The International Society of Peritoneal Dialysis (ISPD) Ad Hoc Advisory Committee on Peritoneal Dialysis Related Infections periodically evaluates the diagnostic and therapeutic literature. The most recent report, published in 2010, provides guidelines for the diagnosis and pharmacotherapy of PD-associated infections (Fig. 54–4).88 These guidelines address the increasing importance of dialysis center–specific antibiotic selection, the effect of residual renal function on the pharmacokinetics of antibiotics, and updated recommendations regarding the use of aminoglycosides and vancomycin.
Pharmacotherapy recommendations for the treatment of bacterial peritonitis in peritoneal dialysis patients. *Choice of empiric treatment should be made based on the dialysis center's and the patient's history of infecting organisms and their sensitivities. **Final choice of therapy should always be guided by culture and sensitivity results. (MRSA, methicillin-resistant Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; S. aureus, Staphylococcus aureus; S. epidermidis, Staphylococcus epidermidis;VRE, vancomycin-resistant enterococci; WBC, white blood cell.)
Intraperitoneal (IP) administration of antibiotics remains the preferred route over IV therapy. The ISPD guidelines provide dosing recommendations for intermittent (1 large dose into 1 exchange per day) and continuous therapy (antibiotic addition to each exchange). In addition, dosing recommendations are modified on the basis of the patient's PD modality (CAPD or APD) and whether or not the patient has RRF (>100 mL/day urine output).
The choice between intermittent and continuous therapies requires careful consideration for several reasons. The dialysate and serum concentrations achieved after these regimens are very different. The pharmacokinetics of intermittent intraperitonealceftazidime and cefazolin are well described. Single daily doses of cefazolin and ceftazidime in CAPD are effective in achieving serum concentrations greater than the minimum inhibitory concentration for sensitive organisms over 48 hours. In CAPD, usually therapy is added as a single daily dose into the exchange with the longest dwell, to ensure maximal bioavailability. Intermittent (once-daily) IP dosing of antibiotics is recommended for CAPD patients with peritonitis. However, APD dosing strategies are different, because of the increased clearances of solutes in such systems. This appears to be particularly important for first-generation cephalosporins. The ISPD guidelines recommend continuous dosing of first-generation cephalosporins because of concerns over inadequate IP drug concentration during the shorter APD dialysate dwells. With regard to residual renal function, in patients with daily urine output greater than 100 mL, the dose should be empirically increased by 25% for drugs that are renally eliminated. The ISPD dosing recommendations for IP antibiotics in CAPD and APD patients are shown in Table 54–10 and Table 54–11, respectively.
Table 54-10 Intraperitoneal Antibiotic Dosing Recommendations for Continuous Ambulatory Peritoneal Dialysis Patients |Favorite Table|Download (.pdf)
Table 54-10 Intraperitoneal Antibiotic Dosing Recommendations for Continuous Ambulatory Peritoneal Dialysis Patients
|Drug||Intermittent (Per Exchange, Once Daily)||Continuous (mg/L, All Exchanges)|
| Amikacina||2 mg/kg||LD 25, MD 12|
| Gentamicina||0.6 mg/kg||LD 8, MD 4|
| Netilmicina||0.6 mg/kg||LD 8, MD 4|
| Tobramycina||0.6 mg/kg||LD 8, MD 4|
| Cefazolina||15 mg/kg||LD 500, MD 125|
| Cefepimea||1,000 mg||LD 500, MD 125|
| Cephalothina||15 mg/kg||LD 500, MD 125|
| Cephradinea||15 mg/kg||LD 500, MD 125|
| Ceftazidimea||1,000–1,500 mg||LD 500, MD 125|
| Ceftizoximea||1,000 mg||LD 250, MD 125|
| Azlocillina||ND||LD 500, MD 250|
| Ampicillina||ND||MD 125|
| Oxacillina||ND||MD 125|
| Nafcillina||ND||MD 125|
| Amoxicillina||ND||LD 250–500, MD 50|
| Penicillin Ga||ND||LD 50,000 units, MD 25,000 units|
| Ciprofloxacina||ND||LD 50, MD 25|
| Vancomycina||15–30 mg/kg Q5-7d||LD 1,000, MD 25|
| Aztreonama||ND||LD 1,000, MD 250|
| Daptomycina||ND||LD 100, MD 20|
| Linezolida||200–300 mg daily PO||200–300 mg daily PO|
| Teicoplanina||15 mg/kg||LD 400, MD 20|
| Amphotericin B||NA||MD 1.5|
| Ampicillin/sulbactama||2 g q 12 h||LD 1,000, MD 100|
| Imipenem/cilastatina||1 g twice daily||LD 500, MD 200|
| Quinupristin/dalfopristinb||25 mg/L in alternate bags||ND|
