Peritoneal Dialysis International, Vol. 37, pp. 584–586 Printed in Canada. All rights reserved.
0896-8608/17 $3.00 + .00 Copyright © 2017 International Society for Peritoneal Dialysis
CORRESPONDENCE Response Letter to the “ISPD Peritonitis Recommendations: 2016 Update on Prevention and Treatment”
584
DISCLOSURES The authors have no financial conflicts of interest to declare.
M.K. van Gelder1,* A. van Eck van der Sluijs1 E.M. van Maarseveen2 P.M.C. Klein Klouwenberg3 A.C. Abrahams1 Department of Nephrology and Hypertension1 Department of Clinical Pharmacology2 Department of Clinical Microbiology3 University Medical Center Utrecht, Utrecht, The Netherlands *email: [email protected] REFERENCES 1. Li PK, Szeto CC, Piraino B, De Arteaga J, Fan S, Figueiredo AE, et al. ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int 2016; 36(5):481–508. 2. Li PK, Szeto CC, Piraino B, Bernardini J, Figueiredo AE, Gupta A, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 2010; 30(4):393–423. 3. Anwar N, Merchant M, Were T, Tooth A, Uttley L, Gokal R. A prospective, randomized study of the comparative safety and efficacy of intraperitoneal imipenem versus vancomycin and netilmicin in the treatment of peritonitis on CAPD. Perit Dial Int 1995; 15(2):167–71. 4. Leung CB, Szeto CC, Chow KM, Kwan BC, Wang AY, Lui SF, et al. Cefazolin plus ceftazidime versus imipenem/cilastatin monotherapy for treatment of CAPD peritonitis—a randomized controlled trial. Perit Dial Int 2004; 24(5):440–6. 5. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26(1):1–10. 6. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with
This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]
Downloaded from http://www.pdiconnect.com/ at Goteborgs universitet on October 2, 2017
Editor: We are writing to discuss the imipenem/cilastatin dosing guideline according to the recently published update of the International Society for Peritoneal Dialysis (ISPD) Peritonitis Recommendations (1). Last year, 1 of our peritoneal dialysis (PD) patients, a 69-year-old male, was diagnosed with a Mycobacterium chelonae peritonitis, for which a combination of intraperitoneal (IP) imipenem with oral clarithromycin was started. According to the then valid 2010 ISPD Peritonitis Recommendations (2), IP imipenem could be dosed both continuously (400 mg/day) and intermittently (1,000 mg twice daily). However, in the new 2016 ISPD Peritonitis Recommendations, the proposed intermittent IP dose of imipenem has been lowered to 500 mg twice daily, based on an older study by Anwar et al. (3). In this study, 2 of the 7 patients who were treated with a 2,000-mg per day regimen developed seizures within 24 hours after treatment, whereas no adverse events were recorded in patients treated with a 1,000-mg per day regimen (n = 23). However, the efficacy of 1,000 mg imipenem per day was significantly lower compared with 2,000 mg per day (complete cure rate 42% vs 85%, respectively). Nonetheless, there is still a marked difference in cumulative daily dose between the current recommended intermittent dose and the continuous dosing advice (1,000 vs 400 mg per day). The latter recommendation is based on the study by Leung et al., who administrated 100 mg imipenem in every 2-L dwell (50 mg/L) in patients with PD peritonitis (4). Although the efficacy was comparable with IP cefazolin/ceftazidime, the primary response rate and complete cure rate were low (49.0% and 43.1%, respectively). The effectiveness of beta-lactam antibiotics like imipenem depends on the duration of the drug concentration above the minimum inhibitory concentration (MIC) (target > 50 – 70% of time) (5). Indeed, continuous intravenous administered beta-lactam antibiotics were more effective than intermittent dosed betalactam antibiotics (6). Therefore, intermittent twice daily IP dosing may be suboptimal from a pharmacological point of view, especially for highly resistant microorganisms such as the M. chelonae in our case (MIC 16 mg/L). Increasing drug concentrations above 4 times the MIC does not enhance bactericidal activity but may enhance toxicity. This provides a
rationale for continuous IP dosing aimed at achieving maximum efficacy with a lower daily drug dosage than is required for intermittent dosing. When determining the dose, one should take into account that due to chemical instability of imipenem in PD solutions at physiological temperatures (7), IP concentrations rapidly fall below the target of around 4 times the MIC (8), especially in the case of resistant microorganisms. Although there are no studies to support our hypothesis, we wonder, given the above considerations, whether continuous IP imipenem dosing in a concentration higher than currently stated in the ISPD guidelines (e.g., 100 mg/L, giving a cumulative amount of 800 mg/day) should be preferred in case of peritonitis with a resistant microorganism to improve efficacy and at the same time prevent toxicity.
