Rifampin has been noted to exhibit exceptional antimicrobial activity against Staphylococcus epidermidis biofilms as compared to commonly used antibiotics. To further explore this unique effect of rifampin, we evaluated the antimicrobial activity of three commercially available preparations of rifampin, two rifampin analogs (CGP29861 and rifapentine) and the parent compound rifamycin SV. These were tested against standardized S. epidermidis biofilms in various milieus. All six members of the rifamycin group tested demonstrated marked antimicrobial activity but with minor foci of resisters when tested in a peptone water environment. The microscopy of the exposed biofilms showed profound lysis and morphological distortion of the remaining cells. The synergistic elimination of the foci of resistance was achieved in an environment of fresh peritoneal dialysis (PD) solution or by the addition of vancomycin. Neither vancomycin nor fresh PD solution demonstrated significant antimicrobial activity when tested alone with biofilm preparations. Spent PD fluid markedly antagonized the activity of the rifamycins with the exception of the rifampin analogs, an effect primarily of pH. The synergistic effect of vancomycin with the rifamycins was not affected either by protein content or pH, leaving the antagonistic properties of spent PD fluid unexplained. The variable activity of the different members of the rifamycin group underlines the importance of structural differences in determining their interaction with bacterial biofilms. Further precision of the nature of these structural interactions is seen to have considerable potential for therapeutic advancement of catheter-associated sepsis.

Peritoneal dialysis (PD) solutions and therapeutic drugs frequently added to PD solutions in clinical practice have been shown to reduce the viability and to impair the function of mouse peritoneal cells. The cytotoxicity of PD solutions, directly related to the dextrose concentration, was more marked towards resident than elicited peritoneal cells. None of the drug additives, heparin and insulin amongst them, were cytotoxic when tested alone or combined with 4.25% PD solution, with the exception of phosphatidylcholine which markedly enhanced the cytotoxicity of the PD solution. While the function of mouse peritoneal macrophages as measured by their hydrogen peroxide production was largely unaffected by PD solutions and drug additives when tested separately, the combination of 4.25% PD solution with any of the drug additives resulted in complete abolition of macrophage respiratory burst. The results should caution against the indiscriminate addition of drugs to PD solutions in dialysis patients.

Continuous ambulatory peritoneal dialysis (CAPD) catheter-assoclated infections can be resistant to conservative therapeutic measures despite the apparent susceptibility of the infecting bacterial strains to antibiotics. This chronicity of Infection has been ascribed to the development of bacteria on the surfaces of catheter material within a protective polysaccharide shield or matrix. CAPD catheters are unique In being exposed to nonphysiological environments of dialysis fluids of varying physical properties and constitution. We determined that the rate of growth of s. epidermldis In the fluid phase In laboratory media or fresh dialysis solution was significantly Influenced by pH. An acid milieu (pH 5) Impaired growth compared to a neutral milieu (pH 7). Spent dialysis fluid, however, which had an approximately neutral pH, also Impaired bacterial growth, the assumption being that this results from properties of spent fluid unrelated to pH. Using rifampin as the test antibiotic, we noted that Its action on S. epidermldis was unaffected by pH or by the differing milieu of fresh and spent fluid. Bacterial growth was arrested regardless of the milieu. We further examined the potential of dialysis fluids to modify the Interaction between rifampin and the matrix-enclosed bacteria of standardized S. epidermidis blofilms. We determined that the pH of the dialysis solution was a critical factor Influencing the outcome of exposure of the biofilm to rifampin. An acid pH enhanced antibiotic activity, whereas a neutral pH was associated with antibiotic antagonism. These findings have Implications in the management of S. epidermldis catheter-associated infections using rifampin. Administration of the antibiotic In fresh peritoneal dialysis solution (pH 5.6) Is Judged more likely to be associated with a successful outcome.

Many drugs are added to peritoneal dialysis solutions In continuous ambulatory peritoneal dialysis (CAPD) patients, principally during episodes of peritonitis when antibiotics and nonantiblotic agents are often administered together. To evaluate the Influence of nonantiblotic drug additives on antibiotic action, we determined the effect of ten drug additives on the antimicrobial activity of rifampin against S. epidermiddis biofilms. None of the additives had any direct effect on biofilm bacteria. While five additives did not affect rifampin action, the other five strongly antagonized rifampin. Insulin and heparin were among these five antagonists. This antagonism suggests that a significant degree of Inhibition of antibiotic action may occur by the coadministration of agents In the treatment of peritonitis, particularty in diabetic patients.