Journal of Antimicrobial Chemotherapy (1990) 25, 853-859
Oral pefloxadn mesylate in the treatment of continuous ambulatory peritoneal dialysis associated peritonitis: an open non-comparative stndy T. F. Rose', R. Effis-Pegkr", J. Collins* and M. Small*
Twenty-two (15 female and 7 male) patients with continuous ambulatory peritoneal dialysis (CAPD) associated peritonitis were entered into an open non-comparative evaluation of oral pefloxacin mesylate. An initial loading dose of 800 mg was followed by 400 mg twice daily. Five patients were subsequently excluded or withdrawn. The mean age of the patients was 44 ± 12-6 years. All three Gram-negative infections (Escherichia coli, Acinctobacter calcoaceticus, Serratia liquefaciens) and all three culture negative infections were cured after 21 days treatment. In contrast one of four (25%) Staphylococcus aurens infections was cured, two persisted during treatment and one relapsed, after treatments of between 10 and 25 days. One of seven (14%) Slaph. epidermidis infections was cured, three persisted and three relapsed after treatments of between nine and 25 days. Two of the five persistent isolates became resistant: all four relapsed isolates remained sensitive. Twelve of the 22 (55%) patients had 16 side effects, most commonly skin or musculo-skeletal. Three stopped pefloxacin because of them, though one had taken an excessive dose in error. Pefloxacin mesylate is not optimal treatment for Gram-positive coccal peritonitis in patients on CAPD, but its role in Gram-negative disease needs further evaluation.
Introduction The major drawback of continuous ambulatory peritoneal dialysis (CAPD) is peritonitis. Seventy per cent of these episodes are caused by Gram-positive organisms, predominantly Staphylococcus epidermidis and Staph. aureus, 20% are caused by Gram-negative organisms and a further 10% are either fungal or culture negative (Rubin et al., 1980; Prowant el al., 1986). We are aware of only a few comparative but many uncontrolled studies of the efficacy of antibiotics in CAPD associated peritonitis. Intraperitoneal antibiotics, in particular second generation cephalosporins and vancomycin have become usual therapy. Parenterally and orally administered antibiotics are not often used because studies have shown either poor entry into dialysate (Glew et al., 1982; Somani et al., 1982; Blevins et al., 1984) or insufficient activity against the usual causative organisms for those antibiotics which do enter (Drew et al., 1984; Boeschoten et al., 1985). Pefloxacin mesylate is a new broad spectrum fluorinated quinolone. It has activity against both Staph. epidermidis and Staph. aureus, including methicillin resistant strains and is also active against Gram-negative bacilli including Pseudomonas sp. (Ligtvoet & Wickerhoff-Minoggio, 1985). It has high bioavailability when taken orally, a long 853 0305-7453/90/050853+07 $02.00/0
© 1990 The British Society for Antimicrobia] Chemotherapy
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'Infectious Diseases Unit; bRenal Unit, Auckland Hospital, Auckland, New Zealand
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plasma elimination half-life and no added toxicity has been shown in end-stage renal failure (Montay et al., 1985; Jungers et al., 1987). Oral ciprofloxacin and intravenous pefioxacin enter dialysate fluid and cure CAPDassociated peritonitis (Denis et al., 1987; Fleming et al., 1987; Scott, Fleming & Stewart, 1987) and we have shown orally administered pefloxacin mesylate achieves adequate plasma and dialysate levels (Rose et al., 1990). We continued that pharmacokinetic study to assess the efficacy of this antibiotic in the treatment of CAPD peritonitis. Materials and methods
Results
We began treatment of 22 patients and subsequently excluded or withdrew five. Fifteen were female and seven were male. The mean age was 44-0 ± 12-6 years and their mean
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The trial was accepted by the Auckland Hospital Research Ethics Committee and patients gave informed written consent to trial entry. We recruited patients between the ages of 18 and 65 with CAPD peritonitis. Initial entry was determined by the presence of a cloudy dialysate bag: subsequent inclusion was confirmed if there were greater than 100 x 106 white blood cells per litre of dialysate with more than 50% being polymorphonuclear leucocytes. Patients with organisms shown to be resistant on disc testing were later excluded. Patients were also excluded if they were terminally ill, pregnant, had a known allergy to quinolones, had impaired hepatic function prior to the acute illness (with serum aspartate transaminase, bilirubin, or alkaline phosphatase greater than three