The prophylactic efficacy of rifampicin-soaked graft in combination with systemic vancomycin in the prevention of prosthetic vascular graft infection: an experimental study

OBJECTIVE: To investigate the prophylactic efficacy of systemic, topical, or combined antibiotic usage in the prevention of late prosthetic vascular graft infection caused by methicillin-resistant Staphylococcus epidermidis (MRSE) and the differential adherence of S. epidermidis to Dacron and ePTFE grafts in a rat model. MATERIALS AND METHODS: Graft infections were established in the back subcutaneous tissue of 120 adult male Wistar rats by implantation of 1-cm(2) Dacron/ePTFE prosthesis followed by topical inoculation with 2 x 10(7) CFU of clinical isolate of MRSE. Each of the series included one group with no graft contamination and no antibiotic prophylaxis (uncontaminated control), one contaminated group that did not receive any antibiotic prophylaxis (untreated control), one contaminated group in which perioperative intraperitoneal prophylaxis with vancomycin (10 mg/kg) was administered, two contaminated groups that received rifampicin-soaked (5 mg/1 ml) or vancomycin-soaked (1 mg/1 ml) grafts, and one contaminated group that received a combination of rifampicin-soaked (5 mg/1 ml) graft with perioperative intraperitoneal vancomycin prophylaxis (10 mg/kg). The grafts were removed sterilely 7 days after implantation and evaluated by using sonication and quantitative blood agar culture. RESULTS: MRSE had significantly greater adherence to Dacron than ePTFE grafts in the untreated contaminated groups (P < 0.001). Rifampicin had better efficacy than vancomycin in topical application, but the difference was not statistically significant (P > 0.05). Intraperitoneal vancomycin showed a significantly higher efficacy than topical vancomycin or rifampicin (P < 0.001). The best results were provided by a combination of intraperitoneal vancomycin in rifampicin-soaked graft groups (P < 0.001). CONCLUSIONS: The combination of rifampicin and intraperitoneal vancomycin seems to be the best choice for the prophylaxis of late prosthetic vascular graft infections caused by MRSE.     

Efficacy of Rifampin-Levofloxacin as a Prophylactic Agent in Preventing Staphylococcus epidermidis Graft Infection

OBJECTIVES: To investigate the efficacy of levofloxacin in the prevention of vascular prosthetic graft infection in a rat model. METHODS: Graft infections were established in the subcutaneous tissue of 225 male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with methicillin-susceptible and methicillin-resistant S. epidermidis. The study included a group without contamination, two contaminated groups without prophylaxis, two contaminated groups with intraperitoneal levofloxacin prophylaxis, two contaminated groups with intraperitoneal cefazolin prophylaxis, two contaminated groups with intraperitoneal teicoplanin prophylaxis and six contaminated groups with rifampin-soaked graft and intraperitoneal levofloxacin, cefazolin or teicoplanin prophylaxis. The grafts were removed after 7 days and evaluated by quantitative culture. RESULTS: The efficacy of levofloxacin against the methicillin-susceptible strain was not different to that of cefazolin or teicoplanin. Levofloxacin showed slight less efficacy than teicoplanin against the methicillin-resistant strain. The combination levofloxacin-rifampin demonstrated to be similarly effective to the combination rifampin-teicoplanin and more effective than the combination rifampin-cefazolin against both strains. CONCLUSIONS: Rifampin-levofloxacin combination seems useful for the prevention of late-appearing vascular graft infections caused by S. epidermidis.     

Quinupristin/dalfopristin bonding in combination with intraperitoneal antibiotics prevent infection of knitted polyester graft material in a subcutaneous rat pouch model infected with resistant Staphylococcus epidermidis.

OBJECTIVE: to investigate the efficacy of quinupristin/dalfopristin in the prevention of prosthetic graft infection in a rat subcutaneous pouch model. METHODS: graft infections were established in the subcutaneous tissue of 140 male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with Staphylococcus epidermidis with intermediate resistance to glycopeptides. The study included one group without contamination, one contaminated group without prophylaxis, one contaminated group that received 50mg/l quinupristin/dalfopristin-soaked graft, one contaminated group that received 10mg/kg intraperitoneal levofloxacin, one contaminated group that received 3mg/kg intraperitoneal doxycycline, and two contaminated groups that received 50mg/l quinupristin/dalfopristin-soaked plus 10mg/kg intraperitoneal levofloxacin or 3mg/kg intraperitoneal doxycycline. Each group included 20 animals. The grafts were removed after 7 days and evaluated by quantitative culture. RESULTS: quinupristin/dalfopristin showed a significantly higher efficacy than levofloxacin and doxycycline, even though quantitative graft cultures for rats that received only quinupristin/dalfopristin-soaked graft showed bacterial growth. Otherwise, the efficacy of levofloxacin was similar to that of doxycycline. Only the group treated with quinupristin/dalfopristin combined with levofloxacin or doxycycline showed no evidence of staphylococcal infection. CONCLUSIONS: quinupristin/dalfopristin as adjunctive topical antibiotic prophylaxis can be useful for the prevention of vascular graft infections caused by staphylococcal strains with high levels of resistance.     

