Role of ethylene diamine tetra-acetic acid (EDTA) in catheter lock solutions: EDTA enhances the antifungal activity of amphotericin B lipid complex against Candida embedded in biofilm.

Ethylene diamine tetra-acetic acid (EDTA) is an anticoagulant with antibiofilm-enhancing activity. We therefore used an in vitro biofilm model to determine the activity of amphotericin B lipid complex (ABLC) with or without EDTA against Candida embedded in biofilm on silicone disk surfaces. Clinical blood isolates from cancer patients infected with Candida albicans or Candida parapsilosis were used. Silicone disks were colonised with C. albicans or C. parapsilosis and were sequentially incubated in plasma and then in Mueller-Hinton broth containing 10(5) colony-forming units of each organism. All tests were performed in triplicate. The disks were subsequently placed and incubated for 6h and 8h in solutions containing ABLC alone, EDTA alone, ABLC+EDTA or broth (control). Disks were then removed, sonicated and colony counts were determined. ABLC+EDTA (30 mg/mL) was significantly more effective than ABLC, EDTA and control against C. parapsilosis at 6h (P < or = 0.01) and against C. albicans at 8h (P < or = 0.04). In patients with catheter-related candidaemia when catheter removal is not feasible, the combination of ABLC+EDTA may be considered for antifungal catheter lock solution as part of a catheter salvage therapy.

The changing epidemiology of invasive candidiasis: Candida glabrata and Candida krusei as the leading causes of candidemia in hematologic malignancy.

BACKGROUND: The objective of the current retrospective study was to compare the epidemiology of candidemia and its risk factors in patients who had hematologic malignancies(HM) with those in patients who had solid tumors (ST). METHODS: The medical and electronic records of all patients with cancer who had candidemia at the authors' institution from 1993 to 2003 were reviewed for demographic data and clinical information, including the use of prophylactic fluconazole, the infecting Candida species, and the source of candidemia (catheter-related vs other apparent sources). RESULTS: Six hundred thirty-five patients with candidemia were analyzed. C. glabrata and C. krusei were the leading causes of candidemia in 31% and 24% of patients with HM, respectively, and in 18% and 2% of patients with ST, respectively (P < .001). A catheter was the source of candidemia in 36% of the patients with ST and in 12% of the patients with HM (P < .001). Response to antifungal therapy occurred in 73% of the ST group compared with 49% of the HM group (P < .001). Multivariate logistic regression analysis revealed that fluconazole prophylaxis was a risk factor for both C. glabrata and C. krusei candidemia. The analysis also identified neutropenia as a risk factor for all candidemia and catheter-related infection as a risk factor for C. parapsilosis candidemia. CONCLUSIONS: The results of this study indicated that C. glabrata and C. krusei were the leading causes of candidemia in patients with HM. Neutropenia was the leading risk factor for all candidemia, whereas the catheter was the leading risk factor for C. parapsilosis candidemia.

Amphotericin B lipid complex versus liposomal amphotericin B monotherapy for invasive aspergillosis in patients with hematologic malignancy.

BACKGROUND: Invasive aspergillosis (IA) is a major cause of morbidity and mortality in patients with hematologic malignancy (HM). There are 2 lipid formulations of amphotericin B (AMB) currently in widespread use: AMB lipid complex (ABLC) and liposomal AMB (L-AMB). There are limited data comparing the efficacy and safety of these 2 agents in the treatment of IA in patients with cancer. METHODS: The authors retrospectively studied 381 consecutive patients with HM who had proven or probable IA (according to European Organization for Research and Treatment of Cancer/Mycosis Study Group of the National Institute of Allergy and Infectious Diseases criteria) between June 1993 and December 2005. Of these patients, 158 received primary antifungal therapy with either L-AMB (n=106) or ABLC (n=52). The number of salvage antifungal regimens given were 51 L-AMB regimens and 30 ABLC regimens. It should be noted that the population described in this report was not typical of the hematologic cancer population with IA because of the advanced stage and the severity of the underlying diseases. RESULTS: Risk factors for IA, such as underlying malignancy, neutropenia, steroid use, admission to an intensive care unit, and the presence of graft-versus-host disease, were comparable among the study drug group in the primary or salvage setting. Likewise, comparable distribution of types of Aspergillus species and the presence of disseminated IA were observed. Response to primary or salvage therapy was equally poor in both drug study groups regardless of treatment modality (range, 7.7-15.8% response). In the primary therapy group, ABLC was associated with significantly higher nephrotoxicity than L-AMB (P<.001). CONCLUSIONS: Among patients with HM, primary therapy and salvage therapy for IA with either ABLC or L-AMB as single agent were associated equally with poor outcome. L-AMB appeared to be less nephrotoxic in the primary therapy setting.

