the amount required by IAMP maintained bactericidal serum levels of MP.

Note: wide conference intervals and retrospective study design.

aNormal renal function defined as: plasma creatinine concentration < 120 mol/L
bPneumonia classified as the presence of infiltrates in the chest X-ray and microbiology tests positive for bacteria in tracheal or bronchial secretions
cSOFA: sepsis-related organ failure assessment

Of note, Roberts et al reported that their patients' Vd (median 22.7 L) and drug clearance (mean 13.6 L/H) were significantly larger compared with healthy volunteers in other studies.8 The increase in Vd was attributed to the level of sickness severity in septic patients. Also, since the relatively youthful cohort population lacked signs of renal dysfunction, increased clearance levels were seen compared with previous studies in critically ill patients. Overall, continuous infusion maintained a higher trough level than intermittent bolus in both plasma and subcutaneous tissue.

Roberts et al also used the Monte Carlo simulation model to determine probability of target attainment (PTAs) (40% fT>MIC) and cumulative fraction of response (CFR) with IB, CI, and EI regimens.8 All three simulated dosing regimens achieved 100% pharmacodynamic targets against most Gram-negative bacteria. Higher doses (3 grams to 6 grams) were required to achieve fT>MIC > 40% with EI and CI regimens in less susceptible organisms such as Pseudomonas aeruginosa (MIC90 8 mg/L) and Acinetobacter species (MIC90 16 mg/L).

In patients with renal failure who require continuous renal replacement therapy, ineffective antimicrobial therapy occurs more frequently than toxicity due to excessively high doses of drug.4 In a prospective, randomized, crossover design, Langgartner and associates studied pharmacokinetic properties of CIMP and IBMP in six critically ill patients receiving continuous haemodiafiltration.4 Median %T>MICs for CIMP at 4mg/L (100%) and 8 mg/L (100%) surpassed %T>MICs seen for IBMP (45.9%-67.9%). Meropenem maintained its potency in the infusion solution at room temperature (25°C) for 12 hours, with a 7% loss in concentration at the end of the dosing interval.

Sakka and associates assessed the free-drug concentrations exceeding the MIC (fT>MIC) value of imipenem in a prospective, randomized, controlled study that included 20 critically ill patients with nosocomial pneumonia.2 Due to stability concerns, the study investigators reconstituted imipenem 250 mg every three hours for patients who underwent continuous infusion. Despite the achievement of fT>MICs of 100% in all patients, three patients died, two from the CI treatment group, and one from the IB treatment group. Logistic-regression analysis revealed that a SOFA (sepsis-related organ failure assessment) score of 8 predicted survival outcome (p = 0.012). The pharmacokinetic analysis revealed a mean clearance of imipenem/cilastatin of 12.3 L/h and a Vd (central compartment) of 12.2 L, similar to that observed in healthy volunteers. However, increases in both parameters were noted in younger patients (≤ 46 years) and in patients with higher body surface areas (BSA ≥ 1.84 m2), suggesting the need for higher doses of imipenem/cilastatin for those patients.

Thalhammer et al analyzed pharmacokinetic properties of meropenem in 15 intensive-care unit patients with suspected or proven community- or hospital-acquired infections.5 This prospective, randomized, crossover study used a CIMP regimen that delivered a 50% lower dose of MP than the intermittent administration (IA) regimen. CIMP yielded a mean steady-state serum concentration of 11.9 mg/L, whereas IAMP treatment resulted in a mean trough serum concentration of 8.5 mg/L. Steady state and trough serum concentrations of MP seen with CI and IA, respectively, exceeded the MICs of most Gram-positive and Gram-negative pathogens recovered in the ICU. No adverse effects were noted in any patients during the study period. The study investigators highlighted the potential cost savings associated with CIMP, given that half of the dose required by IAMP maintained bactericidal serum concentrations of MP.

