In silico trials using Monte Carlo simulation to evaluate ciprofloxacin and levofloxacin dosing in critically ill patients receiving prolonged intermittent renal replacement therapy
© The Author(s) 2016
Received: 4 April 2016
Accepted: 21 July 2016
Published: 7 September 2016
Prolonged intermittent renal replacement therapy (PIRRT) is a growing option to treat acute kidney injury in critically ill patients, but absent pharmacokinetic data challenge optimal drug dosing. Inappropriate antibiotic dosing can cause widespread bacterial resistance and decreased antibiotic utility. The purpose of this study was to evaluate probability of target attainment (PTA) of various ciprofloxacin and levofloxacin regimens in critically ill patients receiving PIRRT, utilizing Monte Carlo simulation (MCS).
The models incorporated published body weights and pharmacokinetic parameters (volume of distribution, non-renal clearance, and extraction coefficients) and their associated variability and ranges. Four different PIRRT effluent/duration combinations (4 L/h × 10 h or 5 L/h × 8 h in hemodialysis or hemofiltration, respectively) occurring at the beginning or 14-16 h after drug administration were modeled. MCS predicted drug disposition during the first 72 h in 5000 virtual patients for each dosing regimen. Desired pharmacodynamic targets to calculate PTA were the 24-h area under the curve/minimum inhibitory concentration (AUC24h:MIC) of ≥125 and ≥50 for Gram-negative and Gram-positive infections, respectively. The “successful” doses were the ones with PTA of ~90 % in all PIRRT settings.
No conventional, FDA-approved regimens attained ~90 % of PTA for Gram-negative infection with Pseudomonas aeruginosa at the MIC of 1 and 2 mg/L for ciprofloxacin and levofloxacin, respectively. The successful doses (ciprofloxacin 1200 mg loading dose, 800 mg q12h, and levofloxacin 2000 mg loading dose, 1000 mg q24h post-PIRRT) greatly exceed the maximum FDA-approved doses. For Gram-positive infections, a levofloxacin 750 mg loading dose and 500 mg q24h post-PIRRT successfully attained PTA ~90 % at the MIC of 1 mg/L for Streptococcus pneumoniae.
Ciprofloxacin and levofloxacin cannot be recommended as empiric monotherapy for serious Gram-negative infections in patients receiving PIRRT due to suboptimal efficacy. This MCS prediction supports rational dosing decisions to treat infected patients receiving PIRRT and should be used until clinical pharmacokinetic trials are conducted in this population.
KeywordsCiprofloxacin In silico modeling Levofloxacin Monte Carlo simulation Prolonged intermittent renal replacement therapy Pharmacodynamics Pharmacokinetics
Prolonged intermittent renal replacement therapy (PIRRT) is a hybrid RRT used in the critical care setting as an alternative to conventional RRTs like intermittent hemodialysis (IHD) or continuous renal replacement therapy (CRRT). The typical duration of PIRRT is 6–12 h, providing the benefits of better patient mobility and less cost compared to CRRT, but a longer treatment period with slower flow rates which allows for better tolerated fluid removal than IHD [1–6]. With these unique qualities and similar patient outcomes compared to conventional RRT, more clinicians are considering PIRRT as a viable treatment option for acute kidney injury in critically ill patients [1–7]. However, very few antibiotic pharmacokinetic studies have been conducted in patients receiving PIRRT, prompting one set of authors to opine that PIRRT is a rational RRT that does not allow for rational drug dosing . Indeed, validated PIRRT dosing recommendations are available for less than 1 % of drugs , and there is a growing understanding that inappropriate empiric antibiotic dosing is associated with poor clinical outcomes in critically ill patients [9, 10]. More than 70 % of critically ill patients receive antibiotics, and the primary mortality cause in these patients is infection . With emerging bacterial resistance and lack of novel antibiotic development, clinicians are more pressured than ever to ensure that they are using appropriate antibiotic doses to maximize bacterial eradication while ensuring safe use. Hence, more pharmacokinetic studies are urgently needed to ensure rational antibiotic dosing in patients receiving PIRRT. Clinical trials are indispensable to establish antibiotic dosing recommendations; however, clinical