Serious infection with vancomycin-resistant enterococci (VRE) usually occurs in patients with significantly compromised host defences and serious co-morbidities, and this magnifies the importance of effective antimicrobial treatment. Assessments of antibacterial efficacy against VRE have been hampered by the lack of a comparator treatment arm(s), complex treatment requirements including surgery, and advanced illness-severity associated with a high crude mortality. Treatment options include available agents which don't have a specific VRE approval (chloramphenicol, doxycycline, high-dose ampicillin or ampicillin/sulbactam), and nitrofurantoin (for lower urinary tract infection). The role of antimicrobial combinations that have shown in vitro or animal-model in vivo efficacy has yet to be established. Two novel antimicrobial agents (quinupristin/ dalfopristin and linezolid) have emerged as approved therapeutic options for vancomycin-resistant Enterococcus faecium on the basis of in vitro susceptibility and clinical efficacy from multicentre, pharmaceutical company-sponsored clinical trials. Quinupristin/dalfopristin is a streptogramin, which impairs bacterial protein synthesis at both early peptide chain elongation and late peptide chain extrusion steps. It has bacteriostatic activity against vancomycin-resistant E. faecium [minimum concentration to inhibit growth of 90% of isolates (MIC(90)) = 2 microg/ml] but is not active against Enterococcus faecalis (MIC(90 )= 16 microg/ml). In a noncomparative, nonblind, emergency-use programme in patients who were infected with Gram-positive isolates resistant or refractory to conventional therapy or who were intolerant of conventional therapy, quinupristin/dalfopristin was administered at 7.5 mg/kg every 8 hours. The clinical response rate in the bacteriologically evaluable subset was 70.5%, and a 65.8% overall response (favourable clinical and bacteriological outcome) was observed. Resistance to quinupristin/dalfopristin on therapy was observed in 6/338 (1.8%) of VRE strains. Myalgia/arthralgia was the most frequent treatment-limiting adverse effect. In vitro studies which combine quinupristin/dalfopristin with ampicillin or doxycyline have shown enhanced killing effects against VRE; however, the clinical use of combined therapy remains unestablished. Linezolid, an oxazolidinone compound that acts by inhibiting the bacterial pre-translational initiation complex formation, has bacteriostatic activity against both vancomycin resistant E. faecium (MIC(90) = 2 to 4 microg/ml) and E. faecalis (MIC(90) = 2 to 4 microg/ml). This agent was studied in a similar emergency use protocol for multi-resistant Gram-positive infections. 55 of 133 evaluable patients were infected with VRE. Cure rates for the most common sites were complicated skin and soft tissue 87.5% (7/8), primary bacteraemia 90.9% (10/11), peritonitis 91.7% (11/12), other abdominal/pelvic infections 91.7% (11/12), and catheter-related bacteraemia 100% (9/9). There was an all-site response rate of 92.6% (50/54). In a separate blinded, randomised, multicentre trial for VRE infection at a variety of sites, intravenous low dose linezolid (200mg every 12 hours) was compared to high dose therapy (600 mg every 12 hours) with optional conversion to oral administration. A positive dose response (although statistically nonsignificant) was seen with a 67% (39/58) and 52% (24/46) cure rate in the high- and low-dose groups, respectively. Adverse effects of linezolid therapy have been predominantly gastrointestinal (nausea, vomiting, diarrhoea), headache and taste alteration. Reports of thrombocytopenia appear to be limited to patients receiving somewhat longer courses of treatment (>14 to 21 days). Linezolid resistance (MIC > or = 8 microg/ml) has been reported in a small number of E. faecium strains which appears to be secondary to a base-pair mutation in the genome encoding for the bacterial 23S ribosome binding site. At present a comparative study between the two approved agents for VRE (quinupristin/dalfopristin and linezolid) has not been performed. Several investigational agents are currently in phase II or III trials for VRE infection. This category includes daptomycin (an acidic lipopeptide), oritavancin (LY-333328; a glycopeptide), and tigilcycline (GAR-936; a novel analogue of minocycline). Finally, strategies to suppress or eradicate the VRE intestinal reservoir have been reported for the combination of oral doxycyline plus bacitracin and oral ramoplanin (a novel glycolipodepsipeptide). If successful, a likely application of such an approach is the reduction of VRE infection during high risk periods in high risk patient groups such as the post-chemotherapy neutropenic nadir or early post-solid abdominal organ transplantation.

Treatment options for vancomycin-resistant enterococcal infections.

Peritoneal dialysis (PD)-associated peritonitis is a serious complication of PD and prevention and treatment of such is important in reducing patient morbidity and mortality. The ISPD 2022 updated recommendations have revised and clarified definitions for refractory peritonitis, relapsing peritonitis, peritonitis-associated catheter removal, PD-associated haemodialysis transfer, peritonitis-associated death and peritonitis-associated hospitalisation. New peritonitis categories and outcomes including pre-PD peritonitis, enteric peritonitis, catheter-related peritonitis and medical cure are defined. The new targets recommended for overall peritonitis rate should be no more than 0.40 episodes per year at risk and the percentage of patients free of peritonitis per unit time should be targeted at &gt;80% per year. Revised recommendations regarding management of contamination of PD systems, antibiotic prophylaxis for invasive procedures and PD training and reassessment are included. New recommendations regarding management of modifiable peritonitis risk factors like domestic pets, hypokalaemia and histamine-2 receptor antagonists are highlighted. Updated recommendations regarding empirical antibiotic selection and dosage of antibiotics and also treatment of peritonitis due to specific microorganisms are made with new recommendation regarding adjunctive oral N-acetylcysteine therapy for mitigating aminoglycoside ototoxicity. Areas for future research in prevention and treatment of PD-related peritonitis are suggested. 