Studies of Critically Ill Patients

Two recent clinical studies have assessed clinical cure rates associated with the use of extended- and continuous-infusion MP regimens.1,9 To date, there is limited published data on the clinical efficacy of other carbapenems administered through continuous- or extended-infusion. Wang et al conducted a prospective cohort study that included 30 patients with hospital-acquired pneumonia caused by multi-drug resistant Acinetobacter baumannii.1 Table 2 summarizes demographic data, inclusion/exclusion criteria, doses reported in this study, as well as the second study discussed in this section. The two treatment groups (extended infusion and intermittent infusion) showed similar clinical efficacy with regard to treatment duration, relapse ratio, and successful bacterial eradication. However, extended-infusion MP lowered total antibiotic cost by 34% (p < 0.01), thereby highlighting the potential cost savings that may occur when replacing intermittent therapy with prolonged-infusion therapy.

Table 2: Clinical Efficacy of Continuous/Extended Infusion Carbapenem in Critically Ill Patients

Author (Year)

Study Design/
Primary Outcomes

Inclusion Criteria

Exclusion Criteria

Patient Population

Dosing Regimens

Results

Wang (2008)

Prospective cohort

Outcomes:

1. Clinical Cure and Bacterial Response: Using Clinical and Pulmonary Infection Score and Ministry of Public Health diagnosis

2. Relapse rate

3. Days of treatment

4. Meropenem (MP) cost

Patients with HAPa due to cultured multidrug-resistantb A. baumannii

N/A

Conventional Bolus (CB) MP (n = 15):

Mean age 39.7 years; Sex(M:F) 9:6; APACHEIIc mean score, 17.33

Extended Infusion (EI) MP (n = 15): Mean age 44.3 years; Sex (M:F) 10:5; APACHEII mean score, 20.33

MIC90 for A. baumannii: 2 mg/L

CB MP: 1 g IV Q8h (infused over 1 hour)

EI MP: 500 mg Q6h (infused over 3 hours)

Clinical Cure for CB vs. EI:
Successful cure rate on day 3, 40% vs. 33% (p > 0.05); day 5, 87% vs. 93% (p > 0.05); day 7, 100% vs. 100% (p > 0.05)

Cost: CB vs. EI ($): 1038.38 vs. 684.05, p < 0.01

Mean days of treatment: 5.27 for CB vs. 4.80 for EI (p > 0.05)

%T>MIC: EI, 75%; CB, 54% (p value not reported)

Lorente (2006)

Retrospective cohort study

Outcomes

To assess the clinical efficacy of continuous vs. intermittent infusion of meropenem for the treatment of ventilator-associated

pneumonia (VAP) caused by Gram-negative bacilli.

Patients with VAPc due to Gram-negative bacteria who were administered MP from July 2002 to June 2005.

≤ 18 years; pregnancy; lactation; β-lactam allergy; VAP caused by MP-resistant microorganism; AIDS; neutropenia (WBC < 1x 103/mm3); solid or hematologic tumor; CrCI < 60 mL/min

Continuous Infusion (CI) (n = 42): mean age 57.25 year; APACHE IIc score on ICU admission, 15.3; common causative organisms for VAP: P. aeruginosa (30.9%), E. coli (16.7%); Serratia marcescens (14.3%); Enterobacter spp (11.9%); K. pneumonia (9.5%); H. influenzae (7.1%)

Intermittent Infusion (II) (n = 47): mean age 56.5 years; APACHE II score on ICU admission, 15.2; common causative organisms for VAP: P. aeruginosa (31.9%), E. coli (17.0%); Serratia marcescens (14.9%); Enterobacter spp (12.8%); K. pneumonia (8.5%); H. influenzae (6.4%)

II: MP 1 g q6h (infused over 30 min.)

CI: MP loading dose 1 g over 30 min, then 1 g q6h (infused over 6 hours)

Cure rates: in all VAP patients, CI (90.5%) vs. II (59.6%), OR 6.4 (95% CI, 2.0-21.1, p < 0.001)

VAP due to Pseudomonas, CI (84.6%) vs. II (40%), OR 8.2 (95% CI, 1.3-51.3, p = 0.02)

MIC > 0.50 mg/L, CI (80.9%) vs. II (29.4%), OR 7.8 (95% CI, 2.3-46.1, p = 0.003)

Note: wide confidence intervals and retrospective study design.

aHAP = Hospital-acquired pneumonia
bMultidrug-resistance defined by: susceptible to no more than one class of antimicrobial agents, excluding colistin, but susceptible to carbapenems (meropenem)
cAPACHE, Acute Physiology and Chronic Health Evaluation
dVAP = ventilator-associated pneumonia as defined by the following: chest radiography showing new or progressive infiltrate; new onset of purulent sputum or alteration in sputum character; body temperature < 35.5°C or > 38°C; white blood cell count > 10,000 cells/mm3 or < 4,000 cells/mm3; tracheal aspirate > 106 colony-forming units/mL or isolation of the same microorganism in respiratory secretions and blood.