trials are often not feasible. Clinical trials are expensive, and the FDA does not mandate drug or RRT device companies to conduct pharmacokinetic trials in PIRRT. The operating characteristics of PIRRT (duration, convective and diffusive modalities, and effluent flow rates) vary widely; consequently, drug dosing may vary as well. This makes it unlikely that sufficient PIRRT pharmacokinetic trials will ever be conducted in these vulnerable patients. Alternative approaches to clinical trials are needed to develop appropriate dosing in PIRRT. For decades, in silico trials using Monte Carlo simulation (MCS) have been used to determine optimal drug regimens during drug discovery and development. This approach has been employed to predict optimal antibiotic doses in patients with IHD and CRRT [12, 13], but not with PIRRT. Antibiotic dosing in patients with PIRRT is challenging, because dosing must take into account the pharmacokinetics altered not only by critical illness and but also by the timing of PIRRT and its associated drug clearance in relation to drug administration . However, in silico trials can integrate our current understanding of PIRRT’s influence on drug disposition and can inform appropriate antibiotic dosing in this patient population with limited available pharmacokinetic data generated from more conventional sources like clinical trials.
Ciprofloxacin and levofloxacin are fluoroquinolone antibiotics, often prescribed to treat moderate to severe infections in critically ill patients. They exert concentration-dependent bactericidal activity against most Gram-negative aerobic pathogens and some Gram-positive organisms. However, the widespread dissemination of fluoroquinolone resistance among key pathogens can limit their use [15, 16]. For example, fluoroquinolone resistance rates in Gram-negative bacilli species such as Pseudomonas aeruginosa in ICUs have more than doubled from 11 % in 1990–1993 to 27.4 % in 2011 [16, 17]. The decline of fluoroquinolone activity may be the most concerning of all antibiotic resistance patterns among Gram-negative pathogens in the ICU. The emergence of fluoroquinolone resistance among many Gram-positive pathogens has also reduced its clinical utility in the ICU [18, 19]. Frequent prescribing and suboptimal dosing contributed to this alarming trend [9, 20]. Previous studies indicated that the 24-h area under the curve (AUC24h):minimum inhibitory concentration (MIC) ratio is the pharmacodynamic parameter most predictive of fluoroquinolone efficacy . A total AUC24h:MIC ≥125 has been correlated with optimal clinical outcomes in critically ill patients infected with Gram-negative pathogens including P. aeruginosa , while a lower target of a total AUC24h:MIC ≥50 is sufficient to treat Gram-positive pathogens such as S. pneumoniae . Fluoroquinolone-associated toxicities are mild-to-moderate in most cases. However, fluoroquinolone-associated cardiovascular toxicity (i.e., prolongation of QT interval) that can potentially lead to life-threatening torsades de pointes [24, 25] is a rising concern, especially in high-risk patient populations such as critically ill patients who may require higher doses. Central nervous system (CNS) adverse effects may be commonly observed with fluoroquinolone therapy, especially in patients with a previous CNS impairment . The risk factors are likely patient-specific, but it is suggested that dosing regimens should not exceed the FDA-approved doses to prevent these toxicities . Currently, no ciprofloxacin pharmacokinetic studies have been published in PIRRT. Levofloxacin has been evaluated in one small study (n = 5) with extended daily dialysis, one type of PIRRT, but the optimal dosing has not been determined . With this lack of available pharmacokinetic dosing data, pharmacist-recommended fluoroquinolone doses in patients receiving PIRRT vary extensively, with up to fivefold dosing differences being proposed . The objective of the present study was to predict the likelihood of pre-defined pharmacodynamic target attainment in intravenous ciprofloxacin and levofloxacin dosing regimens as empiric treatment for serious Gram-negative infections in virtual patients receiving daily PIRRT using MCS techniques. Additionally, intravenous levofloxacin dosing regimens were also evaluated for treatment of Gram-positive infections.
