|Continuous haemodialysis; Piperacillin/tazobactam;
Ciprofloxacin; Critically ill patients; Sepsis
|Critically ill intensive care patients are frequently suffering from
sepsis and multi organ failure associated with a high mortality rate
[1-3]. Diagnosis of severe sepsis or septic shock requires immediate
administration of anti-infective medication because the mortality
rate increases with delayed anti-infective therapy. The initial empiric
antibacterial therapy comprises one or more antibiotics that are effective
against all likely pathogens causing the infection . Piperacillin/
tazobactam, a time dependent antibiotic, and ciprofloxacin, a
concentration dependent antimicrobial agent, are often used for empiric
therapy. While time dependent antibiotics should reach concentrations
higher than four times of the minimal inhibition concentration (MIC)
of the pathogen, a high ratio of the area under the curve (AUC) to MIC
is important for concentration dependent drugs like quinolones [5-8].
The appropriate dosing is crucial for the patients’ outcome. While too
low antibiotic concentrations can lead to treatment failures and induce
bacteria resistance, too high concentrations can increase side effects
and may lead to unnecessary consumption of health care resources.
Pharmacokinetic and pharmacodynamic behavior of the antibiotic
drugs is affected by acute renal failure (ARF) and by continuous renal
replacement therapy (CRRT) .
|Continuous venovenous haemodialysis (CVVHD) and continuous
venovenous haemodiafiltration (CVVHDF) are frequently chosen
modes of CRRT in patients suffering from severe sepsis including ARF.
The diffusion based dialysis in CVVHD and CVVHDF eliminates
antibiotic drugs more effectively than convection based dialysis methods like continuous venovenous haemofiltration (CVVH) [10-12]. However these extracorporeal clearance procedures are known to
be associated with potential underdosing of the antibiotic drug therapy
. The elimination rate of the drugs depends on the physicochemical
nature and pharmacokinetic behavior of the antibiotic compound as
well as the specific dialysis method and its operating conditions used.
Hydrophilic antibiotic drug substances (e.g. β-lactams) are usually
distributed in a limited space and excreted via the renal route as
unchanged drugs, whereas lipophilic substances (e.g. fluoroquinolones)
are widely distributed into the intracellular space and often hepatically
metabolized prior to renal elimination . In acute sepsis the
volume of distribution is known to increase significantly because of
capillary leakage which might lead to unpredictable pharmacokinetic
behavior . With regard to the CRRT method, the extent of drug
removal is expected to correlate with the type and surface area of the
filter membrane and the rate of the dialysate solution. In addition, elimination of the drug substances varies according to the patients’
residual renal function.
|In order to avoid under- or overdosage of antibiotics therapeutic
drug monitoring (TDM) is highly recommended in intensive care
patients undergoing CRRT [15,16]. TDM is based on the measurement
of antimicrobial drug concentrations in the biological matrices using
analytical methods like high performance liquid chromatography
(HPLC) coupled with ultraviolet detection or mass spectrometry. In
order to study the pharmacokinetics of the specified antibiotics a new
HPLC method in combination with solid phase extraction (SPE) for
the simultaneous determination of piperacillin and ciprofloxacin was
developed and validated . The implementation of the analytical
method was a prerogative and part of the clinical study described
here. The aim of the study was to investigate the pharmacokinetics of
piperacillin/tazobactam and ciprofloxacin in critically ill intensive care
patients undergoing CVVHD or CVVHDF under defined operating
conditions. Primary endpoint was the rate of sub therapeutic antibiotic
exposure in these patients determined.
|Materials and Methods
|Study design and population
|A single-centre, prospective, open-label study protocol for
critically ill intensive care patients treated with CVVHD or CVVHDF
and empiric antibiotic therapy was designed. Adult intensive care unit
(ICU) patients (age>18 years) suffering from severe sepsis and the
consecutive clinical need for an antibiotic treatment with piperacillin/
tazobactam and/or ciprofloxacin and suffering from ARF with the need
for CRRT were eligible for the study. Written consent for the study was
given by the patient or his legal surrogate. Patients who were included
in other clinical trials were not eligible.