Intravascular catheter-related infections: advances in diagnosis, prevention, and management.

Indwelling vascular catheters are a leading source of bloodstream infections in critically ill patients and cancer patients. Because clinical diagnostic criteria are either insensitive or non-specific, such infections are often overdiagnosed, resulting in unnecessary and wasteful removal of the catheter. Catheter-sparing diagnostic methods, such as differential quantitative blood cultures and time to positivity have emerged as reliable diagnostic techniques. Novel preventive strategies include cutaneous antisepsis, maximum sterile barrier, use of antimicrobial catheters, and antimicrobial catheter lock solution. Management of catheter-related bloodstream infections involves deciding on catheter removal, antimicrobial catheter lock solution, and the type and duration of systemic antimicrobial therapy. Such decisions depend on the identity of the organism causing the bloodstream infection, the clinical and radiographical manifestations suggesting a complicated course, the underlying condition of the host (neutropenia, thrombocytopenia), and the availability of other vascular access sites.

Correlation between early clinical response after catheter removal and diagnosis of catheter-related bloodstream infection.

We conducted a retrospective post hoc analysis of prospectively collected data of cancer patients with central venous catheters (CVCs) who developed bacteremia with positive quantitative blood cultures (QBCs) drawn simultaneously through peripheral vein and CVC and which grew the same microorganisms from both blood cultures. We investigated whether clinical response of bacteremia, within 24, 48, or 72 h post-CVC removal, could be diagnostic of catheter-related bloodstream infection (CRBSI) when compared with microbiologic methods. Clinical response to antimicrobial therapy within 24 h of CVC removal in a patient with bacteremia was found to be highly suggestive of CRBSI, a finding that correlated well with semiquantitative catheter cultures and differential QBCs. However, response to antimicrobial therapy at >or=48 h after CVC removal was less likely to be diagnostic of CRBSI and could reflect a response to antimicrobial therapy irrespective of the source of the bloodstream infections.

Risk factors for infections with multidrug-resistant Stenotrophomonas maltophilia in patients with cancer.

BACKGROUND: Stenotrophomonas maltophilia is responsible for an increasing number of infections, especially in hospitalized patients. Therapy options are limited and trimethoprim/sulfamethoxazole (TMP/SMX) is often the main treatment option for this infection. In the current study, the risk factors were determined for the emergence of multidrug-resistant (MDR) S. maltophilia. METHODS: A case-control study was conducted to determine risk factors for the development of MDR S. maltophilia in cancer patients. The case group was composed of patients treated at the University of Texas M. D. Anderson Cancer Center for MDR S. maltophilia between 1996 and 2004 (n = 54). Two control groups were used: patients at comparable risk for S. maltophilia (C-controls) and patients with S. maltophilia infection that was susceptible to TMP-SMX and at least 2 other antibiotics (ciprofloxacin, ceftazidime, amikacin, and ticarcillin/clavulanate) (S-controls). RESULTS: When compared with C-controls, prior use of carbapenems or quinolones and admission to an intensive care unit within 30 days of isolation of the pathogen were found to be independently associated with MDR S. maltophilia infection (P < .02), as was an increased overall mortality rate (P = .04). When compared with S-controls, risk factors were history of S. maltophilia infection during the prior year and prior use of TMP-SMX (P = .015). CONCLUSIONS: Judicious use of TMP-SMX, carbapenems, and quinolones is necessary to control the risk for MDR S. maltophilia infection.

Comparative activities of daptomycin, linezolid, and tigecycline against catheter-related methicillin-resistant Staphylococcus bacteremic isolates embedded in biofilm.