Pharmacokinetic model development
Demographic and pharmacokinetic parameters
86.6 ± 29.2 [≥40]
Volume of distribution (L/kg)
1.25 ± 0.4 [0.5–1.92]
1.2 ± 0.4 [0.7–2.08]
Non-renal clearance (mL/min)
116 ± 61 [13–259]
25.7 ± 14 [0.12–67]
0.7 ± 0.2 [0–1]
0.6 ± 0.2 [0–1]
PIRRT operation parameters
Hemofiltration or hemodialysis
Blood flow rate
Dialysate/ultrafiltration flow rate and duration
4 L/h for 10 h or 5 L/h for 8 h
where CLHF is transmembrane clearance in hemofiltration; SC is sieving coefficient; Q uf is ultrafiltrate flow rate; Q plasma is plasma flow rate (Q plasma = Q blood*(1 − hematocrit); hematocrit is 30 % ); Q replacement is replacement fluid flow rate (Q replacement = Q uf); CLHD is transmembrane clearance in hemodialysis; SA is saturation coefficient; Q d is dialysate flow rate; V d is volume of distribution; WT (kg) is body weight; k on is the elimination rate constant during PIRRT; CLNR is non-renal clearance; and k off is the elimination rate constant off PIRRT.
Monte Carlo simulations
Pharmacodynamic exposures were modeled using a one-compartment model with constant intravenous input and first-order elimination (Additional file 1). MCS (Crystal Ball Classroom Edition, Oracle) was performed to generate total serum concentration-time profiles, following a previously published method . Twelve different ciprofloxacin and 17 different levofloxacin dosing regimens including those recommended for patients receiving other types of RRT and those for normal kidney function were simulated with infusion time of 1 h for both agents [40, 41]. Fluoroquinolone disposition was assessed for the first 72 h in order to evaluate the relative influences of loading and maintenance doses even in the extended dosing intervals (e.g., 48 h). In clinical practice, fluoroquinolone doses can be administered at the beginning of, or during the middle of PIRRT, or several hours prior to a PIRRT session. In order to consider all clinical situations, we simulated each fluoroquinolone dosing regimen in the two most extreme scenarios in each of four PIRRT settings. One scenario was when the PIRRT is commenced at the beginning of first fluoroquinolone dose infusion (early PIRRT), and the other scenario was when PIRRT occurred 14 or 16 h after the first fluoroquinolone dose is administered (late PIRRT).
Probability of target attainment prediction
The pharmacodynamic targets used in these in silico trials were AUC24h:MIC ≥125 for each 24 h period during the initial 72 h therapy for Gram-negative infections and AUC24h:MIC ≥50 for Gram-positive infections [23, 24]. AUC24h was calculated by 24-h area under the curve using the linear trapezoidal formula. The reference Gram-negative pathogen was P. aeruginosa which is associated with the increased mortality rates in the ICUs . Based on the Clinical and Laboratory Standards Institute, the clinical breakpoint of P. aeruginosa is 1 mg/L for ciprofloxacin and 2 mg/L for levofloxacin . For Gram-positive infection simulations, S. pneumoniae was chosen and its clinical breakpoint for levofloxacin is 2 mg/L . Probability of target attainment (PTA) was calculated by summing up the virtual patient numbers achieving the pre-defined pharmacodynamic target and dividing by the total number of patients (n = 5000). In addition, PTA of each dosing regimen was calculated at doubling MIC dilutions ranging from 0.25 to 4 mg/L. If a regimen yielded ~90 % of PTA in all PIRRT settings regardless of the time of PIRRT institution in relation to the first drug administration using the smallest daily dose, the dosing regimen was considered “successful.” However, benefits of achieving the pharmacodynamic target had to be weighed against the risk of drug toxicity. No published studies are available to clearly define fluoroquinolone exposure and a toxicity concentration threshold. Given that these patients with PIRRT are more vulnerable to experience fluoroquinolone-associated cardiovascular and CNS toxicities that can be life-threatening, we decided a priori that any dosing recommendation would not exceed within the FDA-approved intravenous doses (1200 mg/day for ciprofloxacin and 750 mg/day for levofloxacin) due to safety concerns [25, 40, 41].