|The study was conducted at the University Medical Center Mainz,
Germany and approved by the Ethics Committee (Institutional Review
Board (IRB) of the Federal State of Rhineland-Palatinate, Germany
(IRB approval number: 837.250.10, September 2010). Clinical trial
approval was granted by the national approval authority Federal
Institute for Drugs and Medical Devices (EudraCT Number 2010-
021369-66). The study was performed according to The Declaration
of Helsinki and Good Clinical Practice Guidelines. Written informed
consent was obtained from the legal surrogates of all patients. 24
patients were enrolled over a period of 12 months. CVVHD and
CVVHDF (multiFiltrate-syteme, Fresenius Medical care, Germany)
were performed using a polysulfone high-flux dialyzer (1.8 m2)
(Ultraflux AV 1000 S). Upper and lower limits set were 100-150 ml/
min for blood flow and 2-2.4 l/h for dialysate flow. During CVVHDF
limits set for flow of the substituate solution were 700-800 ml/h. The
ultrafiltrate flow varied depending on the patients’ renal function. In
addition to the local citrate anticoagulation, systemic anticoagulation
was performed with dalteparin, enoxaparin, heparin or argatroban
according to the individual needs of the patients.
|Dosing and sampling of piperacillin and ciprofloxacin
|In general piperacillin/tazobactam 4/0.5 g was administered
three times per day and ciprofloxacin 200 mg was administered
twice per day in the critically ill patients undergoing CRRT. Due to
a broad pharmacokinetic and pharmacodynamic variability dosage
of antibiotics in continuous renal replacement therapy is challenging.
The dosage of piperacillin/tazobactam and ciprofloxacin has been
derived from several studies [18-27]. Piperacillin is a hydrophilic
antibiotic with an average distribution volume in steady state (VdSS) of about 21 ± 5,5 L [28,29]. Hence a dose adaptation for obesity is
not required. Plasma and dialysate concentrations of piperacillin and
ciprofloxacin were measured in the steady state treatment phase (day
three after start of antibiotic therapy). Blood samples were collected
immediately before and after administration of the antibiotic drug
solution and up to a 12 hour interval. During this interval dialysate
samples were withdrawn whenever the filtrate bags were exchanged.
Serum and dialysate concentrations (Cmax, Cmin) of piperacillin and
ciprofloxacin were analyzed by a previously published validated HPLC
method combined with solid phase extraction for plasma samples .
The method was developed for the simultaneous analysis of piperacillin
and ciprofloxacin in serum and dialysate samples. Method validation
was performed according to the Guideline of the European Medicines
Agency on validation of bioanalytical methods.
|Pharmacokinetic data analysis
|The resulting concentrations were used to calculate the
pharmacokinetic parameters of piperacillin and ciprofloxacin i.e.
half time (t0.5), distribution volume in the steady state (VdSS), area
under the curve (AUC), area under the first moment curve (AUMC),
total clearance (Cltotal), dialysate clearance (ClCRRT) and extrarenal
clearance (Clextrarenal). Clextrarenal was calculated as difference
between Cltotal and ClCRRT (excreted amount of piperacillin and
ciprofloxacin in dialysate divided by the AUC of the collecting interval).
Concentration time curves were calculated and plotted using Microsoft
Excel. Statistical analysis was performed using SPSS version 20 (IBM,
Ehningen, Germany). Optimum exposure to piperacillin is expected
when serum concentrations are maintained 4-5 times higher than
the minimal inhibitory concentration (MIC), i.e. above 64 mg/l over
the complete dosing interval. Optimum exposure to ciprofloxacin is
expected when the ratio (AUIC) of the area under the curve (AUC) and
MIC is ≥ 125 h and the Cmax/MIC ratio amounts to ≥ 10 per dosing
|Statistical analysis was planned in cooperation with the Institute of
Medical Biometry, Epidemiology and Informatics (IMBEI), University
Medical Center Mainz, Germany. For each antibiotic (piperacillin and
ciprofloxacin) 20 patients were planned to take part in the clinical trial.