CORRESPONDENCE
SEPTEMBER 2017 – VOL. 37, NO. 5 PDI
extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis 2013; 56(2):272–82. 7. Deslandes G, Gregoire M, Bouquie R, Le MA, Allard S, Dailly E, et al. Stability and compatibility of antibiotics in peritoneal dialysis solutions applied to automated peritoneal dialysis in the pediatric population. Perit Dial Int 2016; 36(6):676–9. 8. Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998; 27(1):10–22. https://doi.org/10.3747/pdi.2017.00055
Concerns Regarding ISPD Recommendations for Peritonitis in Relation to Imipenem/Cilastatin—In Reply
DISCLOSURES The authors have no financial conflicts of interest to declare.
C.-C. Szeto* P.K.-T. Li 585
*email: [email protected] REFERENCES 1. van Gelder MK, van Eck van der Sluijs A, van Maarseveen EM, Klein Klouwenberg PMC, Abrahams AC. Response letter to the “ISPD peritonitis recommendations: 2016 update on prevention and treatment”. Perit Dial Int 2017; 37(5):584. 2. Li PK, Szeto CC, Piraino B, de Arteaga J, Fan S, Figueiredo AE, et al. ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int 2016; 36:481–508. 3. Brown EA, Bargman JM, Li PK. Managing older patients on peritoneal dialysis. Perit Dial Int 2015; 35:609–11. 4. Szeto CC. Peritoneal dialysis-related infection in the older population. Perit Dial Int 2015; 35:659–62. 5. Deslandes G, Grégoire M, Bouquié R, Le Marec A, Allard S, Dailly E, et al. Stability and compatibility of antibiotics in peritoneal dialysis solutions applied to automated peritoneal dialysis in the pediatric population. Perit Dial Int 2016; 36:676–9. 6. Anwar N, Merchant M, Were T, Tooth A, Uttley L, Gokal R. A prospective, randomized study of the comparative safety and efficacy of intraperitoneal imipenem versus vancomycin and netilmicin in the treatment of peritonitis on CAPD. Perit Dial Int 1995; 15:167–71. https://doi.org/10.3747/pdi.2017.00071
Post-Transplant Lymphoproliferative Disorder Presenting as Cloudy Peritoneal Dialysate Editor: A recent encounter with post-transplant lymphoproliferative disorder (PTLD) manifesting as cloudy peritoneal dialysate prompted a review of the literature which we feel may be of interest to clinicians finding themselves in similar circumstances. A 63-year-old female patient presented acutely with culturenegative peritonitis, having recently commenced peritoneal dialysis (PD). Pertinently, she had developed skin-limited PTLD 2 years previously, which had been treated successfully with rituximab. Peritoneal dialysate fluid microscopy showed a white cell count of 5,680 × 109/L, with 20% polymorphs, 80% lymphocytes, and no organisms on gram staining. Microscopic analysis described “atypical, unidentified white cells.” We found advanced imaging of limited utility as both computed tomography and positron emission tomography of the abdomen demonstrated non-specific panniculitis and peritoneal and omental thickening and stranding. The diagnosis was made via cytological analysis of the PD fluid showing numerous markedly pleomorphic cells with large vesicular nuclei, multiple prominent nucleoli and abundant cytoplasm. The overall appearances were consistent with a PTLD, monomorphic type, with features similar to those seen in the previous skin biopsy. Epstein Barr Virus (EBV) was noted in the PD fluid, and quantitative polymerase chain reaction of serum demonstrated raised EBV levels of 47,456 IU/mL.