| Trimethoprim/sulfamethoxazole||960 mg twice daily PO||960 mg twice daily PO|
Table 54-11 Intermittent Intraperitoneal Antibiotic Dosing Recommendations for Automated Peritoneal Dialysis Patients |Favorite Table|Download (.pdf)
Table 54-11 Intermittent Intraperitoneal Antibiotic Dosing Recommendations for Automated Peritoneal Dialysis Patients
|Vancomycin||Loading dose 30 mg/kg IP in long dwell, repeat dosing 15 mg/kg IP in long dwell every 3–5 days, following levels|
|Tobramycin||Loading dose 1.5 mg/kg IP in long dwell, then 0.5 mg/kg IP each day in long day dwell|
|Fluconazole||200 mg IP in one exchange per day every 24–48 h|
|Cefepime||1 g IP in one exchange per day|
The stability of antibiotics added to peritoneal dialysate is important. In dextrose solutions, most antibiotic additives appear to be stable (usually defined as retaining at least 90% of initial activity) for about 1 week if refrigerated, or 1 to 2 days if left at room temperature. Recent data suggest that cefazolin, ceftazidime, cefepime, vancomycin, gentamicin, tobramycin, netilmicin, and heparin are stable in icodextrin.91–93 It is important to note that some studies may not be indicative of stability; that is, they may assay total concentration of an agent, which may include parent-drug degradation products as well as the active drug product, which, as a result, may not maintain the same degree of pharmacologic activity.
The systemic toxicities of IP regimens remain unclear but are likely similar to those associated with IV and oral antibiotic administration. Intermittent (once-daily) IP dosing of drugs, such as aminoglycosides, may reduce the risk of systemic toxicity (ototoxicity and nephrotoxicity).89 Due to controversial/conflicting clinical trial data,94–96 the current ISPD guidelines state that there is no convincing evidence that short courses of aminoglycosides lead to loss of RRF. They also state that prolonged or repeated courses are probably inadvisable if an alternative approach is possible.89 This latter controversial recommendation was based on the opinion of the committee and restated in the recent K/DOQI document. Since the preservation of RRF is very important for PD patients, routine use of aminoglycosides should be avoided in patients with significant RRF (producing >100 mL urine per day) if other antibiotic choices are available.89
Sidebar: Clinical Controversy
The ISPD guidelines for peritonitis treatment state that patients with significant residual renal function should not receive aminoglycosides if other antibiotic choices are available. Aminoglycosides were found to increase the rate of decline in residual renal function in one study. However, another study refuted this claim.
Initial empiric therapy for peritonitis, regardless of whether a Gram stain was performed or organisms were identified, should include agents effective against both gram-positive and gram-negative organisms. Antibiotic selection should include consideration of the dialysis center and patient history of infecting organisms and the antibiotic sensitivity profile of the organisms. In many cases, a first-generation cephalosporin such as cefazolin in combination with a second drug that provides broader gram-negative coverage, such as ceftazidime, cefepime, or an aminoglycoside, will prove suitable. Patients with documented allergy to cephalosporin antibiotics can be treated with vancomycin and an aminoglycoside. High rates of methicillin resistance have been reported by many dialysis centers, and vancomycin should be used as first-line therapy against gram-positive organisms for patients treated at these centers. Monotherapy with agents providing both gram-positive and gram-negative coverage is an alternative option. Both imipenem-cilastin and cefepime are effective in treating CAPD-related peritonitis.96
After culture and sensitivity results are obtained, antibiotic therapy should be adjusted appropriately (see Fig. 54–4). Table 54–10 and Table 54–11 list doses for antibiotics. Treatment should be continued for 14 to 21 days. If the patient does not show a sign of clinical improvement within 72 hours after antibiotic treatment is initiated, the culture should be repeated and the patient reevaluated. If the peritoneal dialysate white blood cell count remains high after 4 days of appropriate antibiotic therapy, clinicians should consider removing the peritoneal catheter and placing the patient on HD and starting IV antibiotics.
