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Table 5 PK/PD studies of beta-lactams in bronchial-alveolar lavage

From: Pharmacokinetics–pharmacodynamics issues relevant for the clinical use of beta-lactam antibiotics in critically ill patients

Study Endpoints Antibiotic Design Results Conclusions
Kikuchi et al. [52] Compare the PK/PD parameters of biapenem in bronchial ELF given as 0.5-h and 3-h infusions Biapenem Prospective, non-blinded, crossover study
6 healthy adult volunteers
The percentage (mean ± SD) of T > MIC in bronchial ELF ranged from zero (MIC 4 μg/mL) to 34.6% ± 5.2% (MIC 0.25 μg/mL) after the 0.5-h infusion and from 5.1% ± 5.6% (MIC 4 μg/mL) to 52.2% ± 17.0% (MIC 0.25 μg/mL) after the 3-h infusion A 3-h infusion of biapenem tended to produce a higher T > MIC in bronchial ELF, as well as in plasma, than a 0.5-h infusion
These results support the use of prolonged infusions for successful treatment of lower respiratory tract infections based on PK/PD parameters in bronchial ELF
Rodvold et al. [159] To define the exposure targets in lung associated with good microbiological activity in a murine model
To determine drug penetration into ELF in humans
Ceftobiprol Prospective, observational study
Pre-clinical, murine model
Clinical study with 24 healthy volunteers
500 mg every 8 h, 2-h infusion regimen
Murine model: for cell kills of 1 and 2 log10 CFU/g, total drug must be present in ELF at a concentration in excess of the MIC of 12.9% and 24% of a 24-h interval, respectively. ELF penetration was 69% (median)
Mean ELF penetration in human volunteers was 25.5% (median, 15.3%; interquartile range, 7.9% to 30.4%)
Target attainment falls below 90% for a cell kill of 2 log10 CFU/g at a MIC of 1.0 mg/L and for a 1 log10 CFU/g cell kill at a MIC of 2.0 mg/L
Ceftobiprole penetrated into ELF very differently in humans compared to mice
For seriously ill patients, particularly in the ICU, higher doses or longer infusion times (to prolong the time > MIC), or both, will be required to comfortably ensure a 90% target attainment for seriously ill patients with MRSA pneumonia
Conte et al. Determine the plasma and intrapulmonary ELF and AC pharmacokinetic parameters of intravenously administered meropenem Meropenem Prospective, observational
Four doses (8/8 h) of 0.5 g, 1.0 g or 2.0 g were administered intravenously to 20, 20, and 8 healthy adult subjects, respectively
Cmax, AUC, T1/2:
0.5 g group: serum 25.8 ± 5.8 μg /mL, 28.57μg h/mL, 0.77 h; ELF 5.3 ± 2.5 μg/mL, 12.27 μg h/mL, 1.51 h; AC 1.0 ± 0.5μg/mL, 4.30 μg h/mL, 2.61 h
1 g group: serum 53.5 ± 19.7 μg /mL, 55.49μg h/mL, 1.31 h; ELF 7.7 ± 3.1μg /mL, 15.34 μg h/mL, 0.95 h; AC 5.0 ± 3.4 μg/mL, 14.07 μg h/mL, 2.17 h
2 g group: serum 131.7 ± 18.2μg/mL, 156.7 μg h/mL, 0.89 h
T ≥ MIC (MIC90 values of 0.12–4μg/mL):
0.5 g group: serum 28–78%, ELF 18–100%, AC 0–100%
1 g Group: serum 45–100%, ELF 25–88%, AC 24–100%
The prolonged T > MIC90 and high intrapulmonary drug concentrations following every 8 h administration of 0.5–2.0 g doses of meropenem are favorable for the treatment of common respiratory pathogens.