In the setting of catheter-related bloodstream infections, intraluminal antibiotic lock therapy could be useful for the salvage of vascular catheters. In this in vitro study, we investigated the efficacies of the newer antibiotics daptomycin, linezolid, and tigecycline, in comparison with those of vancomycin, minocycline, and rifampin, against methicillin-resistant Staphylococcus aureus (MRSA) embedded in biofilm. We also assessed the emergence of MRSA strains resistant to these antibiotics, alone or in combination with rifampin, after 4-hour daily use for catheter lock therapy. Minocycline, daptomycin, and tigecycline were more efficacious in inhibiting MRSA in biofilm than linezolid, vancomycin, and the negative control (P < 0.001) after the first day of exposure to these antibiotics, with minocycline being the most active, followed by daptomycin and then tigecycline, and with vancomycin and linezolid lacking activity, similar to the negative control. After 3 days of 4-hour daily exposures, daptomycin was the fastest in eradicating MRSA from biofilm, followed by minocycline and tigecycline, which were faster than linezolid, rifampin, and vancomycin (P < 0.001). When rifampin was used alone, it was the least effective in eradicating MRSA from biofilm after 5 days of 4-hour daily exposures, as it was associated with the emergence of rifampin-resistant MRSA. However, when rifampin was used in combination with other antibiotics, the combination was significantly effective in eliminating MRSA colonization in biofilm more rapidly than each of the antibiotics alone. In summary, daptomycin, minocycline, and tigecycline should be considered further for antibiotic lock therapy, and rifampin should be considered for enhanced antistaphylococcal activity but not as a single agent.

Orthopaedic metal devices coated with a novel antiseptic dye for the prevention of bacterial infections.

Gendine is a novel antiseptic dye with broad-spectrum antimicrobial activity that may be used to coat plastics and metal devices. Our objective was to determine the efficacy of gendine-coated orthopaedic metal devices in preventing methicillin-resistant Staphylococcus aureus (MRSA) colonisation. Stainless steel and titanium Schanz rods were coated with gendine. The zone of inhibition (ZoI) around the rods with and without gamma-irradiation was determined by a modified Kirby-Bauer method. A previously published bioprosthetic biofilm colonisation model, modified Kuhn's method, was used to determine the adherence of MRSA to coated and uncoated rods, with and without irradiation, after insertion into bovine bone and after 3 months shelf life followed by 2 weeks of immersion in serum. The gendine-coated Schanz metal rods showed a net ZoI of 16 mm against MRSA before and after irradiation. Gendine-coated rods showed no biofilm formation (0 colony-forming units (CFU)), which was a significant reduction (P<0.001) compared with uncoated controls (>5000 CFU). Coated rods exposed to high-dose gamma-irradiation and coated rods drilled into bone also showed significant efficacy (P<0.001) in preventing biofilm adherence. After 2 weeks, gendine-coated rods maintained significant durability (P<0.01), resulting in 90% reduction in MRSA biofilm adherence compared with uncoated control rods. Results indicate that gendine-coated metal rods are highly efficacious in the prevention of MRSA biofilm.

Antiseptic effect of a novel alcohol-free mouthwash: a convenient prophylactic alternative for high-risk patients.

We developed an efficacious and non-irritant mouthwash that is alcohol-free and that has a low concentration of chlorhexidine, in order to be used for preventing oral cavity infections in immunocompromised and cancer patients. The novel mouthwash solution was tested for its antimicrobial efficacy against both free floating (planktonic) and the biofilm forms of Candida albicans. The solution was also tested against Klebsiella pneumoniae, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA), using a modification of a previously published method. The activity of the novel mouthwash was also compared with that of three commercially available mouthwashes. The experimental mouthwash showed efficacy against C. albicans, both in free-floating form and in biofilm. With higher concentration of chlorhexidine, the solution was also efficacious in inhibiting the growth of K. pneumoniae, P. aeruginosa, and MRSA. The antiseptic activity of the alcohol-free mouthwash against other bacterial organisms and C. albicans was comparable to other commercially available alcohol-based mouthwash solutions. A novel alcohol-free mouthwash solution, that has low concentration of chlorhexidine, showed antiseptic effect against planktonic and biofilm forms of C. albicans and against K. pneumoniae, P. aeruginosa, and MRSA.