ISPD peritonitis guideline recommendations: 2022 update on prevention and treatment

Quinupristin/dalfopristin: a therapeutic review.

Peritoneal dialysis (PD)-associated peritonitis is a serious complication of PD and prevention and treatment of such is important in reducing patient morbidity and mortality. The ISPD 2022 updated recommendations have revised and clarified definitions for refractory peritonitis, relapsing peritonitis, peritonitis-associated catheter removal, PD-associated haemodialysis transfer, peritonitis-associated death and peritonitis-associated hospitalisation. New peritonitis categories and outcomes including pre-PD peritonitis, enteric peritonitis, catheter-related peritonitis and medical cure are defined. The new targets recommended for overall peritonitis rate should be no more than 0.40 episodes per year at risk and the percentage of patients free of peritonitis per unit time should be targeted at >80% per year. Revised recommendations regarding management of contamination of PD systems, antibiotic prophylaxis for invasive procedures and PD training and reassessment are included. New recommendations regarding management of modifiable peritonitis risk factors like domestic pets, hypokalaemia and histamine-2 receptor antagonists are highlighted. Updated recommendations regarding empirical antibiotic selection and dosage of antibiotics and also treatment of peritonitis due to specific microorganisms are made with new recommendation regarding adjunctive oral N-acetylcysteine therapy for mitigating aminoglycoside ototoxicity. Areas for future research in prevention and treatment of PD-related peritonitis are suggested.

The prevalence of antimicrobial-resistant microorganisms in various health care settings, including outpatient dialysis facilities, has increased dramatically in the last decade. Antimicrobial use and patient-to-patient transmission of resistant strains are the two main factors that have contributed to this rapid increase. Methicillin-resistant Staphylococcus aureus (MRSA) and coagulase-negative staphylococci are commonly isolated as a cause of hemodialysis (HD) catheter-related bacteremia and peritoneal dialysis (PD)-related catheter infection and peritonitis. The widespread use of vancomycin in dialysis patients is of concern because of an increase in the prevalence of vancomycin-resistant enterococci (VRE) in dialysis patients. Staphylococci with reduced sensitivity to vancomycin have also appeared in dialysis patients. A more recent problem is the appearance of S. aureus isolates with a high degree of resistance to the topical antimicrobial agent mupirocin. This has been seen in PD patients who have received prophylactic application of mupirocin at the peritoneal catheter exit site. Appropriate antimicrobial use will help protect the efficacy of currently used antibiotics, such as vancomycin. Published guidelines for use of vancomycin should be followed. New antimicrobials such as linezolid and quinupristin/dalfopristin have activity against VRE and MRSA, but resistance to these agents has already occurred. Preventing transmission of antimicrobial-resistant microorganisms in health care settings, including outpatient dialysis facilities, is important in limiting the spread of these resistant organisms.

Infection with antimicrobial-resistant microorganisms in dialysis patients.

Quinupristin-dalfopristin may be useful for treatment of organisms causing peritoneal dialysis-related peritonitis, including methicillin-resistant coagulase-negative staphylococci, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci. The pharmacokinetic profiles of single intravenous doses of this combination streptogramin antibiotic of 7.5 mg/kg of body weight were characterized for eight noninfected patients receiving continuous ambulatory peritoneal dialysis. Comparison was made to pharmacokinetic profiles determined for eight healthy volunteers matched by age, sex, and race. Drug was measured in dialysate up to 6 h following the dose. Plasma and dialysate were assayed for parent compounds and metabolites. Mean pharmacokinetic parameters were compared between groups. No statistically significant differences were observed between groups for maximal concentrations in plasma, times to maximal concentration, areas under the curve, distribution volumes, rates of total body clearance, or half-lives in plasma for quinupristin and dalfopristin. No statistically significant differences were observed in maximal concentrations in plasma, times to maximal concentration, areas under the curve, or half-lives for cysteine, the glutathione conjugates of quinupristin, or the pristinamycin IIA metabolite of dalfopristin. The measurements in dialysate of the parent and most metabolites were below the expected MICs. Dialysis clearance was insignificant. Quinupristin-dalfopristin was well tolerated in both groups, causing only mild adverse events that resolved prior to discharge from the study. The disposition of quinupristin, dalfopristin, or their primary metabolites following a single dose was unaltered in patients receiving peritoneal dialysis. Intravenous dosing of this antibiotic combination is unlikely to be adequate for the treatment of peritonitis associated with peritoneal dialysis.

Claude A. Taylor

Papers

Pharmacokinetics of Quinupristin-Dalfopristin in Continuous Ambulatory Peritoneal Dialysis Patients