Incomplete Activation of Intraperitoneal Clindamycin Phosphate during Peritoneal Dialysis

Abstract

Clindamycin phosphate (C-PO₄) must be hydrolyzed to the active antibiotic, but whether this occurs within the peritoneal cavity during peritoneal dialysis is unknown. Therapeutic peritoneal levels are difficult to achieve after intravenous administration, so direct intraperitoneal instillation is preferred in treating dialysis-associated peritonitis. Therefore, the activation of C-PO₄ in peritoneal dialysate was investigated. Fresh and ‘uremic’ peritoneal dialysates of 1.5 and 4.25% dextrose concentrations at pHs of 5.1 and 7.4 did not activate C-PO₄. Clindamycin hydrochloride in this same fluid was active, ruling out uremic deactivators. A patient with peritonitis was treated with intraperitoneal C-PO₄, and therapeutic ( > 5 μg/ml) serum and peritoneal levels were achieved. Infected (exudative) peritoneal dialysate drained from another patient with peritonitis activated C-PO₄ in vitro. Commercial alkaline phosphatase added to uremic dialysate also activated C-PO₄in vitro. C-PO₄ was instilled into the peritoneal cavities of 10 noninfected patients. Exposure to the peritoneal membrane at two concentrations resulted in a 3% activation of C-PO₄. From these observations it is clear that C-PO₄ is only partially activated intraperitoneally. Uremia or uremic products in the dialysate do not deactivate the antibiotic. Exudative material (bacteria, white blood cells and proteins) in infected dialysate contribute to activation of C-PO₄. The peritoneal membrane further assists in activation. We recommend that C-P0₄ be administered at a concentration of 167 mg/l of dialysate to ensure therapeutic peritoneal levels of the active antibiotic, especially after the exudative phase clears.

Pharmacokinetics of Clindamycin in the Plasma and Dialysate after Intraperitoneal Administration of Clindamycin Phosphoester to Patients on Continuous Ambulatory Peritoneal Dialysis: An Open‐Label, Prospective, Single‐Dose, Two‐Institution Study

“…Unexpectedly, the clindamycin concentration in the peritoneal cavity at time 0 was only 4.43 ± 2.74 μg/mL, and the T dial,max occurred at 2 hr. Similar results were also obtained from another study [11]. This result may be due to the poor rate of activation from clindamycin phosphate to free active clindamycin, as reported by Golper et al.…”

“…Clindamycin is a semi‐synthetic derivative of lincosamycin and is used in its phosphate ester form [9]. Clindamycin phosphate ester is biologically inactive but is rapidly hydrolyzed by alkaline phosphatase in plasma to active clindamycin [10,11]. The hydrolysis (activation) process of clindamycin phosphate is similar to that of chloramphenicol succinate ester to active chloramphenicol by esterases [12].…”

“…Golper et al. [11] reported incomplete (3%) activation of clindamycin phosphate ester to clindamycin during peritoneal dialysis. The International Society for Peritoneal Dialysis in 2010 suggested the use of clindamycin in cases of MRSA infection [6], but no dose recommendation was provided.…”

Bioavailability of Clindamycin during Peritoneal Dialysis

“…Such antibiotics present a major problem to patients on peritoneal dialysis. Several studies have addressed this prob lem and the recommended approach is to add to the dialysis fluid a large excess of the ester form of the antibiotic so that a small amount of the active form can be found in the dialysis return fluid [6], This approach would seem practical except for two problems. First, there is the problem of high cost of the antibiotic when such ex cesses are needed in the dialysis fluid.…”

“…This compound becomes biologically active only if the phosphoester bond is cleaved by phospha tases from the host after administration. As a result, instillation of this antibiotic directly into the site of infection in the peri toneal cavity may not achieve a therapeu tic effect [6]. Despite this, a limited number of recent reports of clindamycin phos phate administration by the way of dialy sis fluid showed favorable clinical results [7].…”