As primary endpoint the rate of subtherapeutic antibiotic exposure in
the patient group was chosen. A t-test was performed for piperacillin
(MIC>64 mg/l after 8 h; n=20; α=5%) and ciprofloxacin (AUIC>125 h;
n=20; α=5%). The binomial distribution of the sample was tested. The
null hypothesis determined for piperacillin were plasma concentrations
<64 mg/l after an interval of 8 hours and for ciprofloxacin an
AUIC<125 h. With the method of Pearson and Clopper the upper
and lower limit of confidence intervals were calculated. The calculated
confidence intervals represent 95% probability of underdosing in the
|Over a period of twelve months 24 patients were included in the
clinical trial. 21 patients were treated with piperacillin/tazobactam
and 20 patients were treated with ciprofloxacin. Only 7 patients were
treated with monotherapy. The patient demographic data and clinical
information are given in Table 1. Most patients were suffering from
septic shock associated with acute renal failure. Five patients also
suffered from liver cirrhosis or liver failure. The mean Apache II score
was 29 ± 7.5, the mean TISS 28 Score was 39 ± 6.8. Nine of the 24 (17
male, 7 female) patients enrolled, died during their stay on the ICU.
21 patients were treated with CVVHD, 3 patients were treated with CVVHDF. During CVVHD blood flows varied between 100-120 ml/
min and dialysate flows between 2-2.2 l/h. During CVVHDF blood flow
was increased up to 150 ml/min, flow of the dialysate solution varied
between 1.3 and 2.6 l/h. The flow of the substituate solution amounted
to 0.7-0.8 l/h. The ultrafiltration rate was kept between 100-450 ml/h.
Except one patient, all patients lost their urine production completely.
|Pharmacokinetic profiles of piperacillin were assessed in 21
patients during treatment with piperacillin/tazobactam 4.0/0.5 g three
times a day (Figure 1). On average the Cmax and Cmin concentrations
amounted to 249 mg/l and 54 mg/l, respectively. The mean Vdss was
calculated to be 25 l with a mean Cltotal of 94 ml/min. The resulting
t0.5 amounted to 7.6 h.
|Pharmacokinetic profiles of ciprofloxacin were assessed in 20
patients during treatment with ciprofloxacin 20 0 mg twice a day
(Figure 2). The mean Cmax and Cmin concentrations amounted to 5.2
mg/l and 1.6 mg/l respectively. The mean Vdss was 66 l with a mean
Cltotal of 154 ml/min and t0.5 of 20 h.
|The mean ClCRRT was similar for piperacillin (27 ml/min) and
ciprofloxacin (24 ml/min). However the Clextrarenal was much
higher for ciprofloxacin (129 ± 107 ml/min) than for piperacillin (67
± 48 ml/min). Related to the Cltotal, 29% of piperacillin and 16% of
ciprofloxacin were eliminated by CRRT. Despite the moderate rate of
ClCRRT the exposure of the patients to piperacillin and ciprofloxacin
revealed to be inadequate.
|At the end of the eight hour dosing interval in 10 out of 21 patients,
plasma concentrations of piperacillin fell below 64 mg/l (Figure 3).
|The t-test was performed for 20 patients treated with piperacillin
and 19 patients treated with ciprofloxacin. Plasma concentrations were
not significantly higher than the MIC of 64 mg/l or the AUIC of 125
h according to the one sided t-test. Ten out of 21 patients treated with
piperacillin were underdosed. Nine out of 20 patients treated with
ciprofloxacin were underdosed (Table 2).