Vascular prosthetic infection with Staphylococcus epidermidis: experimental study of pathogenesis and therapy

To determine whether a slime-producing strain of Staphylococcus epidermidis was capable of producing acute infection of a prosthetic vascular graft, 5 cm segments of knitted Dacron were implanted in the infrarenal aortic position of dogs in three groups of animals. These included a control group (no graft contamination), a contaminated group that received a graft soaked in an S. epidermidis solution (untreated group), and a contaminated group in which perioperative antibiotics (three doses of cefamandole, 100 mg/kg) were administered (prophylaxis group). In all the animals reexploration and graft removal were performed at 10 days, with replacement of the defect being achieved with a new uncontaminated graft. These animals underwent exploration a third time after an additional 10-day period. S. epidermidis was not grown from the control animals (n = 7) but was cultured in 44% of the prophylaxis group (n = 9) and 88% of the untreated group (n = 16) during at least one of the operative procedures (chi 2 = 15.859; p less than 0.001). The pathologic features of acute S. epidermidis infection were best seen in the untreated animals and included anastomotic disruption (56%), periaortic hematoma, and lymphadenopathy (94%). Microscopic examination of the aortic tissues revealed extensive infiltrates of leukocytes, macrophages, and foreign body giant cells with aortic necrosis. These features were less prominent in the prophylaxis animals. We conclude that S. epidermidis is capable of producing acute graft infection with perigraft inflammation and anastomotic disruption. The administration of perioperative antibiotics reduced but did not abolish these effects of bacterial contamination of prosthetic vascular grafts.     

Prophylaxis against Staphylococcus aureus vascular graft infection with mupirocin-soaked, collagen-sealed dacron

A rat model was used to investigate the efficacy of mupirocin in the prevention of vascular prosthetic graft infections. The effect of mupirocin-soaked Dacron was compared with the effect of rifampin-soaked, collagen-sealed Dacron in the rat model of graft infection caused by methicillin-susceptible Staphylococcus aureus and methicillin-resistant S. aureus. Graft infections were established in the back subcutaneous tissue of 195 adult male Wistar rats by implantation of 1-cm(2) Dacron prostheses followed by topical inoculation with 5 x 10(7) colony-forming units of S. aureus. The study included a control group (no graft contamination), two contaminated groups that did not receive any antibiotic prophylaxis, two contaminated groups in which perioperative intraperitoneal amoxicillin clavulanate prophylaxis (50 mg/kg) was administered, four contaminated groups that received mupirocin- or rifampin-soaked graft, and four contaminated groups that received mupirocin- or rifampin-soaked graft and perioperative intraperitoneal amoxicillin clavulanate prophylaxis (50 mg/kg). The grafts were sterilely removed 7 days after implantation and the infection was evaluated by using sonication and quantitative agar culture. Data analysis showed that the efficacy of mupirocin against both strains was significantly different from that of the untreated control. In addition, mupirocin was more effective than rifampin against the methicillin-resistant strain. Finally, only the combination of mupirocin and amoxicillin clavulanate produced complete suppression of growth of all strains.     

Efficacy of vancomycin, teicoplanin and fusidic acid as prophylactic agents in prevention of vascular graft infection: an experimental study in rat.