times normal), or were unable to take oral medications. Significant past illnesses were recorded and the patients were examined. The physical assessment was repeated during the study, at the end of treatment and at follow-up (at two to four weeks). Blood was taken for haematological and biochemical parameters on entry, during treatment, at the end of treatment and at follow-up. Dialysate samples were cultured prior to entry, during treatment after five days and ten days, at the end of treatment and at follow-up. The minimal inhibitory concentration (MIC) for each isolate was determined by the agar dilution method (Rose et al., 1990). Trial entrants were given an 800 mg oral loading dose of pefloxacin mesylate followed by 400 mg twice daily. If they had uncomplicated peritonitis they were to receive ten days of treatment. After an initial high failure rate with the first six patients with staphylococcal peritonitis we subsequently extended treatment to 21 days. In keeping with our routine practice we treated patients with clinical exit site infections complicating peritonitis for 21-30 days. Patients continued their usual peritoneal dialysis regimen except for stopping aluminium hydroxide and calcium-containing preparations because these may impair absorption of pefloxacin mesylate. The first six patients also underwent pharmacokinetic studies (Rose et al., 1990). We classified treatment failure as either persistence or relapse. All patients with culture of the original pathogen from peritoneal fluid at ten days had persistent infection: those with similar culture at five days and with continuing symptoms also had persistent infection. Patients who successfully finished the original treatment with sterile peritoneal fluid culture at that time, but subsequently had reculture of the original isolate from the peritoneal fluid within or at four weeks follow-up, had relapsed infection. Patients with initial eradication of infection and no relapse were cured.
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Table L Microbiological details and outcome
MIC Isolate Staph. aureus Staph. aureus Staph. aureus Staph. aureus Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Escherichia coli Acinetobacter calcoaceticus Serratia liquefaciens Sterile Sterile SterOe
(mg/1)
10 10 0-5 0-5 10 10 10 10 10 10 0-5 0-12
10 10 — — —
Duration (days) (actual/ intended) 10/10 10/10 12/21 25/30 10/10 10/10 10/10 9/21 21/21 9/21 25/30 21/21 21/21 21/21 20/21 22/21 22/21
C, Cure; R, relapse; P, persistence (see text for definitions).
MIC Outcome
R P P C P R R P C P R C C C
•c
'C 'C
(mg/1) (failed isolates)
10 20 40 — 20 10 20 20 — 80 0-5 — — — — — —
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weight was 71 -4 ± 14-1 kg. In addition to renal failure and peritonitis, three had diabetes mellitus, two systemic lupus erythematosus (SLE), one seronegative arthritis and one hidradenitis suppurativa. Fifteen patients were well enough to start treatment at home, two patients were in hospital already for other reasons and five patients were hospitalized because of their peritonitis. None were judged to be severely ill from their peritonitis. The median dialysate white cell count was 1000 (range 100-12,200) x 10*/l with mean percentage polymorphs of 86 ± 10%. The three patients excluded had streptococcal peritonitis. One patient withdrawn developed streptococcal superinfection after five days of pefloxacin treatment of an initial Staph. epidermidis peritonitis while the second patient withdrawn took extra pefloxacin tablets in error, developed nausea, stopped pefloxacin for that reason and was then changed to vancomycin. All the streptococci were resistant by disc testing but were subsequently shown to have MICs between 0-25 and 1-Omg/l. The remaining 17 patients form the basis of this report on microbiological efficacy and the details and outcome are tabulated in Table I. All 22 patients were evaluated for side effects (Table II). All three Gram-negative infections were cured after 21 days treatment. However only one of four (25%) Staph. aureus infections was cured, two patients having persistent organisms after 10 and 12 days of treatment respectively and one relapsing on follow-up. Similarly, only one of seven (14%) Staph. epidermidis infections was cured, three with persistent organisms at ten days of treatment and three relapsing on follow-up. Thus, overall, we cured only two of 11 (18%) staphylococcal infections. All five persistent isolates had higher MICs than on initial isolation, although only two isolates actually became resistant (one Staph. epidermidis and one Staph. aureus with increases from 1-0 to 8-0 after five days and 0-5 to 4-0 mg/1 after ten
856