Sensitivity analyses were performed to investigate the influence of different PIRRT operational settings on fluoroquinolone clearance by PIRRT. As mentioned, fluoroquinolone dosing regimens in early vs. late PIRRT were compared to assess whether “when” to give a drug in relation to PIRRT substantially impacted PTA. Many other RRT-specific factors can affect extracorporeal drug clearance. However, where blood flow rate is much higher than effluent flow rate (like the PIRRT settings in our model), the effluent flow rate is the most important covariate to determine extracorporeal drug clearance in RRT . Consequently, we re-evaluated PTA of the successful fluoroquinolone dosing regimens from this present study in a wide array of effluent flow rates ranging from 2 to 10 L/h using the same treatment duration. Sensitivity analyses were performed for all successful ciprofloxacin and levofloxacin doses for serious Gram-negative infection in 8- and 10-h hemofiltration treatments. Sensitivity analyses could not be performed in hemodialysis experiments because of limited published extraction coefficient data in hemodialysis at varying dialysate flow rates.
Probability of target attainment of selected ciprofloxacin and levofloxacin dosing regimens for Gram-negative infection with P. aeruginosa a in 5000 virtual patients with 8-h hemodialysis PIRRT at dialysate flow rate of 5 L/h during the initial 72 h
Day 1 PTA (%)
Day 2 PTA (%)
Day 3 PTA (%)
Mean PTA (%)
Day 1 PTA (%)
Day 2 PTA (%)
Day 3 PTA (%)
Mean PTA (%)
200 mg q12h
400 mg q12h
800 mg q12h
200 mg q8h
400 mg q8h
600 mg q8h
1200 mg LD, then 800 mg q12h
750 mg q24h
750 mg LD, then 250 mg q24h post-PIRRT
750 mg LD, then 500 mg q24h post-PIRRT
750 mg LD, then 750 mg q24h post-PIRRT
1500 mg LD, then 750 mg q24h post-PIRRT
1500 mg LD, then
1000 mg q24h post-PIRRT
2000 mg LD, then 1000 mg q24h post-PIRRT
Probability of target attainment of selective levofloxacin dosing regimens for Gram-positive infection with S. pneumoniae a in 5000 virtual patients with 8-h hemodialysis PIRRT at dialysate flow rate of 5 L/h during the initial 72 h
Day 1 PTA (%)
Day 2 PTA (%)
Day 3 PTA (%)
Mean PTA (%)
Day 1 PTA (%)
Day 2 PTA (%)
Day 3 PTA (%)
Mean PTA (%)
500 mg q48h
500 mg q24h
750 mg LD, then 250 mg q24h post-PIRRT
750 mg LD, then 500 mg q24h post-PIRRT
750 mg LD, then 750 mg q24h post-PIRRT
PTA sensitivity analyses of “successful” fluoroquinolone dosing recommendation with various effluent flow rates in PIRRT
8-h hemofiltration in early PIRRT
Ultrafiltrate flow rate (L/hr)
This is the first in silico trial using MCS to evaluate various fluoroquinolone dosing regimens to treat critically ill patients with PIRRT. This approach permits incorporation of the commonly used PIRRT settings into the models with existing demographic and pharmacokinetic parameters published from critically ill patients receiving RRT to predict fluoroquinolone serum concentrations in patients receiving PIRRT. The MCS tested the PTA of various fluoroquinolone regimens in a large virtual cohorts (n = 5000) who had the same variability in their personal pharmacokinetic profiles as has been seen in the published fluoroquinolone pharmacokinetic literature conducted in critically ill patients. These in silico trials illustrate that MCS can be highly useful and a cost-effective approach to assess expected efficacy of various antibiotic dosing regimens and to guide appropriate antibiotic dosing in this special patient population with limited pharmacokinetic data.