Optimal antimicrobial catheter lock solution, using different combinations of minocycline, EDTA, and 25-percent ethanol, rapidly eradicates organisms embedded in biofilm.

Antimicrobial lock solutions may be needed to salvage indwelling catheters in patients requiring continuous intravenous therapy. We determined the activity of minocycline, EDTA, and 25% ethanol, alone or in combination, against methicillin-resistant Staphylococcus aureus and Candida parapsilosis catheter-related bloodstream infection strains in two established models of biofilm colonization. Biofilm-colonized catheter segments from a modified Robbins device and a silicone disk biofilm colonization model were exposed to these antimicrobial agents for 15 or 60 min, respectively. After exposure, segments were sonicated and cultured. To determine regrowth after incubation at 37 degrees C, following the brief exposure to the antimicrobial agents, an equal number of segments were washed, reincubated for 24 h, and then sonicated and cultured. The triple combination of minocycline-EDTA (M-EDTA) in 25% ethanol was the only antimicrobial lock solution that completely eradicated S. aureus and C. parapsilosis in biofilm of all segments tested in the two models, and it completely prevented regrowth. In addition, M-EDTA in 25% ethanol was significantly more effective in rapidly eradicating the growth or regrowth of methicillin-resistant S. aureus and C. parapsilosis biofilm colonization in the two models than the other solutions--minocycline, EDTA, M-EDTA, 25% ethanol, and EDTA in ethanol. We conclude that M-EDTA in 25% ethanol is highly effective at rapidly eradicating S. aureus and C. parapsilosis embedded in biofilm adhering to catheter segments.

Comparative in vitro efficacies and antimicrobial durabilities of novel antimicrobial central venous catheters.

We investigated the efficacies and durability of novel antimicrobial central venous catheters (CVCs) in preventing the adherence of microbial organisms to the surfaces of the CVCs. Novel antimicrobial CVCs investigated in this in vitro study were impregnated with antibiotics (minocycline and rifampin), with Oligon agent (silver, platinum, and carbon black), with approved antiseptics (chlorhexidine and silver sulfadiazine), or with a novel antiseptic agent, gendine, which contains gentian violet and chlorhexidine. When tested against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, gendine-coated CVC segments provided protection against bacterial adherence significantly more than all other types of tested CVCs (P < 0.05). Gendine-coated CVCs also provided better protection against Candida albicans and Candida parapsilosis than CVCs impregnated with antibiotics or with silver, platinum, and carbon (P < 0.02). After 28 days of being soaked in serum, the CVCs impregnated with chlorhexidine and silver sulfadiazine and the CVCs impregnated with silver, platinum, and carbon had lost antimicrobial activity against MRSA, P. aeruginosa, and C. parapsilosis, and the CVCs impregnated with minocycline and rifampin had lost activity against P. aeruginosa and C. parapsilosis. The CVCs impregnated with gendine maintained antimicrobial activities against MRSA, P. aeruginosa, and C. parapsilosis after 28 days of being soaked in serum. Central venous catheters impregnated with the novel investigational antiseptic gendine showed in vitro efficacy and provided protection against bacterial adherence more than other approved novel antimicrobial-coated CVCs.

The importance of two-step tuberculin skin testing for newly employed healthcare workers.

At the time of hire, 4059 of 6522 healthcare workers required a 2-step tuberculin skin test; 114 workers (2.8%) demonstrated a boosted reaction after the second step. Boosted reactions were significantly associated with male sex and older age. A verbal history of previous tuberculin skin test results was not a reliable indicator of baseline tuberculin skin test status at the time of hire.

Prospective study of the value of quantitative culture of organisms from blood collected through central venous catheters in differentiating between contamination and bloodstream infection.

Collection of blood through a central venous catheter for the diagnosis of bacteremia is a debated topic. Quantitative cultures of organisms from blood collected through central venous catheters were found to be highly sensitive, specific, and predictive of bacteremia, especially when a cutoff point of 15 colonies of skin organisms was used.

EDTA as an adjunct antifungal agent for invasive pulmonary aspergillosis in a rodent model.