OBJECTIVES: To compare the efficacy of a single prophylactic dose of intra-peritoneal vancomycin and teicoplanin with anti-biotic treated Dacron grafts (vancomycin, teicoplanin, 10 or 40% fusidic acid-soaked grafts) in preventing vascular graft infections in a rat model. DESIGN: Prospective, randomized, controlled animal study. MATERIALS AND METHODS: The graft infections were established in the subcutaneous tissues of 80 female Sprague-Dawley rats by the implantation of Dacron prostheses followed by the topical inoculation with methicillin-resistant Staphylococcus aureus. The study groups were as follows: (1) uncontaminated control group, (2) untreated contaminated group, (3) contaminated group with intra-peritoneal vancomycin, (4) contaminated group with intra-peritoneal teicoplanin, (5) contaminated group received vancomycin-soaked Dacron graft, (6) contaminated group received teicoplanin-soaked Dacron graft, (7) contaminated group received 40% fusidic acid-soaked Dacron graft, and (8) contaminated group received 10% fusidic acid-soaked Dacron graft prophylaxis. The grafts were removed after 7 days and evaluated by a quantitative culture analysis. RESULTS: No infection was detected in controls. The untreated contaminated group had a high bacteria count (6.0 x 10(4) CFU/cm2 Dacron graft). Groups that received intra-peritoneal vancomycin or teicoplanin had less bacterial growth (4.8 x 10(3) and 3.9 x 10(3)CFU/cm2 Dacron graft, respectively). Similarly, the group that received 10% fusidic acid-soaked graft showed less bacterial growth (3.6 x 10(3) CFU/cm2 Dacron graft). The groups with vancomycin-, teicoplanin- and 40% fusidic acid-soaked grafts showed no evidence of infection. Statistical analyses demonstrated that intra-peritoneal prophylactic antibiotic treatment was less effective in inhibiting bacterial growth than high concentration antimicrobial-soaking of grafts. CONCLUSION: The use of vancomycin-, teicoplanin- and 40% fusidic acid-soaked grafts was effective in preventing primary prosthetic vascular graft infection.     

RNAIII-inhibiting Peptide and/or Nisin Inhibit Experimental Vascular Graft Infection with Methicillin-susceptible and Methicillin-resistant Staphylococcus epidermidis

OBJECTIVE: To investigate the efficacy of RNAIII-inhibiting peptide (RIP) and nisin as prophylactic agents in a rat model of vascular graft infection. DESIGN: Prospective, randomized, controlled animal study. MATERIALS: Two hundred and twenty adult male Wistar rats. Staphylococcus epidermidis ATCC 12228 and one clinical isolate of methicillin-resistant S. epidermidis. Drugs: RIP, nisin and rifampin. METHODS: Graft infections were established in the dorsal subcutaneous tissue by implantation of 1 cm(2) sterile Dacron grafts, followed by topical bacterial inoculation: grafts were retrieved at 7 days. The study included a control group (without inoculation) and two series composed of five groups for each staphylococcal strain: one contaminated group that did not receive any antibiotic prophylaxis, three contaminated groups that received grafts soaked with 10 mg/l RIP, 10 mg/l nisin, 10 mg/l rifampin, or RIP+nisin. The main outcome measure was the extent of bacterial at graft harvest. RESULTS: The bacterial counts for methicillin-resistant S. epidermidis on explanted grafts were 6.1+/-2.8x10(2), 7.8+/-3.0x10(3) and 5.5+/-2.9x10(4) for RIP, nisin and rifampin, respectively. RIP and nisin used in combination reduced the bacterial count to <10. The results for S. epidermidis were similar. CONCLUSIONS: RIP and nisin could be used in combination to coat medical devices to prevent drug resistant S. epidermidis infections.     

Prophylactic antibiotics prevent bacterial biofilm graft infection.

Bacterial biofilm graft infection is due to prostheses colonization by Staphylococcus epidermidis, a pathogen frequently recovered from perigraft tissues of man during vascular procedures despite the use of asepsis and prophylactic antibiotics. The effect of preoperative intraperitoneal cefazolin, administered at a standard (15 or 30 mg/kg) and high (120 mg/kg) dose, on the prevention of bacterial biofilm infection was studied in a rat model. Seventy-four Dacron grafts, colonized in vitro with S. epidermidis to produce an adherent biofilm (3.19 +/- 0.71 x 10(7) colony-forming units/cm2 graft), were implanted in the dorsal subcutaneous tissue at 0.5, 2, and 4 hr after antibiotic administration. The study strain was a slime-producing clinical isolate with minimum inhibitory concentration (MIC) of 15-30 micrograms/ml to cefazolin. Subcutaneous tissue antibiotic levels were determined at each time interval. One week after implantation, the concentration of bacteria in the surface biofilm by quantitative agar culture was significantly decreased (P less than 0.05) only for grafts implanted when antibiotic tissue levels were greater than or equal to the MIC of the study strain. The result of no growth by biofilm broth culture was significantly achieved (P less than 0.01) only for grafts implanted 0.5 hr after high dose cefazolin, in which the tissue antibiotic level was above the MIC of the study strain. Antibiotics can markedly reduce the bacteria concentration of a prosthetic surface biofilm. The effectiveness of prophylactic antibiotics on the prevention of graft infection is dependent upon maintaining an adequate antibiotic level in the perigraft tissues for the duration of the procedure.     