T. F. Rose et aL Table IL Adverse reactions to pefloxacin (16 episodes in 12 of 22 patients) Reaction
n
Severity
Musculoskeletal
7
Skin
4
Gastrointestinal CNS
3 2
3 mild, 4 moderate 1 mild, 1 moderate, 2 severe 3 moderate 2 mild
Response Analgesic (1) Stop pefloxacin (2), doubtful relationship (1) Stop (1), reduce (2) pefloxacin Doubtful relationship (2)
Discussion The patients entered into this trial were typical of CAPD peritonitis in both their clinical presentation and the microbial aetiology (Prowant et al., 1986; Miller et al., 1990). Pefloxacin mesylate cured all three Gram negative infections and all three culture negative 'infections'. In contrast 45% (5 of 11) of the staphylococcal infections persisted after about ten days treatment and a further 36% (4 of 11) had relapsed at follow-up within four weeks of treatment stopping. Thus, overall, we cured only 18%
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days, respectively). In contrast three of the four relapsed isolates had identical sensitivities to those measured originally. Three patients with culture negative peritonitis recovered clinically and did not relapse during follow-up. All six patients who were studied pharmacokinetically achieved therapeutic concentrations greater than 1 mg/1 in the plasma within 30 min and in the dialysate within 4 h of starting treatment. Dialysate levels of pefloxacin reached a steady state of about 10 mg/1 after three days (Rose et al., 1990). We monitored patient compliance with pefloxacin medication. Five patients did not take tablets exactly as prescribed. One took twice the stated dose on the second and third days of treatment and withdrew on the fourth day because of nausea. Three took slightly fewer tablets than had been prescribed but were cured. One other patient took extra tablets but failed. We could not ascribe any adverse changes in clinical, haematological or biochemical parameters to pefloxacin treatment. Eight female and four male patients of the 22 entered (55%) experienced 16 side effects (Table II). Muscle and joint reactions were reported by seven patients (32%), presenting as aching leg muscles in two and Achilles tendonitis in five. All were mild to moderate in severity, resolving during pefloxacin treatment in two and after completing treatment in the other five. Four patients (18%) had skin reactions. None were photosensitivity reactions. Two were bullous eruptions: one was pseudoporphyria cutanea tarda which is a common skin lesion in dialysis patients and probably not pefloxacin-related: the other was a severe exacerbation of an SLE rash. This latter patient stopped pefloxacin because of this rash (although she was failing treatment as well) as did one of the two other patients with pruritis (although this patient was cured). Three patients had nausea and vomiting: in two the dose was decreased successfully but the third had taken excessive doses in error and withdrew because of this symptom. Two patients had minor central nervous system side effects, headache and tinnitus.
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of these infections, 25% (one of four) of those due to Staph. aureus and 14% (one of seven) of those due to Staph. epidermidis. This was a surprising result in view of the known efficacy of pefloxacin and other quinolones in staphylococcal infections and the ability of these drugs to enter both normal and inflamed tissue. In the pharmacokinetic phase of this study (Rose et al., 1990), we showed that pefloxacin reached concentrations well above these MICs in peritoneal dialysate within 4 h of initial dosing. We also knew that these concentrations persisted throughout treatment and that our patients were compliant Others have reported quinolones to be effective in staphylococcal CAPD peritonitis. Scott et al. (1987) cured all six episodes (one due to Staph. aureus and five due to Staph. epidermidis) with oral ciprofloxacin. Chan, Chu & Chan (1988) cured all six episodes of Staph. epidermidis CAPD peritonitis and three of four due to Staph. aureus with oral ofloxacin. Denis et al. (1987) cured three of four Staph. aureus and three of four Staph. epidermidis infections using an initial intravenous and subsequent oral dosing regimen of pefloxacin 400 mg daily for ten days. All these groups also showed effective penetration of the quinolone into peritoneal dialysate. The reasons for the apparently lower success rate for staphylococcal infection in this study are unknown, although there are several potential explanations for our poor results. Perhaps the most compelling is the recent demonstration (Weissauer-Condon, Engels & Daschinen, 1987) that the MICs of many organisms to quinolones (in particular pefloxacin, enoxacin, ciprofloxacin and ofloxacin) are