Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams

Several studies have addressed meropenem PK in ICU septic patients. High V_d and Cl have usually been reported, as well as a low binding fraction: < 10% [18]. Consequently, a large heterogeneity of PK parameters was found, exceeding a twofold variation (Table 1 and Figure 3). The larger reported V_d, a mean of 34.4 L, was noted on the second day of therapy in eight ventilator-associated pneumonia (VAP) patients [19] with a mean body weight of 73 kg. In a Thai VAP population (N = 9) with a lower mean body weight (only 54.2 kg), the mean V_d was 6.0 L despite also being measured after 48 hours of therapy with meropenem [20]. This supports the hypothesis of a potential relationship between body weight and V_d.

Meropenem Cl ranged from a mean of 4.7 L/hour to a mean of 15.4 L/hour and was generally found to be closely correlated to Cr Cl. In fact, in patients with severe sepsis, the six patients with the lower Cr Cl (< 50 mL/minute) had the higher T > MIC and area under the concentration time curve (AUC) (230.2 mg × hour/L vs. 119.4 mg × hour/L; P = 0.001), despite a reduction in the dose administered, from 1 g every 8 h (tid) to 1 g every 12 h (bid) [21].

One study addressed the variability of individual meropenem PK between the first and fourth days of therapy in 11 surgical patients [22]. Despite an increase in Cr Cl from a mean of 63.9 to 79.1 mL/minute during the study period, meropenem V_d, Cl and AUC remain unchanged. Nevertheless, in another study, by Taccone et al. [23], predefined targets were reached in only 75% of severe sepsis and septic shock patients after the first dose of 1 g of meropenem (Table 2), despite the inclusion of patients with acute renal failure (22%) who did not receive renal replacement therapy. These authors concluded that PK changes induced by sepsis were largely unpredictable and that none of the evaluated clinical parameters were predictive of PK adequacy: namely, age, severity, presence of shock, use of vasopressors and mechanical ventilation. Also, Roberts et al. [24] showed that the V_d in patients with severe sepsis had great variability, both in the same patient (especially the central compartment: roughly 45%) and in different patients (nearly 27%). In their study, despite the fact that all patients had a serum Cr < 1.36 mg/dL, the meropenem Cl variability (in the same patient and between patients) still ranged between 10% and 20%.

The time of infusion of meropenem has also been shown to influence its T > MIC. In a cross-over study of nine Thai VAP patients [20], after 48 hours of therapy, 1 g of meropenem tid in 30-minute infusions provided an adequate T > MIC in 74.7% of the patients, for a MIC of 1 mg/L. However, with a MIC of 16 mg/L, only the meropenem regimen of 2 g tid given in an extended infusion (two hours) led to a T > MIC > 40% [20].

Meropenem tissue PK have been evaluated by microdialysis in several studies (Table 3). The tissue-to-plasma meropenem mean ratio on the first day of antibiotic therapy was found to be 0.74 in the peritoneum [25] and 0.44 in subcutaneous fat [24]. The meropenem CFR was calculated for the 10 patients for whom serum levels were measured in this study according to the Mystic microbiological database [26]. The CFRs were 100% for Enterobacteriaceae and 40.6% for Pseudomonas aeruginosa after bolus dosing, whilst with continuous infusion they were 100% for both bacteria, despite the use of a small daily dose (2 g/day) [27].

In ICU patients, increased V_d and Cl of imipenem have also been reported (Table 1). Therefore, its T_1/2 and T > MIC may be difficult to predict, depending on the relative changes of these two parameters. This difficulty was shown by Belzberg et al. [28] in a cohort of ICU surgical and trauma patients with presumed Gram-negative sepsis. In this relatively young population (mean age 45.2 ± 17 years and mean body weight 79.7 ± 17.7 kg), 44% of patients presented trough levels lower than the intended 4 mg/L at steady state. A mean Cr Cl of 103.8 mL/minute was found, but with large variability: two patients had renal failure and nineteen patients had a Cr Cl > 120 mL/minute. Nevertheless, no correlation was found between PK parameters and body weight, severity of disease, blood pressure or renal function [28].