The present study predicts that even maximal recommended ciprofloxacin (1200 mg/day) and levofloxacin (750 mg/day) doses would not yield adequate antibiotic exposure to treat Gram-negative infections with P. aeruginosa (MIC of 1 mg/L for ciprofloxacin and 2 mg/L for levofloxacin) in most critically ill patients receiving PIRRT. The simulation results indicate that a total of 2000 mg of ciprofloxacin is required on day 1 and 1600 mg for days 2 and 3 to attain the accepted pharmacodynamic target (AUC24h:MIC ≥125) in ~90 % or greater of virtual patients. For levofloxacin, 2000 mg was required for day 1 and 1000 mg on days 2 and 3. These MCS results are not surprising, because of the growing realization that conventional fluoroquinolone doses do not reliably achieve the pharmacodynamic target of AUC24h:MIC ≥125 in infected critically ill patients with or without RRT [36, 45–49]. In a recent report, ciprofloxacin 1600 mg/day was necessary to attain AUC24h:MIC ≥125 (bacterial susceptibility of MIC ≤ 1 mg/L) at a steady state in an obese critically ill patient receiving CRRT . A previous study with 14 critically ill patients with P. aeruginosa infection receiving CRRT also reported the commonly recommended ciprofloxacin dose (400 mg q24h) for CRRT  was inadequate to attain even a less rigorous pharmacodynamic target (AUC24h:MIC ≥100) . The present study shows that even the use of conventional doses recommended for normal renal function in patients with PIRRT would yield inadequate drug exposure. However, no clinical studies have been conducted to evaluate the safety of fluoroquinolone doses that are higher than recommended in critically ill patients. Consequently, it is advised that ciprofloxacin and levofloxacin should not be used as empiric monotherapy for serious Gram-negative infections in patients receiving PIRRT due to concerns of suboptimal antibiotic exposure. In situations when fluoroquinolones are to be used in combination with another primary antibiotic, we would recommend the maximal doses, at least 400 mg q8h for ciprofloxacin and 750 mg loading dose, followed by 750 mg q24h post-PIRRT for levofloxacin.
Modeled fluoroquinolone clearances and half-lives in PIRRT and comparison to pharmacokinetic data in other types of RRT
PIRRT (present study)
55.0 ± 13.3a
108.3 ± 48.3a
t½ ON-RRT (h)
8.2 ± 5.0a
3.2 ± 0.4a
t½ OFF-RRT (h)
13.9 ± 10.5a
5.8 ± 0.9a
PIRRT (present study)
48.3 + 15.0a
24.7 + 11.7a
t½ ON-RRT (h)
16.7 + 6.0a
t½ OFF-RRT (h)
52.8 + 17.0a
Sensitivity analyses evaluated the influence of different PIRRT operation settings on PTA of fluoroquinolone dosing regimens. It has been suggested that for PIRRT, “when” to administer a drug relative to PIRRT institution may be a more important factor than “how much” drug to give . Sensitivity analyses indicate that this is the case for a drug with longer half-life that is given infrequently like levofloxacin. For example, PTA of levofloxacin q24h–q48h dosing regimens differed by up to 20 % in early vs. late PIRRT as shown in Tables 2 and 3. However, ciprofloxacin, which is given more frequently with q8h–q12h dosing regimens yielded only 1–6 % PTA difference in early vs. late PIRRT (Table 2). PIRRT operating settings vary from institution to institution, and the PIRRT variable that is most varied between institutions is effluent rate. Some centers are more aggressive and use high effluent rates, while others use rates closer to what is seen in CRRT. We assessed the influence of this commonly modified parameter in Table 4. Interestingly, the effluent rate had a surprisingly small influence on PTA rates. Varying effluent rates from 2 to 10 L/h (our models used 4 and 5 L/h) for 8–10 h only changed PTA by 2–4 %. This 2–4 % difference caused by effluent flow rates is dwarfed by the change in PTA caused by “when” the dose is given in relation to PIRRT.