This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]
Downloaded from http://www.pdiconnect.com/ at Goteborgs universitet on October 2, 2017
Editor: We appreciate the comments from van Gelder et al. (1) on the use of intraperitoneal (IP) imipenem/cilastatin described in the recent recommendations by the International Society for Peritoneal Dialysis (ISPD) (2). We fully agree with their comment that continuous IP dosing of the beta-lactam group of antibiotics offers a theoretical advantage and should be the preferred regimen. As van Gelder clearly points out, continuous IP dosing ensures an adequate IP drug level throughout the day, facilitates bacterial killing by agents whose activity is time-dependent (i.e., the reduction in bacterial density being proportional to the time above minimal inhibitory concentration [MIC]), takes away the concern regarding drug stability in the peritoneal dialysis (PD) solution, and requires a lower daily dose, which is less expensive and has a lower risk of neurotoxicity. Nonetheless, we believe it is valuable to describe intermittent dosing regimens that have been found to be reasonably effective. With the rising prevalence of elderly PD patients (3), many would require helpers or healthcare visitors for the administration of IP antibiotics (4), and intermittent dosage may be the only practical solution, especially when the injection could only be performed once or twice daily and drug stability in the PD solution is a concern (5). Intermittent dosage is also the only possible means of administering antibiotics for patients treated with automated PD (APD) when temporary conversion to continuous ambulatory peritoneal dialysis (CAPD) is not feasible (2). Since extrapolation of pharmacokinetic data from CAPD to APD may result in significant underdosing in APD patients when antibiotics are given IP intermittently (2), a higher daily dose is generally required. As illustrated by Anwar et al. (6) and rightly pointed out by van Gelder et al. (1), the dosage to be administered depends on the intricate balance between adequate therapeutic response and the risk of toxicity.
Department of Medicine & Therapeutics Prince of Wales Hospital The Chinese University of Hong Kong Shatin, Hong Kong, China
0896-8608/17 $3.00 + .00 Copyright © 2017 International Society for Peritoneal Dialysis
CORRESPONDENCE Response Letter to the “ISPD Peritonitis Recommendations: 2016 Update on Prevention and Treatment”
584
DISCLOSURES The authors have no financial conflicts of interest to declare.
M.K. van Gelder1,* A. van Eck van der Sluijs1 E.M. van Maarseveen2 P.M.C. Klein Klouwenberg3 A.C. Abrahams1 Department of Nephrology and Hypertension1 Department of Clinical Pharmacology2 Department of Clinical Microbiology3 University Medical Center Utrecht, Utrecht, The Netherlands *email: [email protected] REFERENCES 1. Li PK, Szeto CC, Piraino B, De Arteaga J, Fan S, Figueiredo AE, et al. ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int 2016; 36(5):481–508. 2. Li PK, Szeto CC, Piraino B, Bernardini J, Figueiredo AE, Gupta A, et al. Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 2010; 30(4):393–423. 3. Anwar N, Merchant M, Were T, Tooth A, Uttley L, Gokal R. A prospective, randomized study of the comparative safety and efficacy of intraperitoneal imipenem versus vancomycin and netilmicin in the treatment of peritonitis on CAPD. Perit Dial Int 1995; 15(2):167–71. 4. Leung CB, Szeto CC, Chow KM, Kwan BC, Wang AY, Lui SF, et al. Cefazolin plus ceftazidime versus imipenem/cilastatin monotherapy for treatment of CAPD peritonitis—a randomized controlled trial. Perit Dial Int 2004; 24(5):440–6. 5. Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26(1):1–10. 6. Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with
This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]
Downloaded from http://www.pdiconnect.com/ at Goteborgs universitet on October 2, 2017