Boselli et al. [161] Determine the steady-state serum and alveolar concentrations of piperacillin/tazobactam administered in continuous infusion (12/1.5 g/day or 16/2 g/day) at various degrees of renal failure (terminal renal failure excluded) Piperacilin/tazobactam Prospective, open-label, comparative, single center
40 ICU patients with ventilator-associated pneumonia
Samples collected after 2 days of treatment
Median (interquartile) serum and alveolar piperacilin concentrations
No/mild renal failure (creatinine clearance ≥ 50 mL/min)
Serum 25.3 mg/L (23.1–32.6) and alveolar 12.7 mg/L (6.7–18.0) for 12/1.5 g/day
Serum 38.9 mg/L (32.9–59.6) and alveolar 19.1 mg/L (14.0–21.5) for 16/2 g/day
Moderate/advanced renal failure (creatinine clearance < 50 mL/min)
Serum 102.4 mg/L (97.4–112.6) and alveolar 44.1 mg/L (33.4–48.3) for 12/2 g/day
Serum 135.3 mg/L (119.5–146.2) and alveolar 54.9 mg/L (45.2–110.3) for 16/2 g/day
Alveolar penetration was 40–50% for piperacillin and 65–85% for tazobactam
There was a positive linear relationship between ELF and serum concentration in both patients receiving 12/1.5 g/day (r = 0.8437, P < 0.0001) and 16/2 g/day (r = 0.7935, P < 0.0001)
T > MIC was 100% (assuming MIC > 16 mg/L) in both serum and ELF in all patients with moderate/advanced renal failure; in patients with no/mild renal failure this threshold was not reached in 6 patients with 12/0.5 g dosing and 4 patients with 16/2 g dosing
The administration of daily continuous infusions of P/T 12/1.5 g or even 16/2 g might provide insufficient alveolar concentration to eradicate high-risk pathogens with high MICs such as multi-drug resistant P. aeruginosa in patients with no or mild renal insufficiency
A linear relationship between alveolar and serum piperacillin concentration was observed in this study, with ELF piperacillin concentration being 40–50% of corresponding serum values
Cousson et al. [162] Compare continuous vs intermittent administration of drug
Determine average concentration in ELF
Determine the fraction of time, during the first 48 h of treatment, where serum concentrations remained above the 20 mg/L plasma threshold
Ceftazidime Single-center, controlled, randomized trial in two parallel groups comparing two modes of administration: group A, loading dose 20 mg/kg + 60 mg/kg/day; group B, 20 mg/kg over 30 min every 8 h
34 adult ICU patients with ventilator-associated pneumonia due to Gram-negative bacilli.
The mean MIC of ceftazidime for P. aeruginosa was estimated at 2 mg/L. The target threshold value for ceftazidime in the ELF was thus fixed at 8 mg/L, with a corresponding serum threshold of 20 mg/L
Plasma T > 20 mg was 100% in group A versus 46% in group B (P < 0.003)
In the ELF, the median concentration was 12 mg/L in group A versus 6 mg/L in group B (P < 0.08)
A threshold of 8 mg/L in the epithelial lining fluid was achieved twice as often in group A as in group B
Continuous infusion presents advantages in terms of PD and predictable efficacy in patients presenting ventilator-associated pneumonia
Burkhardt et al. [163] Determine in vivo penetration into LT, ELF, and AC after 1 g of ertapenem (infusion period 30 min) for perioperative prophylaxis Ertapenem Single-center, prospective, observational of 15 patients undergoing thoracotomy
BAL performed at 1, 3, and 5 h after ertapenem infusion
Plasma concentration collected up to 24 h after infusion
LT collected at time of lung extraction
Mean concentrations in plasma, ELF, and AC were: at 1.0 h, 63.1, 4.06, 0.004 mg/L; at 3.0 h, 39.7, 2.59, 0.003 mg/L; at 5.0 h, 27.2, 2.83, 0.007 mg/L
Mean (range) concentration in LT was 7.60 (2.5–19.4) mg/kg tissue, 1.5 to 4.5 h after infusion and LT plasma concentration ratio was 23.6 ± 12.3%
Mean level of ELF penetration was 7.48% ± 8.17%, and the highest degree of penetration was recorded at 5 h after infusion (mean ± SD, 9.40% ± 10.7%)
A 1-g dose, once daily, results in drug plasma concentrations
higher than MICs of most community-acquired respiratory pathogens during the entire dosing interval
Mean concentrations in ELF exceeded MIC90 values of highly or moderately penicillin-sensitive Pneumococci and of H.