Comparative study of cefazolin, cefamandole, and vancomycin for surgical prophylaxis in cardiac and vascular operations. A double-blind randomized trial.

Three-hundred twenty-one adults undergoing cardiac or major vascular operations were randomized to receive intravenous cefazolin, cefamandole, or vancomycin for prophylaxis against surgical infection in a double-blind trial. All three regimens provided therapeutic blood levels throughout operation in patients studied undergoing cardiopulmonary bypass. The prevalence of surgical wound infection was lowest with vancomycin (4 infections [3.7%] versus 14 [12.3%] and 13 [11.5%] in the cefazolin and cefamandole groups, respectively; p = 0.05); there were no thoracic wound infections in cardiac operations in the vancomycin group (p = 0.04). The mean duration of postoperative hospitalization was lowest in the vancomycin group (10.1 days; p < 0.01) and highest in the cefazolin group (12.9 days). Prophylaxis with vancomycin or cefamandole, compared with cefazolin, did not prevent nosocomial cutaneous colonization by methicillin-resistant coagulase-negative staphylococci; colonization or infection with vancomycin-resistant staphylococci or enterococci was not detected. Adverse effects attributable to the prophylactic regimen were infrequent in all three groups. Eight patients given vancomycin became hypotensive during administration of a dose, despite infusion during a 1-hour period; however, slowing the rate of administration and pretreating with diphenhydramine allowed vancomycin to be resumed and prophylaxis completed uneventfully in five of the patients. We conclude that administration of vancomycin (approximately 15 mg/kg), immediately preoperatively, provides therapeutic blood levels for surgical prophylaxis throughout most cardiac and vascular operations, resulting in protection against postoperative infection superior to that obtained with cefazolin or cefamandole. Vancomycin deserves consideration for inclusion in the prophylactic regimen (1) for prosthetic valve replacement and prosthetic vascular graft implantation, to reduce the risk of implant infection by methicillin-resistant coagulase-negative staphylococci and enterococci; (2) for any cardiovascular operation if the patient has recently received broad-spectrum antimicrobial therapy; and (3) for all cardiovascular operations in centers with a high prevalence of surgical infection with methicillin-resistant staphylococci or enterococci. Guidelines for dosing and administration of vancomycin for cardiovascular surgical prophylaxis are provided.     

Linezolid alone and in combination with rifampicin prevents experimental vascular graft infection due to methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis

BACKGROUND: In this report we describe the in vivo antibacterial activity of linezolid in an experimental graft infection model in rats and compare it with teicoplanin. The objective of this study was also to determine the effects of the interaction of linezolid when it was combined with rifampicin and test this effect against strains of methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. MATERIALS AND METHODS: Graft infections were established in the subcutaneous tissue of 130 Wistar rats by implantation of Dacron grafts followed by a topical inoculation with 2 x 10(7) CFU of clinical isolates of MRSA and MRSE. The study included a control group and six groups for each of the staphylococcal strains: an inoculated group that did not receive any antibiotic prophylaxis, two inoculated groups that received intraperitoneal prophylaxis with teicoplanin or linezolid alone, an inoculated group that received rifampicin-soaked grafts, and two inoculated groups that received a combination prophylaxis consisting of intraperitoneal teicoplanin or linezolid and rifampicin-soaked grafts. RESULTS: There was a reduction in the quantitative bacterial graft cultures in all prophylaxis groups when compared with inoculated control groups. There was not a statistically significant difference between linezolid and teicoplanin prophylaxis groups. The best results were obtained by a combination of rifampicin-soaked grafts with linezolid or teicoplanin. CONCLUSIONS: We found no evidence to suggest that linezolid differs from teicoplanin regarding effectiveness in the prevention of prosthetic vascular graft infection. Linezolid plus rifampicin and teicoplanin plus rifampicin are demonstrated to be valuable prophylactic regimens.     