raised, often to resistant levels, when measured in peritoneal dialysis fluid. They are also raised, but to a lesser extent, when measured in the fluid recovered at the end of dialysis. This latter fluid presumably represents most closely that in which antibiotics work for most of the time in the peritoneal cavity of patients with CAPD peritonitis. These in-vitro trends were generally most pronounced with pefloxacin, enoxacin and ofloxacin and least with ciprofloxacin. For all drugs the effect was most dramatic with Staph. epidermidis and Staph. aureus, so that these drugs might be ineffective against staphylococci. In contrast, however, all of them, and especially ciprofloxacin, should usually be effective against Gram-negative bacteria (with the probable exception of Pseudomonas aeruginosa), as we found. An alternative or perhaps additional explanation lies in the ability of Staph. epidermidis to become embedded in dense accumulations of extracellular slime on the peritoneal catheters (Evans & Holmes, 1987). Currently most episodes of peritonitis are treated with intraperitoneal antibiotic instilled through the peritoneal catheter there will certainly be antibiotic in the catheter lumen during treatment using this method. In contrast, oral treatment may result in little or no antibiotic in the catheter lumen. The dialysate might then be cleared of infection during oral antibiotic treatment, but once treatment was discontinued peritoneal reinfection would occur from sequestered Staph. epidermidis. Our relapse rate after treatment of Staph. epidermidis infection would be compatible with this explanation. Finally, development of resistance would obviously cause failure. It is interesting to note that all five staphylococci which persisted during pefloxacin treatment had increased MICs on reisolation. Two became frankly resistant, while the other three isolates had twofold increases. While we acknowledge the small numbers, of the four relapsed isolates only one had an MIC increase, and that only twofold, while the other three had MICs identical with pre-treatment values. If this observation were confirmed by others in larger series, it would provide support for the idea that the original
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Acknowledgements We thank Mrs Marianne Rendle of Rhone-Poulenc New Zealand Ltd for assistance with this trial and Rhone-Poulenc New Zealand Ltd for financial support. We thank the staff of the Clinical Microbiology Laboratory, Auckland Hospital, for organism identification and pefloxacin sensitivity data. Mrs Wignall typed the manuscript. References Blevins, R. D., Halstenson, C. E., Salem, N. G. & Matzke, G. R. (1984). Pharmacokinetics of vancomycin in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrobial Agents and Chemotherapy 25, 603-6. Boeschoten, E. W., Rietra, P. J. G. M., Krediet, R T., Visscr, M. J. & Arisz, L. (1985). CAPD peritonitis: a prospective randomized trial of oral versus intraperitoneal treatment with cephradine. Journal of Antimicrobial Chemotherapy 16, 789-97. Chan, M. K., Chau, P. Y. & Chan, W. W. N. (1988). Oral treatment of peritonitis in CAPD patients with two dosage regimens of ofloxacin. Journal of Antimicrobial Chemotherapy 22, 371-5. Denis, F., Mounier, M., Lagarde, C. & Benevent, D. (1987). Traitement des peritonites des insuffisants renaux en dialyse peritoneale continue ambulatoire par la pefloxacine. Resultats et pharmacocinetique. Pathologie Biologic 35, 652-5. Drew, P. J. T., Casewell, M. W., Desai, N., Houang, E. T., Simpson, C. N. & Marsh, F. P. (1984). Cephalexin for the oral treatment of CAPD peritonitis. Journal of Antimicrobial Chemotherapy 13, 153-9. Evans, R. C. & Holmes, C. J. (1987). Effect of vancomycin hydrochloride on Staphylococcus epidermidis biofilm associated with silicons elastomer. Antimicrobial Agents and Chemotherapy 31, 889-94. Fleming, L. W., Moreland, T. A., Scott, A. C , Stewart, W. K. & White, L. O. (1987). Ciprofloxacin in plasma and peritoneal dialysate after oral therapy in patients on continuous ambulatory peritoneal dialysis. Journal of Antimicrobial Chemotherapy 19, 493-503. Glcw, R. H., Pavuk, R. A., Shuster, A. & Alfred, H. J. (1982). Vancomycin pharmacokinetics in patients undergoing chronic intermittent peritoneal dialysis. International Journal of Clinical Pharmacology, Therapy and Toxicology 20, 559-63. Jungers, P., Gancval, D., Hannedouche, T., Prieur, B. & Montay, G. (1987). Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment. European Journal of Clinical Pharmacology 33, 463-7. Ligtvoet, E. E. J. & Wickerhoff-Minoggio, T. (1985). In-vitro activity of pefloxacin compared with six other quinolones. Journal of Antimicrobial Chemotherapy 16, 485-90.