Rats immunosuppressed by the administration of cyclophosphamide and cortisone acetate and then infected with Aspergillus fumigatus were treated with an antifungal drug, EDTA, or a combination of one of the antifungal agents, amphotericin B lipid complex (ABLC; 5 mg/kg of body weight/day for 7 days), and EDTA (30 mg/kg/day for 7 days). The mortality rate was reduced, the duration of survival was increased, fewer A. fumigatus organisms were recovered from the lungs, and less-severe lung lesions were seen histopathologically in the rats receiving the combination treatment than in the rats receiving either an antifungal agent or EDTA alone. Further studies regarding the mechanisms of EDTA and its interactions with ABLC are warranted, and further studies are needed to more fully examine the safety, tolerance, and optimal dosing of EDTA in the treatment of this and other fungal infections.

Central venous catheter and Stenotrophomonas maltophilia bacteremia in cancer patients.

BACKGROUND: Stenotrophomonas maltophilia bacteremia is frequently found in cancer patients. This study attempted to determine how often the catheters were the source of this infection and the risk factors associated with catheter-related bacteremias. METHODS: The microbiology records were retrospectively reviewed of all cancer patients having S. maltophilia bacteremia and indwelling central venous catheters seen between January 1998 and January 2004. In a multivariate analysis the patients' clinical characteristics, antimicrobial therapy, outcome, and source of bacteremia that were significantly associated with definite catheter-related S. maltophilia bacteremia as opposed to secondary bacteremia were identified. RESULTS: A total of 217 bacteremias were identified in 207 patients: 159 (73%) were primary catheter-related (53 definite, 89 probable, and 17 possible), 11 (5%) were primary noncatheter-related, and 47 (22%) were secondary. Multivariate analysis showed the following factors to be independently associated with definite catheter-related bacteremias: 1) polymicrobial bacteremia (odds ratio [OR], 7.6; 95% confidence interval [95% CI], 1.3-45.5); 2) no prior intensive care unit admission (OR, 0.06; 95% CI, 0.005-0.578); and 3) nonneutropenic status at onset (OR, 0.07; 95% CI, 0.013-0.419). The response rate to appropriate antibiotics and catheter removal was 95% in the patients with definite catheter-related bloodstream infections, compared with only 56% in the patients with secondary bacteremias (P = .001). CONCLUSIONS: The majority of the S. maltophilia bacteremias occurring in cancer patients with indwelling central venous catheters appear to be catheter-related and are often polymicrobial. Catheter-related S. maltophilia bacteremias occurred more frequently in noncritically ill, nonneutropenic patients, and prompt removal of the catheter was found to be associated with a better prognosis.

Chest tube-related empyema due to methicillin-resistant Staphylococcus aureus: could the chest tube be coated with antiseptics?

We reviewed the epidemiology, clinical manifestations, and outcomes of 3 cases of chest tube-related empyema due to methicillin-resistant Staphylococcus aureus (MRSA). Antiseptic-impregnated chest tubes were inserted in cultures containing MRSA isolates from these 3 patients, and zone of inhibition were measured. Chest tube-related MRSA empyema might complicate tube thoracostomy, and coating the chest tube with antiseptic agents could prevent this complication.

Clinical and radiologic predictors of invasive pulmonary aspergillosis in cancer patients: should the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria be revised?

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening infection in immunocompromised patients. The outcome of such infections depends on early diagnosis and prompt initiation of therapy. The objective of the current study was to determine the significant predictive factors that characterize IPA in patients with cancer. METHODS: The clinical characteristics and computed tomography (CT) findings for 47 cases with IPA were retrospectively reviewed and compared with 49 controls (patients diagnosed on autopsy with nonfungal pneumonias). Data from all 96 patients were modeled using multivariate logistic regression. Subgroups of patients with common characteristics and outcomes were identified. RESULTS: Leukemia, neutropenia, cavitation, and nodular lesions occurred significantly more often among cases than controls (P = 0.04, 0.004, 0.04, and 0.02, respectively). A quantitative scoring system was developed that could be used to identify patients as being at low, medium, and high risk for IPA. CONCLUSIONS: IPA should be highly suspected in leukemia patients with profound neutropenia, pleuritic chest pain, and cavitary or nodular lesions detected on CT scan. These predictive factors can be used to indicate when early prophylactic and therapeutic antifungal interventions should be initiated.