Impact of postantibiotic effect on bacterial adherence to vascular prostheses

The brief exposure of bacteria to high antibiotic concentrations can result in prolonged suppression of bacterial growth termed postantibiotic effect (PAE). A pathogenic Staphylococcus epidermidis strain (RP-62) was exposed to 2X and 6X minimum inhibitory concentrations (MIC) of cefazolin, vancomycin, or rifampin for 1 hr and incubated for 2 to 24 hr in inhibitory-free broth. PAE was defined as the difference in time required for a 1.0 log increase in test (T) vs control (C) cultures (PAE = T-C). PAE was observed only for rifampin: 6 hr at 2X MIC and 8 hr at 6X MIC. Bacterial adherence to Dacron grafts was calculated in PAE vs control cultures by a quantitative culture technique for graft specimens incubated 2 to 24 hr. A demonstrable PAE and its impact on adherence were found to be both antimicrobial and concentration dependent. A significant decrease in staphylococcal adherence to velour-knitted Dacron was demonstrated by rifampin at 2X MIC (P less than 0.05) and 6X MIC (P less than 0.01). This phenomena may be useful in reducing bacterial adherence and colonization of bioprosthetics in the perioperative period. Preoperative suppression of staphylococcal skin flora by high dose antimicrobials can alter the capacity of these organisms to adhere to vascular prosthetic grafts and, if incorporated into antibiotic prophylaxis regimens, may reduce graft colonization.     

A rat model of polypropylene graft infection caused by Staphylococcus epidermidis

BACKGROUND: The aim of this study was to constitute a valid graft infection model with Staphylococcus epidermidis in rats. METHODS: Rats were divided into seven groups. In groups 1 and 2, 2 cm x 2 cm polypropylene grafts were incubated with 10(8) c.f.u./mL slime-positive S. epidermidis at 37 degrees C for 2 and 24 h and were then placed subfascially to the groins of rats. In the third group, naive grafts were placed and 0.5 mL of 3 x 10(7) c.f.u. slime-positive S. epidermidis were injected on the inside of the wounds. Rifampicin (30 mg/kg) in group 4 and teicoplanin (20 mg/kg) in group 5 were applied i.p. to rats with 2-h incubated grafts for prophylaxis. The same prophylactic regimens were given to groups 6 and 7 in which rats were incubated for 24 h. At eighth day, rats were killed and wounds were assessed with macroscopic evaluation and cultures. RESULTS: No death occurred in any of the groups. In groups 1 and 2, 100% infection rates were achieved. However, graft infection was detected in only two (20%) of the rats in group 3 (P = 0.001). Prophylactic application of teicoplanin or rifampicin decreased the infection rates significantly in the short-incubation groups. CONCLUSION: Incubation of polypropylene grafts with slime-producing S. epidermidis for 2 and 24 h in the pre-application period achieved the occurrence of a standardized graft infection. Prophylactic use of teicoplanin and rifampicin decreased the infection rates. We propose to use this reproducible and reliable animal model of graft infection in future studies.     

Infection of vascular prostheses caused by bacterial biofilms

A canine model was developed to study the efficacy of graft replacement as treatment for vascular prosthesis infections from Staphylococcus epidermidis. Infrarenal aortic graft infections were established in 18 dogs by implantation of Dacron prostheses colonized in vitro with a slime-producing strain of S. epidermidis to form an adherent bacteria-laden biofilm (5 X 10(6) colony-forming units/cm2 graft). Study animals developed a graft infection with anatomic and microbiologic characteristics typical of late prosthetic graft infections in humans (sterile perigraft exudate, absent graft incorporation, and normal serum leukocyte count and sedimentation rate). The S. epidermidis study strain was isolated from 14 of 18 explanted grafts (78%) by mechanical disruption of the graft surface biofilm and culture in broth media. Four dogs with sterile graft cultures had histologic evidence of bacterial infection. The established prosthetic surface biofilm infection was treated by graft excision, parenteral cefazolin, and graft replacement with a Dacron or polytetrafluoroethylene (PTFE) vascular prosthesis. One month after graft replacement, no PTFE graft had signs of infection, but perigraft exudate and inflammation involved three of nine Dacron grafts (33%). The study strain was recovered from four of nine PTFE grafts (44%) and two of nine Dacron (22%) replacement grafts (p greater than 0.05). Prosthetic replacement of Dacron prostheses infected by S. epidermidis as a bacteria-laden surface biofilm can result in early graft healing, but persistent colonization of one third of replacement grafts signify that recurrent clinical infection remains a risk.     