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sensitive organisms, at relapse, have simply reinfected the peritoneal cavity from some sequestered antibiotic free site. Overall oral pefloxacin was not well tolerated by these patients with 55% recording some side effects and three patients having to stop the drug because of them. Seven developed aching calf muscles or frank Achilles tendonitis, a side effect not previously documented with pefloxacin. We acknowledge that open evaluations do not allow critical comparison. Nevertheless, we conclude that oral pefloxacin and probably most other quinolones are unlikely to be optimal agents for treating Gram-positive coccal peritonitis, despite their appealing pharmacokinetics. Oral pefloxacin could have a role as the Gram-negative component of combined treatments, or even as definitive treatment of proven Gramnegative infections, Nevertheless such an approach requires further evaluation and comparisons of efficacy and relative toxicity with presently used regimens.
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{Received 23 November 1989, accepted 11 January 1990)
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Miller, T. E., Ormrod, D. & Collins, J. (1990). Host defences and infection in dialysis patients. In Clinical Dialysis, 2nd edn (Nissenson, A. R., Fine, R. N. & Gentile, D. E., Eds), pp. 559-78. Appleton & Lange, East Norwalk, CT. Montay, G., Jacquot, C , Bariety, J. & Cunci, R. (1985). Phannacokinetics of pefloxacin in renal insufficiency. European Journal of Clinical Pharmacology 29, 345-9. Prowant, B., Nolph, K., Ryan, L., Twardowski, Z. & Khanna, R. (1986). Peritonitis in continuous ambulatory peritoneal dialysis: analysis of an 8-year experience. Nephron 43, 105-9. Rose, T. F., Bremncr, D. A., Collins, J., Ellis-Pcgler, R., Isaacs, R., Richardson, R. et al. (1990). Plasma and dialysate levels of pefloxacin and its metabolites in patients on continuous ambulatory peritoneal dialysis with peritonitis. Journal of Antimicrobial Chemotherapy 25, 657-64. Rubin, J., Rogers, W. A., Taylor, H. M., Everett, E. D., Prowant, B. F., Fruto, L. V. et al. (1980). Peritonitis during continuous ambulatory peritoneal dialysis. Annals of Internal Medicine 92, 7-13. Scott, A. C, Fleming, L. W. & Stewart, W. K. (1987). Efficacy of ciprofloxacin in treatment of CAPD peritonitis. European Journal of Clinical Microbiology 6, 599. Somani, P., Shapiro, R. S., Stockard, H. & Higgins, J. T. (1982). Unidirectional absorption of gentamidn from the peritoneum during continuous ambulatory peritoneal dialysis. Clinical Pharmacology and Therapeutics 32, 113-21. Weissauer-Condon, C , Engels, I. & Deschner, F. D. (1987). In vitro activity of four new quinolones in Mueller-Hinton broth and peritoneal dialysis fluid. European Journal of Clinical Microbiology 6, 324-6.
Oral pefloxadn mesylate in the treatment of continuous ambulatory peritoneal dialysis associated peritonitis: an open non-comparative stndy T. F. Rose', R. Effis-Pegkr", J. Collins* and M. Small*
Twenty-two (15 female and 7 male) patients with continuous ambulatory peritoneal dialysis (CAPD) associated peritonitis were entered into an open non-comparative evaluation of oral pefloxacin mesylate. An initial loading dose of 800 mg was followed by 400 mg twice daily. Five patients were subsequently excluded or withdrawn. The mean age of the patients was 44 ± 12-6 years. All three Gram-negative infections (Escherichia coli, Acinctobacter calcoaceticus, Serratia liquefaciens) and all three culture negative infections were cured after 21 days treatment. In contrast one of four (25%) Staphylococcus aurens infections was cured, two persisted during treatment and one relapsed, after treatments of between 10 and 25 days. One of seven (14%) Slaph. epidermidis infections was cured, three persisted and three relapsed after treatments of between nine and 25 days. Two of the five persistent isolates became resistant: all four relapsed isolates remained sensitive. Twelve of the 22 (55%) patients had 16 side effects, most commonly skin or musculo-skeletal. Three stopped pefloxacin because of them, though one had taken an excessive dose in error. Pefloxacin mesylate is not optimal treatment for Gram-positive coccal peritonitis in patients on CAPD, but its role in Gram-negative disease needs further evaluation.