|According to the Pearson-Clopper test 26-70% of the patients
treated with piperacillin and 29-76% of the patients treated with
ciprofloxacin were underdosed. Plasma concentrations of both
antibiotics were lower than the target concentrations associated with
optimal antibiotic efficacy.
|Pharmacokinetics of antibiotics can be altered intensely in critically
ill patients especially when they undergo CRRT. Loss of organ function
like ARF influences the excretion of the drugs. Furthermore in patients
exposed to CRRT excretion is altered by the type of CRRT, dialysate
and blood flow as well as the ultrafiltration rate.
|Out of 24 patients included in the clinical study, 21 patients received
piperacillin/tazobactam and 20 patients received ciprofloxacin. 17
patients received both antibiotics as a combination therapy. The
sample size of patients is higher than in other published studies [18-22,26,30] and underscores the validity of the study results. Of
note the study population is homogenous with regard to antibiotic
treatment, renal function, and type and conditions of CRRT. The
mean Apache II score (29 ± 7.5 points) of the study population is
comparable to those enrolled in other studies [19,21,27] or even higher
[24,30]. Nearly all patients lost their urine production completely and
underwent continuous hemodialysis procedures. According to the
study protocol pharmacokinetic data of the three patients treated with CVVHDF were evaluated together with the 21 patients treated with
CVVHD. Differences in the pharmacokinetics of the antibiotics were
not observed. Conditions of CVVHD (blood flow 100-150 ml/min;
dialysate flow 2-2.4 l/h) were similar in all patients included in the study.
Fluid balance was regulated by ultrafiltration. The resulting blood flow
was comparable to those used in other studies [18-24,27,30,31] while
the surface of the inserted polysulfone filters (1.8 m2) was considerably
larger than in other studies (0.5-0.7 m2) [18,20,26].
|Today it is well accepted that concentrations of time dependent
antibiotics should remain in critically ill patients four times higher than
the MIC [5,32,33] over the complete dosing interval [5,6]. However
in clinical practice standard doses are used to start empiric antibiotic
therapy. According to the product information and published results
[15,30,34] in this pharmacokinetic study piperacillin/tazobactam 4.0
g/0.5 g was infused three times daily. Because of the wide therapeutic
index of tazobactam plasma concentrations were not analyzed. Only
one study reports an accumulation of tazobactam .
|Only 11 out of 21 patients reached the target plasma levels on day
3 of piperacillin therapy. The fact that 26-70% of the included patients
were underdosed corresponds to other findings published. Intermittent
infusion of piperacillin/tazobactam 4 g two to four times daily was also
associated with underdosage [13,22].
|With a total piperacillin clearance of 94 ml/min the clearance is
higher than reported in previous studies [18,20-22]. This is due to
the larger membrane surface of the polysulfone filter [18,20,26]. This
explanation is confirmed by the finding that the calculated volume of
distribution of 0.28 l/kg is similar to those already reported [21-23].
Acute renal failure can alter pharmacokinetics of critical ill patients
. The prolonged half life and variable values of Cmax of piperacillin are due to several CRRT parameters (CRRT method; dialysate flow;
rate of ultrafiltration; blood flow), membrane specific factors (material;
surface; coefficient of ultrafiltration) and specifics of patients (organ
function; comorbidity, additional drugs). The results are comparable
to other studies [18,22-24]. Trotman et al. recommend a piperacillin/
tazobactam dosage of 2.25-3.38 g every 6 hours . According
to a review of Pea et al. and the study of Arzuaga et al. piperacillin/
tazobactam 4.0/0.5 g is to be administered three to four times a day
[15,30]. A continuous or prolonged infusion of piperacillin/tazobactam
was also tested in clinical trials [32,35-37], but there was no proof of
lower mortality rates in a meta analysis . In the study reported
here, short-term infusion of piperacillin/tazobactam 4.0/0.5 g resulted
in a high interindividual variance. Nearly 50% of the included patients
did not match target values during the eight hour dosing interval. In
order to avoid underdosing, in a patient population and therapy setting
comparable to ours, we recommend increased piperacillin doses. We
conclude that in severe sepsis with ARF leading to CRRT when TDM is
not available, piperacillin/tazobactam 4.0/0.5g should be administered
every six hours.