Editorial Commentary: Is It Time for the Vancomycin Wrap to Become a Universal Recommendation for the Prevention of Septic Arthritis Following Anterior Cruciate Ligament Reconstruction?

Septic arthritis is a devastating complication of anterior cruciate ligament (ACL) reconstruction, which can still occur in approximately 1% of patients despite appropriate intravenous antibiotic prophylaxis and other recommended preventative measures being undertaken. The infection is most likely secondary to the autograft becoming contaminated during harvest and preparation, introducing bacteria into the joint on insertion. Presoaking ACL grafts in 5 mg/mL vancomycin is a novel method developed to eradicate this bacterial contamination and is supported by compelling Level III evidence from multiple observational trials showing a dramatic reduction in infection rates without any evidence of increased graft failure. As such, it is time for this technique to become a universal recommendation? That said, as observational studies using a historical cohort as a comparator are at risk of various biases, Level I evidence is ultimately required for infection prophylaxis methods to be recognized as a universal recommendation in infection control guidelines. Consequently, future research endeavors on the “vancomycin wrap” should focus on randomized controlled trials, possibly nested within ACL registries.     

Use of an antibiotic-bonded graft for in situ reconstruction after prosthetic graft infections.

We have developed an infection resistant vascular prosthesis by bonding rifampin to Dacron grafts with the use of a collagen matrix release system. The purpose of this study was to determine the efficacy of this antibiotic-bonded graft in resisting infection after an in situ reconstruction of a previously infected prosthetic bypass. Eighty-three adult mongrel dogs underwent implantation of a 3 cm untreated Dacron graft into the infrarenal aorta. This initial graft was deliberately infected, at the time of operation, with 10(2) organisms of Staphylococcus aureus by direct inoculation. One week later, the dogs were reexplored, the retroperitoneum debrided, and the animals randomized to undergo an end-to-end in situ graft replacement with either one of two types of prosthetic grafts: group I (collagen, n = 36) received control collagen-impregnated knitted Dacron grafts; group II (rifampin, n = 47) received experimental collagen-rifampin-bonded Dacron grafts. Each group of animals was then subdivided to receive one of four treatment protocols: (a) no antibiotic therapy, (b) cephalosporin peritoneal irrigation solution (cefazolin 500 mg/1000 ml) during operation and two doses of cephalosporin (cefazolin, 500 mg intramuscularly) postoperatively, (c) treatment as in protocol group b plus 1 week of cephalosporin (cefazolin, 500 mg intramuscularly, twice daily), and (d) treatment as in protocol group b plus 2 weeks of cephalosporin (cefazolin, 500 mg intramuscularly, twice daily). All grafts were sterilely removed between 3 and 4 weeks after implantation. There were no anastomotic disruptions and all grafts were patent at the time of removal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vancomycin Prophylaxis for Total Joint Arthroplasty: Incorrectly Dosed and Has a Higher Rate of Periprosthetic Infection Than Cefazolin

Background

In total joint arthroplasty (TJA), vancomycin is used as perioperative antibiotic prophylaxis in patients with penicillin allergy or in patients colonized with methicillin-resistant Staphylococcus aureus (MRSA). Although vancomycin dosing should be weight-based (15 mg/kg), not all surgeons are aware of this; a fixed 1-g dose is instead frequently administered.

Questions/purposes

(1) Is there a difference in the risk of periprosthetic joint infection (PJI) in patients receiving vancomycin or cefazolin prophylaxis after primary TJA? (2) What proportion of patients is adequately dosed with vancomycin? (3) Compared with actual fixed dosing, does weight-based dosing result in a greater proportion of patients staying above the recommended 15-mg/L level at the beginning and end of surgery? (4) Are patients overdosed with vancomycin at greater risk of developing nephrotoxicity and acute kidney injury?

Methods

A single-institution, retrospective study was performed on 1828 patients undergoing primary TJAs who received vancomycin prophylaxis between 2008 and 2014. During the same period, 5810 patients underwent primary TJA and received cefazolin monotherapy. A chart review was performed to obtain patient characteristics, antibiotic dose and timing of administration, and microbiology data. Adequate vancomycin dosing was defined as 15 mg/kg and within the 125-mg range. Vancomycin levels were calculated at the beginning and end of surgery using pharmacokinetic equations. Levels of 15 mg/L were considered adequate. Logistic regression, chi square tests, and analysis of variance were performed.