Introduction The major drawback of continuous ambulatory peritoneal dialysis (CAPD) is peritonitis. Seventy per cent of these episodes are caused by Gram-positive organisms, predominantly Staphylococcus epidermidis and Staph. aureus, 20% are caused by Gram-negative organisms and a further 10% are either fungal or culture negative (Rubin et al., 1980; Prowant el al., 1986). We are aware of only a few comparative but many uncontrolled studies of the efficacy of antibiotics in CAPD associated peritonitis. Intraperitoneal antibiotics, in particular second generation cephalosporins and vancomycin have become usual therapy. Parenterally and orally administered antibiotics are not often used because studies have shown either poor entry into dialysate (Glew et al., 1982; Somani et al., 1982; Blevins et al., 1984) or insufficient activity against the usual causative organisms for those antibiotics which do enter (Drew et al., 1984; Boeschoten et al., 1985). Pefloxacin mesylate is a new broad spectrum fluorinated quinolone. It has activity against both Staph. epidermidis and Staph. aureus, including methicillin resistant strains and is also active against Gram-negative bacilli including Pseudomonas sp. (Ligtvoet & Wickerhoff-Minoggio, 1985). It has high bioavailability when taken orally, a long 853 0305-7453/90/050853+07 $02.00/0
© 1990 The British Society for Antimicrobia] Chemotherapy
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'Infectious Diseases Unit; bRenal Unit, Auckland Hospital, Auckland, New Zealand
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plasma elimination half-life and no added toxicity has been shown in end-stage renal failure (Montay et al., 1985; Jungers et al., 1987). Oral ciprofloxacin and intravenous pefioxacin enter dialysate fluid and cure CAPDassociated peritonitis (Denis et al., 1987; Fleming et al., 1987; Scott, Fleming & Stewart, 1987) and we have shown orally administered pefloxacin mesylate achieves adequate plasma and dialysate levels (Rose et al., 1990). We continued that pharmacokinetic study to assess the efficacy of this antibiotic in the treatment of CAPD peritonitis. Materials and methods
Results
We began treatment of 22 patients and subsequently excluded or withdrew five. Fifteen were female and seven were male. The mean age was 44-0 ± 12-6 years and their mean
Downloaded from http://jac.oxfordjournals.org/ at New York University on June 24, 2015
The trial was accepted by the Auckland Hospital Research Ethics Committee and patients gave informed written consent to trial entry. We recruited patients between the ages of 18 and 65 with CAPD peritonitis. Initial entry was determined by the presence of a cloudy dialysate bag: subsequent inclusion was confirmed if there were greater than 100 x 106 white blood cells per litre of dialysate with more than 50% being polymorphonuclear leucocytes. Patients with organisms shown to be resistant on disc testing were later excluded. Patients were also excluded if they were terminally ill, pregnant, had a known allergy to quinolones, had impaired hepatic function prior to the acute illness (with serum aspartate transaminase, bilirubin, or alkaline phosphatase greater than three times normal), or were unable to take oral medications. Significant past illnesses were recorded and the patients were examined. The physical assessment was repeated during the study, at the end of treatment and at follow-up (at two to four weeks). Blood was taken for haematological and biochemical parameters on entry, during treatment, at the end of treatment and at follow-up. Dialysate samples were cultured prior to entry, during treatment after five days and ten days, at the end of treatment and at follow-up. The minimal inhibitory concentration (MIC) for each isolate was determined by the agar dilution method (Rose et al., 1990). Trial entrants were given an 800 mg oral loading dose of pefloxacin mesylate followed by 400 mg twice daily. If they had uncomplicated peritonitis they were to receive ten days of treatment. After an initial high failure rate with the first six patients with staphylococcal peritonitis we subsequently extended treatment to 21 days. In keeping with our routine practice we treated patients with clinical exit site infections complicating peritonitis for 21-30 days. Patients continued their usual peritoneal dialysis regimen except for stopping aluminium hydroxide and calcium-containing preparations because these may impair absorption of pefloxacin mesylate. The first six patients also underwent pharmacokinetic studies (Rose et al., 1990). We classified treatment failure as either persistence or relapse. All patients with culture of the original pathogen from peritoneal fluid at ten days had persistent infection: those with similar culture at five days and with continuing symptoms also had persistent infection. Patients who successfully finished the original treatment with sterile peritoneal fluid culture at that time, but subsequently had reculture of the original isolate from the peritoneal fluid within or at four weeks follow-up, had relapsed infection. Patients with initial eradication of infection and no relapse were cured.