A retrospective cohort study conducted by Lorente and colleagues featured 89 patients with ventilator-associated pneumonia (VAP) primarily caused by Pseudomonas aeruginosa, Escherichia coli, Serratia marcescens, and Enterobacter species.9 Outcome measures included: 1) overall clinical cure rates in VAP patients (given CIMP or intermittent infusion (II) MP), 2) clinical cure rates observed in patients with VAP caused by Pseudomonas aeruginosa, and 3) clinical cure rates observed in patients infected with pathogens with MIC90 ≥ 0.50 mg/L. CIMP-treated patients showed improved clinical cure rates compared with IIMP-treated patients (90.5% vs. 59.6%; OR 6.4, 95% CI, 2.0-21.1, p < 0.001). In addition, CIMP therapy resulted in superior cure rates compared with IIMP (84.6% vs. 40%; OR 8.2, 95% CI 1.3-51.3, p = 0.02) in the treatment of VAP caused by Pseudomonas aeruginosa and when the MIC of the organism was 0.5 μg/mL or greater (80.9% vs. 29.4%; OR 7.8, 95% CI 2.3-46.1, p = 0.003).

Stability

Earlier studies have shown that carbapenems lack the stability shown by other antimicrobial agents, such as ceftazidime or piperacillin, in concentrated solutions stored under warmer incubation conditions.10 Berthoin et al examined the influence of time and concentration on degradation rates of MP and doripenem solutions at lower and higher temperatures (25°C, 37°C).10 MP concentrations in excess of 4 g/100 mL reached the degradation threshold of 10% in 12 hours at 250C. The 10% degradation threshold occurred at 6 hours for MP 4 g/100 mL stored at 370C and for MP 6 g/100 mL stored at 25°C. In contrast, doripenem 1 g/100 mL (maximal approved concentration, 0.5 g/100 mL) maintained its potency for 12 hours at 37°C and for 24 hours at 25°C. The study investigators recommended limiting the concentration of MP to 4 g/100 mL and maintaining temperatures at or below 25°C.

Conclusion

Over the past decade, novel dosing strategies for β-lactams, such as prolonged and continuous infusion, have been considered over traditional intermittent infusion in an attempt to optimize efficacy against challenging pathogens. Pharmacokinetic/ pharmacodynamic studies of meropenem, the best-studied carbapenem, have primarily utilized loading doses ranging from 0.5 g to 2 grams and doses of continuous-infusion meropenem ranging from 2 g to 3 g/24 hours in critically ill patients. Clinical studies assessing the efficacy of continuous-infusion/extended-infusion regimens have used daily doses of meropenem ranging from 2 g/day up to 4 g/day.

Numerous pharmacodynamic studies have established the efficacy of continuous-infusion meropenem regimens in attaining 40% T>MIC. However, randomized clinical studies with larger patient populations are warranted to further substantiate the benefits of continuous infusion of meropenem.

Package inserts for meropenem, imipenem/cilastatin, ertapenem, and doripenem recommend usage within 4, 4, 6, and 12 hours, respectively, at room temperature.11-14 Based on the standards set forth by U.S. pharmaceutical companies, continuous infusion of carbapenems cannot be performed without the possibility of excessive drug degradation. However, investigators of studies that used continuous- or extended-infusion meropenem regimens argued in favor of the maintenance of drug potency at room temperature despite prolonged use.

Meropenem is traditionally given as a 1 g intravenous dose administered every 8 hours. However, doses as low as 2 g infused over 24 hours (extended- or continuous-infusion) have been studied in pharmacodynamic/pharmacokinetic and clinical studies. Given that continuous- or extended-infusion meropenem regimens potentially require lower doses than conventional intermittent dosing regimens, additional pharmacoeconomic studies are warranted to further elucidate the benefits of prolonged-infusion carbapenem regimens.

References

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