Results

Among primary TJAs, patients receiving vancomycin had a higher rate of PJI (32 of 1828 [2%]) compared with patients receiving cefazolin prophylaxis (62 of 5810 [1%]; adjusted odds ratio, 1.587 [1.004–2.508]; p = 0.048). Ten percent of PJIs in the vancomycin underdosed group (two of 20) was caused by MRSA, and no patients with adequate dosing or overdosing of vancomycin developed PJI with MRSA. Of all procedures in which vancomycin monotherapy was used, 28% (518 of 1828) was adequately dosed according to weight-based dosage recommendations. Furthermore, 94% (1726 of 1828) of patients received a fixed 1-g dose of vancomycin, of whom 64% (1105 of 1726) were underdosed. All patients had vancomycin infusion initiated within 2 hours before incision. A weight-based protocol would have resulted in fewer patients having unacceptably low vancomycin levels (< 15 mg/L) compared with those with actual fixed dosing, both for the beginning of surgery at the time of incision (zero of 1828 [0%] versus 471 of 1828 [26%]; odds ratio, 0.001 [0.000–0.013]; p < 0.001) and at the end of surgery (33 of 1828 [2%] versus 746 of 1828 [41%]; odds ratio, 0.027 [0.019–0.038]; p < 0.001). Between the vancomycin dosage groups, there were no differences in the rate of nephrotoxicity (underdosed: 12 of 1130 [1%], adequately dosed: five of 518 [1%], overdosed: four of 180 [2%], p = 0.363) and acute kidney injury (underdosed: 28 of 1130 [2%], adequately dosed: 10 of 518 [2%], overdosed: six of 180 [3%], p = 0.561).

Conclusions

The majority of patients given vancomycin prophylaxis are underdosed according to the weight-based dosage recommendations, and MRSA did not occur in patients who were adequately dosed with vancomycin. Surgeons should thus ensure that their patients are adequately dosed with vancomycin using the recommendation of 15 mg/kg and that the dose of vancomycin is administered in a timely fashion. Furthermore, and based on the findings of this study, we have moved toward limiting the utilization of vancomycin prophylaxis for patients undergoing elective arthroplasty at our institution.

Level of Evidence

Level III, therapeutic study.

     

Ozone therapy as an adjunct to vancomycin enhances bacterial elimination in methicillin resistant Staphylococcus aureus mediastinitis

Background

We aimed to investigate the influence of intraperitoneal ozone therapy on bacterial elimination and mediastinal inflammation in experimental Staphylococcus aureus mediastinitis.

Materials and methods

Forty Wistar-Albino rats were randomized into five groups (eight per group) as follows: uncontaminated group, untreated contaminated group, ozone group, vancomycin group, and vancomycin + ozone group. Uncontaminated group underwent upper median sternotomy. The remaining four groups were inoculated with 0.5 mL 10⁸ colony-forming units/mL methicillin-resistant Staphylococcus aureus in the mediastinal and sternal layers. Untreated contaminated group had no treatment. Rats in the vancomycin group received intramuscular vancomycin (40 mg/kg/d), and ozone was administered intraperitoneally (70 μg/mL, 1 mg/kg/d) in the ozone group for the treatment of mediastinitis. Vancomycin + ozone group rats were treated by the combination of both methods. At the end of 10 d, quantitative bacterial cultures and sternal tissue samples were obtained for determination of bacterial counts and histologic degree of inflammation.

Results

Both the vancomycin and the ozone treatments caused significant reduction of bacterial counts in quantitative bacterial cultures. Combination of vancomycin and ozone treatments resulted in further reduction of bacterial counts in mediastinum and sternum. Histologic examination of tissue samples revealed significant reduction in severity of mediastinitis related inflammation in vancomycin and vancomycin + ozone groups compared with untreated contaminated group.

Conclusions

Ozone therapy as an adjunct to vancomycin leads to enhanced bacterial elimination in infected sternal and mediastinal tissues in experimental methicillin-resistant Staphylococcus aureus mediastinitis. The benefit of adjuvant ozone therapy is suggested to be related to its bactericidal effect.     