Vancomycin-resistant Enterococcus faecium: catheter colonization, esp gene, and decreased susceptibility to antibiotics in biofilm.

To evaluate the molecular characteristics and antibiotic susceptibility in biofilm of vancomycin-resistant Enterococcus faecium (VREF) organisms that had caused catheter-related VREF bacteremia (VREF-CRB), we compared 22 isolates causing bacteremia obtained from patients with VREF-CRB with 30 isolates from control patients with gastrointestinal colonization by VREF. Using pulsed-field gel electrophoresis, we identified 17 unique strains among the 22 VREF-CRB isolates and 23 strains among the gastrointestinal isolates. The esp gene was detected in 53% (9 of 17) of the VREF-CRB and 61% (14 of 23) of the control strains (P = 0.6). VREF-CRB produced heavier biofilm colonization of silicone disks than did control organisms (P < 0.001). Daptomycin, minocycline, and quinupristin-dalfopristin were each independently more active than linezolid in reducing biofilm colonization by VREF-CRB (P < 0.01), with daptomycin being the most active, followed by minocycline. In conclusion, the esp gene in VREF is not associated with heavy biofilm colonization or catheter-related bacteremia. In biofilm, daptomycin and minocycline were the most active antibiotics against VREF, and linezolid was the least active.

Catheter-related vancomycin-resistant Enterococcus faecium bacteremia: clinical and molecular epidemiology.

OBJECTIVE: To study the clinical and molecular epidemiology of vancomycin-resistant Enterococcus faecium organisms causing catheter-related bacteremia in patients with cancer. DESIGN: Retrospective case-control study. SETTING: University of Texas M. D. Anderson Cancer Center, a tertiary-care hospital in Houston, Texas. PATIENTS: Case-patients were patients with cancer who had catheter-related vancomycin-resistant E. faecium bacteremia and control-patients were patients with cancer and vancomycin-resistant E. faecium gastrointestinal colonization without infection. RESULTS: Ten case-patients with catheter-related vancomycin-resistant E. faecium bacteremia were compared with 30 control-patients with gastrointestinal colonization by vancomycin-resistant E. faecium. Patients with catheter-related vancomycin-resistant E. faecium bacteremia were more likely to have required mechanical ventilation (P < .01), received total parenteral nutrition (P < .01), and had polyurethane catheters (P < .01) inserted in the femoral vein (P = .01). With the use of pulsed-field gel electrophoresis, 4 of the 10 catheter-related vancomycin-resistant E. faecium bacteremia isolates were genetically indistinguishable, whereas only 2 of the 30 control vancomycin-resistant E. faecium isolates displayed this same DNA pattern (P = .03). CONCLUSION: This study suggests that catheter-related vancomycin-resistant E. faecium bacteremia occurs more frequently in patients who receive total parenteral nutrition, mechanical ventilation, and femoral catheters.

Risk factors for infections with multidrug-resistant Pseudomonas aeruginosa in patients with cancer.

BACKGROUND: Pseudomonas aeruginosa is responsible for a wide range of infections. In immunocompromised patients with cancer, the emergence of multidrug resistant P. aeruginosa may have grave consequences. METHODS: Patients with cancer who were infected with multidrug-resistant P. aeruginosa with polyclonal DNA restriction patterns were used as the case group. Two control groups were used: one group of cancer patients who were infected with multidrug-susceptible P. aeruginosa and another group of cancer patients who had the same underlying disease and the same intensive care unit exposure as patients in the case group but who were not infected or colonized by P. aeruginosa. RESULTS: Risk factors that were associated significantly with multidrug-resistant P. aeruginosa infection were the use of carbapenem for > or = 7 days, a history of P. aeruginosa infection during the preceding year, and a history of chronic obstructive pulmonary disease (P < 0.01). CONCLUSIONS: Carbapenems may need to be used more judiciously as first-line empirical therapy for cancer patients with prior pseudomonal infection or chronic obstructive pulmonary disease who require hospitalization, and alternative, antipseudomonal antibiotic regimens may need to be considered, especially in this patient population.