This study has some limitations. Simulations were performed under the assumption that patients were adult-sized with negligible renal drug clearance and were characterized with literature-based demographic and pharmacokinetic parameters. The model also incorporated “daily” PIRRT. Thus, our recommendation should be applied to those who match these demographic and pharmacokinetic characteristics and receive daily PIRRT. Any time that MCSs are used to inform antibiotic dosing, clinical validation is warranted. However, in this case, it would appear to be unethical to conduct a fluoroquinolone PIRRT pharmacokinetic trial with the doses that achieved 90 % PTA because these doses are likely to be toxic. We have confidence that the model performed accurately based on the fact that our findings independently corroborate reports that conventionally dosed fluoroquinolones rarely achieve therapeutic targets in critically ill patients, and like those reports [36, 45–49], we also do not recommend their use as empiric monotherapy in this population receiving PIRRT due to the concern for suboptimal serum concentration attainment that contributes to increasing bacterial resistance. Although smaller levofloxacin doses can be used to treat S. pneumonia in PIRRT patients based on our data, the maximal FDA-approved fluoroquinolone dose should be used as empiric treatment for infected critically ill patients with PIRRT as combination therapy when necessary. Even as adjunctive therapy, fluoroquinolones are associated with potentially life-threatening cardiovascular and CNS toxicities [24–26]. Thus, close monitoring for cardiovascular- and neurotoxicity should be followed when this fluoroquinolone dosing is used to treat these vulnerable patients.
In silico trials using MCS are useful and may be the only alternative to guide appropriate antibiotic dosing where pharmacokinetic data are absent and clinical trials are not likely to be conducted. This simulation study indicated that none of the conventional ciprofloxacin and levofloxacin dosing regimens are likely to be efficacious as empiric treatment for Gram-negative infections caused by P. aeruginosa in critically ill patients with daily PIRRT. Pharmacodynamic target attainment during the initial 72 h required up to three to fourfold higher fluoroquinolone doses than the maximally approved doses in these patients. Use of these extreme dosing regimens cannot be recommended because of concerns of fluoroquinolone-associated toxicity in these vulnerable patients. These in silico simulations support rational dosing decision for clinicians treating infected patients receiving PIRRT and should be used until clinical pharmacokinetic trials are conducted in this population.
AUC24h, 24-h area under the curve; CLHD, transmembrane clearance in hemodialysis; CLHF, transmembrane clearance in hemofiltration; CLNR, non-renal clearance; CNS, central nervous system; CRRT, continuous renal replacement therapy; IHD, intermittent hemodialysis; MCS, monte carlo simulations; MIC, minimum inhibitory concentration; PIRRT, prolonged intermittent renal replacement therapy; PTA, probability of target attainment; Q d, dialysate flow rate; Q plasma, plasma flow rate; Q replacement, replacement fluid flow rate; Q uf, ultrafiltrate flow rate; RRT, renal replacement therapy; SA, saturation coefficient; SC, sieving coefficient; V d, volume of distribution
This study was funded by NxStage Medical, Inc.
SJL and BAM contributed to the conception and design, data collection, and analysis and interpretation of the data. WC and AS contributed to data acquisition, analysis, and interpretation. SJL and BAM drafted the manuscript. All authors were involved in revising it critically for important intellectual content. All authors read and approved the final approval of the present version of the manuscript to be published.
SJL is an assistant professor at the Department of Pharmacy Practice, University of Findlay College of Pharmacy, 1000 N., Main Street, Findlay, Ohio, 45840, USA. WC works at the Pharmacy Faculty at Siam University, Bangkok, Thailand. AS is a Critical Care Nephrology Research Fellow at the Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, Michigan, 48109, USA. BAM is a professor and an associate dean of Academic Affairs at the Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church Street, Ann Arbor, Michigan, 48109, USA
Drs. Mueller and Lewis have received grant funding from NxStage Medical, Inc., to support this work.
Dr. Mueller has served on NxStage Medical, Inc.’s speaker’s bureau.
Portions of this paper were accepted as abstracts and were presented as a poster presentation at Acute Kidney Injury Continuous Renal Replacement Therapy 2016 International Conference, San Diego, CA, on February 16–19, 2016.
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