influenzae within 1 to 5 h after start of infusion and were partly below the MIC90 of penicillin-resistant Pneumococci
These results, combined with the reported MIC90 of most CAP bacteria, support the previously observed clinical efficacy of ertapenem in the treatment of community-acquired pneumonia
Boselli et al. [164] Determine the steady-state serum and ELF concentrations of unbound ertapenem administered once daily to critically ill patients with early-onset ventilator-associated pneumonia Ertapenem Prospective, open-label study in an intensive care unit
15 patients with VAP received 1-h intravenous infusions of 1 g ertapenem once daily
Samples obtained at steady-state, after 2 days of therapy
ELF obtained by mini-BAL
Median (interquartile range) Cmax, C12, and Cmin concentrations (mg/l) 1, 12, and 24 h after the end of infusion were: 30.3 (27.1–37.8), 4.8 (3.9–6.4), and 0.8(0.5–1.2) in serum and 9.4 (8.0–10.7), 2.0 (1.1–2.5), and 0.3 (0.2–0.4) in ELF, respectively
Median free percentage penetration in ELF approximately 30–40%
Concentrations exceeding the MIC90 values of most of the causative pathogens (0.25–2 mg/l for S. pneumoniae, 0.06–0.125 mg/l for Haemophilus influenzae, 0.25–0.5 mg/l for oxacillin-susceptible S. aureus, and 0.03–0.125 mg/l for Enterobacteriaceae and anaerobes 0.5–1 mg/l was encountered in early-onset VAP during 50–100% time
1 g intravenous ertapenem once daily should be effective for early-onset VAP ICU patients with no known risk factors for
multidrug-resistant pathogens
Boselli et al. [165] To determine the steady-state plasma and ELF concentrations of
ceftazidime administered in continuous infusion to critically ill patients
with severe nosocomial pneumonia
Ceftazidime Prospective, open-label study.
15 adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation
Administration of 30 min infusion of 2 g ceftazidime followed by continuous infusion 4 g over 24 h
Blood and mini-BAL samples collected by the third day of antibiotic therapy (8:00 am, 12:00 pm, and 6:00 pm)
The mean ± SD steady-state plasma and ELF concentrations in continuous infusion were 39.6 ± 15.2 g/mL and 8.2 ± 4.8 g/mL, respectively, showing a mean ± SD percentage penetration of ceftazidime into ELF of 20.6 ± 8.9% The administration of the applied dose in critically ill patients with severe nosocomial pneumonia provides concentrations in excess of the MIC of many susceptible organisms over the course of therapy in both serum and ELF. However, for some pathogens such as P. aeruginosa, higher doses of ceftazidime should be administered, or another agent should be used in combination
Felton et al. [166] To assess plasma and intra-pulmonary PK of piperacillin/tazobactam in critically ill patients
Quantify pulmonary penetration
Identify factors that may influence pulmonary penetration
Piperacilin/tazobactam Prospective, open label, single arm study
18 ICU adult patients with pneumonia
Administration of 4/0.5 g infusion every 8 h daily
Samples collected at steady-state (mean of 8.8 doses (range 2–16).
Non-directed bronchial lavage was performed for ELF sampling
Median piperacilin and tazobactam pulmonary penetration ratio was 49.3% and 121.2% respectively.