Editor: We are writing to discuss the imipenem/cilastatin dosing guideline according to the recently published update of the International Society for Peritoneal Dialysis (ISPD) Peritonitis Recommendations (1). Last year, 1 of our peritoneal dialysis (PD) patients, a 69-year-old male, was diagnosed with a Mycobacterium chelonae peritonitis, for which a combination of intraperitoneal (IP) imipenem with oral clarithromycin was started. According to the then valid 2010 ISPD Peritonitis Recommendations (2), IP imipenem could be dosed both continuously (400 mg/day) and intermittently (1,000 mg twice daily). However, in the new 2016 ISPD Peritonitis Recommendations, the proposed intermittent IP dose of imipenem has been lowered to 500 mg twice daily, based on an older study by Anwar et al. (3). In this study, 2 of the 7 patients who were treated with a 2,000-mg per day regimen developed seizures within 24 hours after treatment, whereas no adverse events were recorded in patients treated with a 1,000-mg per day regimen (n = 23). However, the efficacy of 1,000 mg imipenem per day was significantly lower compared with 2,000 mg per day (complete cure rate 42% vs 85%, respectively). Nonetheless, there is still a marked difference in cumulative daily dose between the current recommended intermittent dose and the continuous dosing advice (1,000 vs 400 mg per day). The latter recommendation is based on the study by Leung et al., who administrated 100 mg imipenem in every 2-L dwell (50 mg/L) in patients with PD peritonitis (4). Although the efficacy was comparable with IP cefazolin/ceftazidime, the primary response rate and complete cure rate were low (49.0% and 43.1%, respectively). The effectiveness of beta-lactam antibiotics like imipenem depends on the duration of the drug concentration above the minimum inhibitory concentration (MIC) (target > 50 – 70% of time) (5). Indeed, continuous intravenous administered beta-lactam antibiotics were more effective than intermittent dosed betalactam antibiotics (6). Therefore, intermittent twice daily IP dosing may be suboptimal from a pharmacological point of view, especially for highly resistant microorganisms such as the M. chelonae in our case (MIC 16 mg/L). Increasing drug concentrations above 4 times the MIC does not enhance bactericidal activity but may enhance toxicity. This provides a
rationale for continuous IP dosing aimed at achieving maximum efficacy with a lower daily drug dosage than is required for intermittent dosing. When determining the dose, one should take into account that due to chemical instability of imipenem in PD solutions at physiological temperatures (7), IP concentrations rapidly fall below the target of around 4 times the MIC (8), especially in the case of resistant microorganisms. Although there are no studies to support our hypothesis, we wonder, given the above considerations, whether continuous IP imipenem dosing in a concentration higher than currently stated in the ISPD guidelines (e.g., 100 mg/L, giving a cumulative amount of 800 mg/day) should be preferred in case of peritonitis with a resistant microorganism to improve efficacy and at the same time prevent toxicity.
CORRESPONDENCE
SEPTEMBER 2017 – VOL. 37, NO. 5 PDI
extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis. Clin Infect Dis 2013; 56(2):272–82. 7. Deslandes G, Gregoire M, Bouquie R, Le MA, Allard S, Dailly E, et al. Stability and compatibility of antibiotics in peritoneal dialysis solutions applied to automated peritoneal dialysis in the pediatric population. Perit Dial Int 2016; 36(6):676–9. 8. Turnidge JD. The pharmacodynamics of beta-lactams. Clin Infect Dis 1998; 27(1):10–22. https://doi.org/10.3747/pdi.2017.00055
Concerns Regarding ISPD Recommendations for Peritonitis in Relation to Imipenem/Cilastatin—In Reply
DISCLOSURES The authors have no financial conflicts of interest to declare.