Fungal peritonitis is associated with a poor prognosis and high morbidity and mortality. One problem with prospective assessment of antifungal regimens is the infrequency with which these infections occur. This makes it difficult to design and implement comparative studies. Most literature about antifungal treatment is therefore retrospective or limited to reports of local experience.97 As a result, the ISPD recommendations for treatment of fungal peritonitis are somewhat vague, and treatment should be based on culture and sensitivity results. However, one area that has been clarified is the question as to whether the PD catheter should be removed. The ISPD recommendations are to remove the catheter immediately after identifying fungi. If the Gram stain indicates the presence of yeast, treatment may be initiated with amphotericin B and oral flucytosine. Once culture and sensitivity results are available, fluconazole, caspofungin, or voriconazole may replace amphotericin B. Treatment with these agents should be continued orally for an additional 10 days after catheter removal. It remains unclear whether there is any benefit from fungal prophylaxis.98 Recommendations are also provided for the treatment of mycobacterial, or tuberculous, peritonitis. Although this infection is a rare complication, it can be difficult to diagnose, and treatment requires multiple drugs.
Topical antibiotics and disinfectants appear to be effective agents for the prevention of exit-site infections.99–101 Gram-positive organisms should be treated with oral penicillinase-resistant penicillin or a first-generation cephalosporin such as cephalexin (Fig. 54–5). Rifampin may be added if necessary, in slowly resolving or particularly severe S. aureus infections. Vancomycin should be avoided in routine or empiric treatment of gram-positive catheter-related infections, but it will be necessary for methicillin-resistant S. aureus. Gram-negative organisms should be treated with oral quinolones. The effectiveness of oral quinolones may be diminished owing to the chelation drug interactions with divalent and trivalent metal ions, which are commonly taken by dialysis patients. Administration of quinolones should occur at least 2 hours prior to these drugs. In cases where Pseudomonas aeruginosa is the pathogen, a second antipseudomonal drug should be added. IPceftazidime may be considered. In all cases antibiotics should be continued until the exit site appears normal; 2 to 3 weeks of therapy may be necessary. A patient with a catheter-related infection that progresses to peritonitis will usually require catheter removal.90
Management strategy of exit-site infections for peritoneal dialysis patients. (IP, intraperitoneal; PO, orally.) (From reference 89)
Prevention of Peritonitis and Catheter Exit-Site Infections
Attempts to prevent peritonitis and catheter-related infections have included refinement of connector system technology (Luer-Lok connectors), enhanced patient training techniques, and the use of prophylactic antibiotic regimens and vaccines.102 Several studies have examined the impact of antibacterial agents as prophylaxis against both peritonitis and tunnel-related infections. Intermittent rifampin, 300 mg orally twice a day for 5 days, repeated every 3 months, appears to decrease the number of catheter-related infections but not the incidence of peritonitis. The efficacy of other antibiotic prophylaxis for peritonitis and catheter-related infections is limited. Long-term, extended-duration prophylaxis with penicillins or cephalosporins is not effective.90
Nasal carriage of S. aureus is associated with an increased risk of catheter-related infections and peritonitis. In addition, diabetic patients and those on immunosuppressive therapy are at increased risk for S. aureus catheter infections. Prophylaxis with intranasal mupirocin (twice daily for 5 to 7 days every month), mupirocin (daily) at the exit site, or oral rifampin can effectively reduce S. aureus exit-site infections. Because of the minimal toxicity of mupirocin and the risk of rifampin resistance, mupirocin regimens are preferred.90 However, it is important to note that S. aureus isolates with a high degree of resistance to mupirocin have been isolated from PD patients using prophylactic mupirocin at the peritoneal catheter exit site,103 although a recent study did not observe resistance patterns with the use of mupirocin. Patients in this study applied mupirocin to the exit-site either once or thrice weekly. After 3 years exit-site infections and peritonitis rates were significantly lower in the thrice weekly application group.104 In addition, gentamicin cream applied daily to the exit site has been found to effectively reduce both S. aureus and P. aeruginosa exit-site infections.90