ELF protein/plasma protein ratio, as a surrogate measure of lung permeability, was found to have a statistically negative correlation between piperacilin pulmonary penetration ratio and pulmonary permeability. There was no statistically significant correlation for tazobactam
14–18% of patients will have suboptimal drug exposure (ELF 50%T > MIC) when infected with a “susceptible” (MIC < 16 mg/L) organism
Piperacilin and tazobactam plasma concentrations do not precisely predict ELF concentrations of both drugs
Current piperacilin-tazobactam regimens is inadequate for effective treatment and suppression of emergence of antimicrobial resistance in an unacceptably high proportion of critically ill patients, especially those with pneumonia resulting from infection with a less susceptible organism
Boselli et al. [167] To determine the steady-state plasma and ELF concentrations of cefepime administered in continuous infusion
in critically ill patients with severe bacterial pneumonia
Cefepime Prospective, open-label study
20 ICU adult patients with severe nosocomial bacterial pneumonia
All subjects received a 30-min intravenous infusion of cefepime 2 g followed by a continuous infusion of 4 g over 24 h
Samples were collected after 48 h of therapy. Blood and mini BAL samples were collected at 8:00 am, 12:00 pm, and 6:00 pm
Mean ± SD steady-state plasma and ELF concentrations were 13.5 ± 3.3 g/mL and 14.1 ± 2.8 g/mL, respectively, with a mean percentage penetration into epithelial lining fluid of about 100% Administration of cefepime in continuous infusion in critically ill patients with severe nosocomial pneumonia appears to optimize the pharmacodynamic profile of this beta-lactam by constantly providing concentrations in excess of MIC of most of the susceptible organisms over the course of therapy in both serum and ELF
For some pathogens such as Acinetobacter spp. and P. aeruginosa higher doses should be administered
Boselli et al. [168] To determine the steady-state plasma and epithelial lining fluid concentrations of piperacillin/tazobactam administered to critically ill patients with severe bacterial pneumonia Piperacilin/tazobactam Prospective, open label study
10 ICU adult patients with severe nosocomial pneumonia
30-min intravenous infusion 4/0.5 g every 8 h
Samples were obtained at steady-state, after 2 days of treatment. Blood samples were collected at three
predetermined time points at 7:00 am (trough), 8:00 am (peak), and 12:00 pm (intermediate)
Mini BAL was performed simultaneously to blood sampling at 12:00 pm
Mean ± SD steady-state plasma trough, peak, and intermediate concentrations were 8.5 ± 4.6 μg/mL, 55.9 ± 21.6 μg/mL, and 24.0 ± 13.8 μg/mL for piperacillin, and 2.1 ± 1.0 μg/mL, 4.8 ± 2.1 μg/mL, and 2.4 ± 1.2 μg/mL for tazobactam
Mean ± SD steady-state intermediate ELF concentrations were 13.6 ± 9.4 μg/mL for piperacillin and 2.1 ± 1.1 μg/mL for tazobactam, respectively
Mean percentage penetration of piperacillin and tazobactam into ELF was 56.8% and 91.3%, respectively
Treatment of severe nosocomial pneumonia with a regimen of P/T 4/0.5 g every 8 h might provide insufficient concentrations into lung tissue to exceed the MIC of many causative pathogens
Lodise et al. [169] To describe the PD profile of cefditoren in plasma and ELF Cefditoren Open, noncontrolled,
dual-center, phase I study
24 adult patients with scheduled bronchoscopy
Single oral dose 400 mg cefditoren
Three sampling time windows (1–2 h, 2–3 h, or 3–4 h post-administration)
Plasma/ELF concentrations (mg/L)/penetration ratios
1–2 h: 1.78 ± 1.27/0.39 ± 0.21/38.1 ± 50.1%
2–3 h: 1.33 ± 0.95/0.34 ± 0.25/23.2 ± 18.1%
3–4 h: 1.03 ± 0.51/0.30 ± 0.18/31.8 ± 19.2%
AUC ELF/AUC plasma penetration ratio (mean ± SD) was 0.33 ± 0.48
PTA in plasma fT > MIC of 60 to 70% was < 90% for MICs of > 0.03 mg/L
PTA in ELF T > MIC of 60% and 70% were 90.26% and 86.65%, respectively, at a MIC of 0.0125 mg/L and were significantly less for higher MICs
Cefditoren penetrates reasonably well into the ELF, as defined by the mean AUCELF/AUCplasma penetration ratio
The overall probability of target attainment (T > MIC > 50%) in plasma and ELF, however, was suboptimal (< 90%)
  1. AC alveolar cells, AUC area under the curve, BAL bronchoalveolar lavage, CAP community-acquired pneumonia, Cmax maximal concentration, C12 concentration at 12 h, Cmin trough concentration, CFU colony forming unit, ELF epithelial lining fluid, ICU intensive care unit, LT lung tissue, MIC minimal inhibitory concentration, MIC90 minimal inhibitory concentration for 90% of isolates, MRSA methicillin-resistant Staphylococcus aureus, P/T piperacillin/tazobactam, PTA probability of target attainment, SD standard deviation, T1/2 half-life, T > MIC percentage of time above minimal inhibitory concentration, VAP ventilator-associated pneumonia