Another study compared meropenem and imipenem first-dose PK in patients with normal renal function (serum Cr < 1.5 mg/dL). Again, both V_d and Cl were significantly elevated, although more so in the meropenem group [29]. However, their T > MIC for sensitive isolated pathogens were similar. Again, there was a relationship between Cr Cl and T_1/2: Patients with a Cr Cl < 50 mL/minute had a significantly longer T_1/2 for both antibiotics.

The PD efficacy of imipenem is also influenced by the dose and the time of infusion [30]. Using PK data from a cross-over steady-state study of VAP patients, Jaruratanasirikul and Sudsai [30] showed by modelling of imipenem PD that, for a MIC of 4 mg/L, a 500-mg dose delivered every 6 hours (qid) for 30 minutes achieved a T > MIC of 64.7% and increased to 76.5% with a 2-hour infusion. However, this study excluded shock and renal failure patients (Cr Cl < 60 mL/minute). With PD modelling of PK data derived from another 20 VAP patients [31], continuous infusion led to improved PTA despite the use of lower dosages (Table 2). In this latter study, all patients had f imipenem T > MIC of 100%, but three patients died.

Tissue microdialysis had been used to assess imipenem PK, but with very dissimilar results (Table 3): namely, the tissue-to-plasma ratio. This has been found to be markedly depressed in a cohort of severe critically ill patients compared to healthy volunteers (subcutaneous tissue-to-plasma 0.14 vs. 0.43 and muscle tissue-to-plasma 0.11 vs. 0.5, respectively) [32]. However, Dahyot et al. [33] disputed these results and found f imipenem in plasma and muscle to be virtually superimposed at any time, both in patients and in healthy volunteers. Some differences exist between these two studies. In the Tegeder et al. study [32], the patients had lower Cr Cl (medians 32.8 mL/minute vs. 156 mL/minute) and samples were collected at steady state and not after the first dose. Moreover, Dahyot et al. [33] accounted only for the f imipenem in plasma and found higher imipenem V_d and Cl. Different methods of calculating in vivo microdialysis recovery rates may also explain some of the diverse observed results. Nevertheless, low imipenem penetration ratios, as low as 0.06 [34, 35], in bronchial secretions were reported in pneumonia patients (Table 3).

Similarly to other β-lactams, piperacillin V_d and Cl have generally been found to be increased in ICU patients (Table 1). However, most studies have excluded renal failure patients.

Piperacillin Cl and trough concentrations were strongly related to Cr Cl [36‐38]. Taccone et al. [23] showed that only 15% of patients with high Cr Cl (> 50 mL/minute) maintained piperacillin concentrations > 50% of T > 4 × MIC after the first antibiotic dose, as opposed to 71% of patients with lower Cr Cl (P = 0.03). In contrast, in 10 young burn patients (mean total burned area 40.8 ± 3.1%) with a mean Cr Cl of 119.8 mL/minute and Pseudomonas aeruginosa infection, the authors found a 20% increase in T_1/2 after the first dose of antibiotic compared to the third day of therapy, which was related to a larger V_d (mean of 19.6 L vs. 16.4 L) [38]. Overall, the piperacillin AUC was similar in the two measurements (mean of 640 mg × hour/L vs. 622 mg × hour/L).

Piperacillin is stable for at least 24 hours at room temperature, making it a suitable choice for continuous infusion. With this strategy, higher steady-state concentrations are expected, theoretically providing a higher T > MIC even with the use of a lower daily dose [39]. A study by Rafati et al. [40] also supports this strategy. These authors showed that, for a MIC = 16 mg/L, the T > MIC was higher with continuous infusions (8 g/day) than with bolus dosing (3 g tid) (100% vs. 62%, respectively). However, the mortality rate was similar.

In VAP patients, piperacillin showed good penetration in bronchial secretions [41‐43]. Nevertheless, its epithelial lining fluid (ELF) steady-state concentration was lower than the MIC for Pseudomonas aeruginosa after a 4.5-g tid dose [41]. With continuous infusion, an increase in pulmonary concentration was found, at least in the subset of patients with moderate renal failure (measured Cr Cl < 50 mL/minute), about three times higher than in the patients with normal renal function [43]. However, no relationship was found between ELF piperacillin concentration and clinical success. Similar concentrations were found in the eight patients who died or had persistent infections and in those who experienced therapeutic success [43].