|The calculated total clearance of 154 ml/min is similar or lower
than published study results [19,24,25,27,31]. The mean maximum and
minimum serum concentrations were lower than those given in the
product information of ciprofloxacin (7.2 mg/l) . A high MIC of
bacteria like Pseudomonas aeruginosa leading to low AUIC levels are
often resulting in therapeutic failures . MIC levels of 0.5 mg/l are
in accordance with the EUCAST guideline for a calculated antibiotic
|Concentration dependent antibiotics like ciprofloxacin should
result in an AUIC > 125 h and a Cmax /MIC ratio ≥10 in order to
guarantee optimum efficacy and tolerability [7,8]. In former studies
dosages of 100-400 mg bid were investigated in patients undergoing
continuous renal replacement therapy [19,24,26,27]. There is only a case
study available reporting the administration of 800 mg ciprofloxacin
twice daily in a critically ill patient with multi organ failure . In
our study only 9 of 20 patients treated with ciprofloxacin 200 mg twice
daily reached the target levels in terms of AUIC and Cmax/MIC. With
95% probability 29%-76% of patients treated with ciprofloxacin were
underdosed and the exposure to ciprofloxacin was too low. A dosage of
400 mg twice daily resulted in a mean AUIC of 161 hours  while in
the supernatant study a dosage of 200 mg to times a day resulted in an
AUIC equal to 124 hours. In accordance with the results of other studies
higher doses of ciprofloxacin and TDM is recommended in critically ill
patients [34,42]. We conclude that in severe sepsis with ARF leading
to CRRT when TDM is not available dosing of ciprofloxacin should be
increased to 400 mg twice daily.
|Critical illness and the clinical interventions may have various
effects on patients‘physiology and the pharmacokinetics of drugs. The
increase in the volume of distribution in septic patients might result
in underdosing. According to the present study results underdosing
of piperacillin and ciprofloxacin is most likely. However there is a
high inter individual variability. Therefore TDM should be conducted
to ensure that antibiotic target concentrations are achieved in the
individual patient with respect to the individual state of disease and
pathophysiology. Blood sampling and analysis, e.g. simultaneous
assaying of different antibiotics as described here, allow direct
measurement of antibiotic clearance and calculation of appropriate
subsequent dosage in order to achieve target concentrations in the individual patient.
|Concentrations of the antibiotics were measured in plasma which
might differ from concentrations at the infection side . CRRT
technology got more and more advanced during the last decade. Results
and recommendations derived from a specific dialysis procedure
cannot be readily transferred to another CRRT setting. Results cannot
be extrapolated to other dialysis systems and membranes. Sampling
and analysis of the drug concentrations were performed in the steady
state phase of antibiotic therapy; results are not representative for
the initial phase of treatment. Because early and appropriate dosing
of antibiotics is crucial for the outcome loading doses of antibiotics
during the first day of treatment are to be considered. The loading dose
was not investigated here.
|Despite the moderate rate of ClCRRT, the exposure of the patients
to piperacillin and ciprofloxacin revealed to be inadequate. In critically
ill patients undergoing CRRT, piperacillin/tazobactam 4.0/0.5 g
should be administered four times a day and ciprofloxacin 400 mg
twice daily in order to avoid underdosing. Moreover individualized
dosing of antibiotic therapy in terms of therapeutic drug monitoring is
worthwhile for critical ill patients undergoing CRRT.
|In patients undergoing CRRT, piperacillin/tazobactam 4.0/0.5 g
should be administered four times a day and ciprofloxacin 400 mg
twice daily in order to avoid underdosing.
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