Abstract
Editor:
Surprisingly few data on pharmacodynamics specific to continuous ambulatory peritoneal dialysis (CAPD) peritonitis are available. Especially in cases with no or moderate response to treatment, pharmacokinetics and pharmacodynamics of the antibiotic as well as checking for alternative methods of identification and susceptibility testing of the cultured organism might prevent treatment failure. For example, a discrepancy may exist between the results of the disk diffusion determination and that of the minimal inhibiting concentration (MIC).
Pharmacodynamic concepts can be used to optimize dosing, to prevent the emergence of resistance, to rationalize the determination of antimicrobial susceptibility (1), and to prevent collateral damage (toxicity to the peritoneum, patient, and surroundings).
For drugs that exhibit time-dependent bactericidal action like beta-lactams and vancomycin, without a substantial post-antibiotic effect, the once daily dosing method—as mentioned in the International Society for Peritoneal Dialysis (ISPD) guidelines—may not be optimal in the treatment of infections caused by bacteria with a high MIC. In such cases, it can be argued that a frequent or continuous dosing strategy is preferred since efficacy is determined by the amount of time drug levels are above the MIC (1). Such a scheme is less convenient and requires more bag interventions, but it prevents prolonged exposure to high levels that are not necessary to cure the infection but may harm patients. Using a longer dosing interval requires a larger dose, running the risk for incurring periods with sub-therapeutic drug levels, since absorption of intraperitoneal antibiotics into the systemic circulation is highly variable during peritonitis. Indeed, substantial periods of sub-therapeutic levels in dialysis fluid during intermittent treatment for peritonitis have been found for both vancomycin and ceftazidime (2,3). Despite this, a good clinical outcome can be present (3), but it is unknown—probably due to publication bias—how often the advised treatment schedule would lead to treatment failure or resistance.
Antibiotics at sub-inhibitory concentrations have the potential to induce different biological responses, leading to a general modification in the antibiotic resistance profiles of bacteria (4). However, serum and dialysate drug levels are surrogate markers for those at the biophase. There is deficient rather than negative evidence on whether continuous infusion regimens for vancomycin (as advocated in children with PD-peritonitis) are likely to substantially improve patient outcomes when compared with intermittent infusions, though a small study has suggested that the percentage of time that the vancomycin concentration at the biophase is above the MIC can be optimized using continuous infusion (5).
More research is necessary to explore the risk:benefit ratio and cure rates of the different dosing regimens. A reporting database and/or a quick response from an online expert team might help to gather data on treatment failures and the emergence of resistance.
In the meantime, the ISPD guidelines could emphasize the differences in dosing strategies, taking into account the characteristics of the antimicrobial agent and of the microbe in order to ensure a safe, sustainable, and effective use of antibiotics.
More judicious use of antibiotics may slow down the spread of drug-resistant bacteria and the emergence of new antibiotic-resistant pathogens (4).