Pharmacokinetics of intermittent intravenous cefazolin and tobramycin in patients treated with automated peritoneal dialysis

There is increasing use of intermittent dosing of antibiotics to treat peritoneal dialysis (PD)-related peritonitis. The disposition of intravenous cefazolin and tobramycin was studied in automated PD (APD) patients. Ten patients were recruited and received a single intravenous dose of cefazolin (15 mg/kg) and tobramycin (0.6 mg/kg). Blood and dialysate samples were collected at the beginning, middle, and end of dwells 1 to 3 (on cycler), and at the end of dwells 4 to 5 (off cycler) for a 24-h period. Baseline and 24-h urine samples were collected. Pharmacokinetic parameters were calculated using a monoexponential model. Cefazolin and tobramycin half-lives were markedly different on cycler than off cycler (cefazolin on cycler : 10.67 +/- 4.66 h; cefazolin off cycler : 23.09 +/- 5.6 h; P = 0.001; tobramycin on cycler : 14.27 +/- 4.53 h; tobramycin off cycler : 68. 5 +/- 26.47 h; P < 0.001). Mean serum and dialysate concentrations were above minimum inhibitory concentrations of susceptible organisms throughout the 24-h period for both drugs with intravenous administration. A model was developed to examine serum and dialysate concentrations after intermittent intraperitoneal administration of 15 mg/kg cefazolin and 0.6 mg/kg tobramycin. Model-predicted intraperitoneal cefazolin provides adequate serum and dialysate concentrations for 24 h. Intermittent intraperitoneal tobramycin doses must be 1.5 mg/kg for one exchange during the first day and then given as 0.5 mg/kg thereafter. It is concluded that the current empiric dosing recommendations for PD-related peritonitis may be adequate for cefazolin (15 to 20 mg/kg); however, tobramycin doses must be changed to 1.5 mg/kg intraperitoneally on day 1, then to 0.5 mg/kg intraperitoneally thereafter in APD patients.     

Rifampin protection against experimental graft sepsis

The risk of infection in vascular prosthetic conduits appears to be greatest in the perioperative period and the organism most frequently found is Staphylococcus aureus. Previous work suggests that antibiotics must be chemically bonded to the material to resist rapid washout caused by the flow of blood through the graft. The exception to this is rifampin, which remains fixed in Dacron prostheses after passive addition of the agent to aliquots of blood used to clot the interstices of porous Dacron grafts. This characteristic of rifampin is presumed to be caused by its poor water solubility. This potential infection resistance was challenged in a standard model of a canine infrarenal aortic graft by intravenous infusion of S. aureus organisms (10(7)) in the perioperative period. The grafts of five animals were preclotted with 9 ml of autogenous blood plus 1 ml of rifampin (60 mg/ml). A second group had similar procedures with 1 ml of cefazolin (238 mg/ml) substituted for the rifampin, and a control group had 1 ml of saline solution added to the 9 ml aliquot of blood. The animals were killed at 3 weeks and examined for clinically apparent infection. Rings of the graft material were also removed aseptically and cultured. All five grafts preclotted with cefazolin had clinical and culture evidence of infection (S. aureus), as did the grafts of three of the five control dogs. None of the grafts preclotted with rifampin was infected (p less than 0.05). Addition of rifampin to the blood used to clot the graft interstices appears to be a simple way of imparting graft resistance to perioperative sepsis.     

Treatment of established prosthetic vascular graft infection with antibiotics preferentially concentrated in leukocytes

The efficacy of treating established vascular graft infections with rifampin and clindamycin (preferentially concentrated in leukocytes) and cefazolin (not concentrated in leukocytes) was studied in a canine model. Infrarenal aortic, 6 mm by 6 cm knitted Dacron double velour grafts were implanted and infected with 10(8) colony-forming units (CFU) of coagulase-positive Staphyloccus aureus organisms injected intravenously immediately after graft placement. Antibiotic therapy was instituted at 3 months postimplantation. Three groups were studied: (I) untreated controls (n = 3); (II) therapy with intravenous cefazolin 15 mg/kg/8 hr for 28 days (n = 7); and (III) combined therapy with intravenous rifampin 13 mg/kg/24 hr and intravenous clindamycin 13 mg/kg/8 hr for 28 days (n = 7). Grafts were removed for quantitative bacteriologic studies after the 28-day course of therapy. Two group I control grafts remained patent with 6.4 X 10(6) and 8.1 X 10(3) CFU S. aureus/gm of graft. The third control graft was thrombosed. Two group II animals demonstrated 1.6 X 10(7) and 2.3 X 10(5) CFU S. aureus organisms/gram of graft, respectively; the remaining five group II grafts were free of organisms. All group III grafts were sterile--a significant difference (p less than 0.05) from group I grafts. In this experimental model, established prosthetic graft infections were eradicated by intensive treatment with antibiotics preferentially concentrated in leukocytes.