C.-C. Szeto* P.K.-T. Li 585
*email: [email protected] REFERENCES 1. van Gelder MK, van Eck van der Sluijs A, van Maarseveen EM, Klein Klouwenberg PMC, Abrahams AC. Response letter to the “ISPD peritonitis recommendations: 2016 update on prevention and treatment”. Perit Dial Int 2017; 37(5):584. 2. Li PK, Szeto CC, Piraino B, de Arteaga J, Fan S, Figueiredo AE, et al. ISPD peritonitis recommendations: 2016 update on prevention and treatment. Perit Dial Int 2016; 36:481–508. 3. Brown EA, Bargman JM, Li PK. Managing older patients on peritoneal dialysis. Perit Dial Int 2015; 35:609–11. 4. Szeto CC. Peritoneal dialysis-related infection in the older population. Perit Dial Int 2015; 35:659–62. 5. Deslandes G, Grégoire M, Bouquié R, Le Marec A, Allard S, Dailly E, et al. Stability and compatibility of antibiotics in peritoneal dialysis solutions applied to automated peritoneal dialysis in the pediatric population. Perit Dial Int 2016; 36:676–9. 6. Anwar N, Merchant M, Were T, Tooth A, Uttley L, Gokal R. A prospective, randomized study of the comparative safety and efficacy of intraperitoneal imipenem versus vancomycin and netilmicin in the treatment of peritonitis on CAPD. Perit Dial Int 1995; 15:167–71. https://doi.org/10.3747/pdi.2017.00071
Post-Transplant Lymphoproliferative Disorder Presenting as Cloudy Peritoneal Dialysate Editor: A recent encounter with post-transplant lymphoproliferative disorder (PTLD) manifesting as cloudy peritoneal dialysate prompted a review of the literature which we feel may be of interest to clinicians finding themselves in similar circumstances. A 63-year-old female patient presented acutely with culturenegative peritonitis, having recently commenced peritoneal dialysis (PD). Pertinently, she had developed skin-limited PTLD 2 years previously, which had been treated successfully with rituximab. Peritoneal dialysate fluid microscopy showed a white cell count of 5,680 × 109/L, with 20% polymorphs, 80% lymphocytes, and no organisms on gram staining. Microscopic analysis described “atypical, unidentified white cells.” We found advanced imaging of limited utility as both computed tomography and positron emission tomography of the abdomen demonstrated non-specific panniculitis and peritoneal and omental thickening and stranding. The diagnosis was made via cytological analysis of the PD fluid showing numerous markedly pleomorphic cells with large vesicular nuclei, multiple prominent nucleoli and abundant cytoplasm. The overall appearances were consistent with a PTLD, monomorphic type, with features similar to those seen in the previous skin biopsy. Epstein Barr Virus (EBV) was noted in the PD fluid, and quantitative polymerase chain reaction of serum demonstrated raised EBV levels of 47,456 IU/mL.
This single copy is for your personal, non-commercial use only. For permission to reprint multiple copies or to order presentation-ready copies for distribution, contact Multimed Inc. at [email protected]
Downloaded from http://www.pdiconnect.com/ at Goteborgs universitet on October 2, 2017
Editor: We appreciate the comments from van Gelder et al. (1) on the use of intraperitoneal (IP) imipenem/cilastatin described in the recent recommendations by the International Society for Peritoneal Dialysis (ISPD) (2). We fully agree with their comment that continuous IP dosing of the beta-lactam group of antibiotics offers a theoretical advantage and should be the preferred regimen. As van Gelder clearly points out, continuous IP dosing ensures an adequate IP drug level throughout the day, facilitates bacterial killing by agents whose activity is time-dependent (i.e., the reduction in bacterial density being proportional to the time above minimal inhibitory concentration [MIC]), takes away the concern regarding drug stability in the peritoneal dialysis (PD) solution, and requires a lower daily dose, which is less expensive and has a lower risk of neurotoxicity. Nonetheless, we believe it is valuable to describe intermittent dosing regimens that have been found to be reasonably effective. With the rising prevalence of elderly PD patients (3), many would require helpers or healthcare visitors for the administration of IP antibiotics (4), and intermittent dosage may be the only practical solution, especially when the injection could only be performed once or twice daily and drug stability in the PD solution is a concern (5). Intermittent dosage is also the only possible means of administering antibiotics for patients treated with automated PD (APD) when temporary conversion to continuous ambulatory peritoneal dialysis (CAPD) is not feasible (2). Since extrapolation of pharmacokinetic data from CAPD to APD may result in significant underdosing in APD patients when antibiotics are given IP intermittently (2), a higher daily dose is generally required. As illustrated by Anwar et al. (6) and rightly pointed out by van Gelder et al. (1), the dosage to be administered depends on the intricate balance between adequate therapeutic response and the risk of toxicity.
Department of Medicine & Therapeutics Prince of Wales Hospital The Chinese University of Hong Kong Shatin, Hong Kong, China