Subcutaneous tissue-to-plasma ratio and PK have been assessed in microdialysis studies. In six septic shock patients (mean norepinephrine dose 0.8 μg/kg/minute) [44], the subcutaneous tissue-to-plasma AUC ratio was only 0.1, one-third of that measured in healthy volunteers. Peak tissue concentration was also delayed in patients (122 minutes in patients compared with 27 minutes in healthy volunteers), and T_1/2 in tissues was nearly nine times longer. In 13 younger patients with less severe sepsis [45], the AUC tissue-to-plasma ratio was roughly 0.2. In accordance with their serum PK (as well as PK of another five patients) [46], piperacillin/tazobactam CFR was calculated to be 92.3% with continuous infusion (13.5 g/day) and 53.4% with bolus dosing (4.5 g qid, or 18 g/day). Again, no correlation was found between tissue concentration and outcomes. Despite the low tissue concentration levels, all patients in both groups survived [45].

Cefpirome PK studies have produced heterogeneous results. A 2-g dose was adequate in young trauma patients (Cr Cl ≥ 50 mL/minute) and in similar healthy volunteers. After the first dose, the mean T > MIC were 75% and 80%, respectively (with a MIC of 4 mg/L, P = 0.76) [47]. However, in 12 similar patients, a lower T > MIC (60%) was found, which was probably related to higher cefpirome Cl [48]. After four days of therapy, the cefpirome mean PK parameters remained similar (T > MIC 67% and AUC 242 mg × hour/L vs. 306 mg × hour/L at steady state). Further analyses [49] showed a strong correlation between Cr Cl and either cefpirome or cefepime Cl (r² = 0.81). Patients with the lower range of T > MIC had a higher Cr Cl, usually above 144 mL/minute [49]. According to these measured PK data, the authors performed a simulation to demonstrate improved CFR of cefpirome given as a continuous infusion to treat Pseudomonas aeruginosa infection, from 56.1% to 84.4% (Table 2) [50].

Cefpirome tissue PK were evaluated on the basis of microdialysis. Sauermann et al. [51] found a low subcutaneous tissue concentration in patients with severe sepsis, almost half of healthy volunteers, despite a longer plasma T_1/2 (183 minutes vs. 95 minutes; P < 0.05). Similar results were reported by Joukhadar et al. [52], who found muscle-to-plasma ratios of 0.63 in patients and 0.83 in healthy volunteers (Table 3).

Roughly a twofold variation of cefepime V_d has been reported in PK studies (Table 1) of severe sepsis and septic shock patients [23], elderly septic patients [53], young burn patients [54] and nosocomial pneumonia patients [55]. Cefepime Cl has also been found to be closely correlated with Cr Cl in this last listed cohort (r² = 0.77) [55], in another cohort of septic patients (r² = 0.74) [56] and in burn patients (r² = 0.58) [57]. Therefore, patients with renal dysfunction may experience toxicity.

In 21 septic patients receiving cefepime at a dose of 2 g bid, more than twofold peak variations and roughly 40-fold trough variations were observed. Again, the cefepime Cl correlated with Cr Cl (r² = 0.77). Two patients with low Cr Cl (19 and 12 mL/minute) had trough levels > 20 mg/L despite dosage adjustment. They both had neurologic symptoms (namely, confusion and muscle jerks) that were not identified as toxicity but resolved promptly after drug arrest [55].

A cefepime bolus of 2 g bid was found to be insufficient to reach a high PD target after the first dose (Table 2), both in 80% of young burn patients (burn area 21.8%) with high mean Cr Cl (119.2 mL/minute) [54] and in the Taccone et al. study [23], in which only 16% of patients achieved the intended target.

Two other studies have evaluated cefepime PK, one of which addressed the first day of therapy for 55 nosocomial pneumonia or bacteraemia patients (67% trauma) [58] and the other of which described the status of 32 VAP patients on the second day of cefepime treatment [59]. Both studies unveiled a relationship between V_d and total body weight as well as between excretion, either elimination rate constant [59] or Cl [58], and Cr Cl. However, significant interpatient variability was again observed, with regard to both cefepime Cl (58%) and central compartment V_d (67%) [58].

