Can the ALT Eradicate Biofilms

In reviewing the results of case studies, when high concentrations of the antimicrobial agent (usually in the milligram per milliliter range) were used for dwell times of 12 h or more, most studies showed that within 14 days of treatment bloodstream infections associated with catheter biofilms of different bacteria were treated successfully. However, for most of the studies shown in Tables 2-6 (Krzywda et al. 1995; Messing et al. 1988; Bailey et al. 2002; Johnson et al. 1994; Benoit et al. 1995), treatment efficacy was based upon negative blood cultures (collected through the CVC) following treatment and/or absence of clinical symptoms in the patient. None of these studies provided definitive evidence for the presence or absence of biofilms on the catheter surface. However, Capdevila et al. (1993) and Rao et al. (1992) did examine catheter tips for biofilms using the roll tip method (with its questionable accuracy [Donlan 2001]) and found that negative blood cultures and absence of clinical symptoms predicted biofilm eradication, though the number of samples in each of these studies was relatively small. Therefore, the evidence from case studies (and studies using animal models) supporting the ability of the antimicrobial lock treatment to eradicate biofilms is weak. On the other hand, studies using in vitro models suggest that antimicrobial agents can eradicate bacterial biofilms, when used in sufficiently high concentrations for extended periods of time. The agents that were most effective against bacterial biofilms of Gram-positive organisms were vancomy-cin, teicoplanin, linezolid, rifampin, and ciprofloxacin. Gentamicin was effective against biofilms of Gram-negative organisms. ALTs that contain combinations of antimicrobial agents with differing modes of action may also be effective. For example, the macrolides can degrade the biofilm EPS and enhance diffusion of other supplemental bactericidal agents through this matrix. Fungal biofilms appear to be much more difficult to eradicate, though the use of liposomal amphotericin B or the echinocandins appear promising.

One concern with the use of antimicrobial agents at such high concentrations is the possibility of toxicity to the patient resulting from the diffusion of the lock solution into systemic circulation or if the lock is inadvertently flushed into circulation. Berrington and Gould (2001) suggested highest practical concentrations for antimicrobial agents in the ALT, including vancomycin (50 mg ml-1), gentamicin (40 mg ml-1), and teicoplanin (133 mg ml-1). These levels are generally well above effective concentrations used in most of the in vitro model system studies discussed, so this would suggest that drug concentrations used in these studies would be relevant in patient treatment. Conditions impacting biofilm growth and susceptibility of biofilm organisms to the antimicrobial agent would be substantially different in an animal or human than in an in vitro model, supporting the case for more rigorous testing conditions in order to provide more clinically relevant data. For example, inclusion of serum proteins, use of mixed species biofilms, and growth of the biofilms for extended time periods would provide a more clinically relevant biofilm model system. This in turn could provide stronger evidence for the efficacy of the ALT against biofilms of different microorganisms.

Another concern with the use of antimicrobial agents in antimicrobial locks is the potential for the development of resistance. The increased use of antimicrobial agents in the healthcare setting, especially in intensive care units, has selected for resistant organisms. For example, the increase in vancomycin-resistant enterococci (VRE) in healthcare institutions has been linked in part to the increase in vancomycin use, which in turn provided selective pressure leading to the spread of VRE (Tenover 2001; Schwalbe et al. 1987; Kaplan et al. 1988; Sieradzki et al. 2003). Proportions of resistant staphylococci, enterococci, and pseudomonads are highest in organisms isolated from patients in intensive care units where use of antimicrobial agents is greatest (Archibald et al. 1997). In light of the concern for the development and spread of organisms resistant to vancomycin, the CDC has recommended that the use of ALTs containing vancomycin should be discouraged (Centers for Disease Control and Prevention 1995) or used only in special circumstances, such as the treatment of patients with long-term cuffed or tunneled catheters or ports who have had a history of multiple CRBSI (Centers for Disease Control and Prevention 2002).

As noted by Berrington and Gould (2001), until a systematic study comparing the use of the ALT alone, ALT plus systemic antimicrobial agents, and systemic antimicrobial agents alone for the treatment of catheter-related infections is conducted, the results of such studies evaluating the ALT should be viewed cautiously.

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