A PD model was developed with this VAP population PK data: despite a 2-g tid dose, PTA > 90% was achieved only with a MIC ≤ 8 mg/L [59]. In another cefepime PD model, the CFR of a 2-g bid dose, used to treat both Escherichia coli and Klebsiella pneumoniae, was 78.9%. However, for Pseudomonas aeruginosa, CFR was only 53.6% (Table 2) and increased with either 2 g tid or continuous infusion (4 g/day or 6 g/day) to 84.9%, 91.7% and 94.8% respectively. Nevertheless, the CFR for Acinetobacter baumanii [60], even with a continuous infusion of 6 g/day, was only 75%, reemphasizing the importance of appropriate dosing and the potential benefit of continuous infusion against difficult-to-treat bacteria.

Also, the cefepime tissue concentration was assessed in biopsy samples collected from the skin of burn patients three to five hours after a bolus dose on day 3 of antibiotic therapy. A mean biopsy-to-plasma cefepime ratio of 1.5 (range 0.4 to 5.1) was found [61]. Klekner et al. [62] were unable to detect cefepime in bronchial secretions from any of the five studied patients six hours after an 80 mg/kg dose. However, using continuous infusion (4 g/day) to treat VAP patients, Boselli et al. [63] found, at steady state, higher and similar plasma and ELF concentrations (mean of 13.5 mg/L and 14.1 mg/L, respectively). Although different sampling methods may have influenced these differences, continuous infusion seems to prolong T > MIC in the lungs. Nevertheless, no correlation with therapeutic outcomes was reported.

Several studies have shown ceftazidime PK heterogeneity in ICU septic patients with Pseudomonas infections (mostly nosocomial pneumonia) [64], severe sepsis [65, 66] and burns [54]. Similarly to other β-lactams, the authors noted a large variation of both V_d and Cl (Table 1) and consequently significant interpatient variability in T_1/2 and trough concentrations. Also, a correlation between Cl and Cr Cl was usually reported [65, 66].

Continuous infusion of ceftazidime was compared with bolus dosing in five different studies [67‐71]. In all, there was an increase in T > MIC with continuous infusion despite lower daily doses. However, only in severe melioidosis was this strategy associated with lower mortality (3 of 10 patients vs. 9 of 11 patients) [71]. Those patients had low Cr Cl (26.6 mL/minute) and received ceftazidime dosages adjusted to their body weight (4 mg/kg/hour or 40 mg/kg tid, for a mean body weight of 49.4 kg). Ceftazidime steady-state concentration was measured in another cohort of 92 patients receiving continuous infusions [72]. Therapeutic drug monitoring was performed on the second day of therapy. The mean serum concentration was 46.9 mg/L, but again with a very wide range of serum concentrations (7.4 to 162.3 mg/L). Therefore, dosage modification was common because of low serum levels (36.9%) and high serum levels (27.2%), with the latter being associated with lower Cr Cl (mean of 51 mL/minute compared with 103 mL/minute for patients with low serum levels). Similar results were shown in another large ceftazidime PK study assessing a mixed septic population with a higher mean Cr Cl (123 mL/minute) [73]. The lower T > MIC was found in patients with the higher Cr Cl, especially after bolus dosing (Table 2).

Continuous infusion of ceftazidime (4.5 g/day) was also associated with a higher peritoneal AUC at day 2 compared to bolus dosing (1.5 g tid) in surgical patients with peritonitis (522 mg × hour/L vs. 316 mg × hour/L; P = 0.01) [74], despite similar serum AUC (and Cr Cl > 30 mL/minute). Therefore, although serum T > 4 × MIC was > 90% in all patients, peritoneal T > 4 × MIC was still > 90% with continuous infusion but only 44% with bolus dosing. Nevertheless, no difference in mortality was noted (25% vs. 33%; P = 1.0). A PD model of ceftazidime in ICU patients also showed higher PTA with continuous infusion (100% for MIC ≤ 8 mg/L) than with bolus dosing [75].

Ceftazidime concentration in bronchial secretions was measured in four studies of VAP patients. Very low concentrations, < 0.5 mg/L and < 0.3 mg/L, were found in two of them [62, 76]. Bressole et al. [77] found a higher ratio between bronchial secretions and plasma concentration (0.76) in patients infected after abdominal surgery. A longer T_1/2 (6.1 hours) and a lower Cl (4.2 L/hour) may explain some of these differences. With continuous infusion, a ratio of 0.21 between ELF and serum was observed [69].