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Table L Microbiological details and outcome
MIC Isolate Staph. aureus Staph. aureus Staph. aureus Staph. aureus Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Staph. epidermidis Escherichia coli Acinetobacter calcoaceticus Serratia liquefaciens Sterile Sterile SterOe
(mg/1)
10 10 0-5 0-5 10 10 10 10 10 10 0-5 0-12
10 10 — — —
Duration (days) (actual/ intended) 10/10 10/10 12/21 25/30 10/10 10/10 10/10 9/21 21/21 9/21 25/30 21/21 21/21 21/21 20/21 22/21 22/21
C, Cure; R, relapse; P, persistence (see text for definitions).
MIC Outcome
R P P C P R R P C P R C C C
•c
'C 'C
(mg/1) (failed isolates)
10 20 40 — 20 10 20 20 — 80 0-5 — — — — — —
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weight was 71 -4 ± 14-1 kg. In addition to renal failure and peritonitis, three had diabetes mellitus, two systemic lupus erythematosus (SLE), one seronegative arthritis and one hidradenitis suppurativa. Fifteen patients were well enough to start treatment at home, two patients were in hospital already for other reasons and five patients were hospitalized because of their peritonitis. None were judged to be severely ill from their peritonitis. The median dialysate white cell count was 1000 (range 100-12,200) x 10*/l with mean percentage polymorphs of 86 ± 10%. The three patients excluded had streptococcal peritonitis. One patient withdrawn developed streptococcal superinfection after five days of pefloxacin treatment of an initial Staph. epidermidis peritonitis while the second patient withdrawn took extra pefloxacin tablets in error, developed nausea, stopped pefloxacin for that reason and was then changed to vancomycin. All the streptococci were resistant by disc testing but were subsequently shown to have MICs between 0-25 and 1-Omg/l. The remaining 17 patients form the basis of this report on microbiological efficacy and the details and outcome are tabulated in Table I. All 22 patients were evaluated for side effects (Table II). All three Gram-negative infections were cured after 21 days treatment. However only one of four (25%) Staph. aureus infections was cured, two patients having persistent organisms after 10 and 12 days of treatment respectively and one relapsing on follow-up. Similarly, only one of seven (14%) Staph. epidermidis infections was cured, three with persistent organisms at ten days of treatment and three relapsing on follow-up. Thus, overall, we cured only two of 11 (18%) staphylococcal infections. All five persistent isolates had higher MICs than on initial isolation, although only two isolates actually became resistant (one Staph. epidermidis and one Staph. aureus with increases from 1-0 to 8-0 after five days and 0-5 to 4-0 mg/1 after ten
856
T. F. Rose et aL Table IL Adverse reactions to pefloxacin (16 episodes in 12 of 22 patients) Reaction
n
Severity
Musculoskeletal
7
Skin
4
Gastrointestinal CNS
3 2
3 mild, 4 moderate 1 mild, 1 moderate, 2 severe 3 moderate 2 mild
Response Analgesic (1) Stop pefloxacin (2), doubtful relationship (1) Stop (1), reduce (2) pefloxacin Doubtful relationship (2)
Discussion The patients entered into this trial were typical of CAPD peritonitis in both their clinical presentation and the microbial aetiology (Prowant et al., 1986; Miller et al., 1990). Pefloxacin mesylate cured all three Gram negative infections and all three culture negative 'infections'. In contrast 45% (5 of 11) of the staphylococcal infections persisted after about ten days treatment and a further 36% (4 of 11) had relapsed at follow-up within four weeks of treatment stopping. Thus, overall, we cured only 18%
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days, respectively). In contrast three of the four relapsed isolates had identical sensitivities to those measured originally. Three patients with culture negative peritonitis recovered clinically and did not relapse during follow-up. All six patients who were studied pharmacokinetically achieved therapeutic concentrations greater than 1 mg/1 in the plasma within 30 min and in the dialysate within 4 h of starting treatment. Dialysate levels of pefloxacin reached a steady state of about 10 mg/1 after three days (Rose et al., 1990). We monitored patient compliance with pefloxacin medication. Five patients did not take tablets exactly as prescribed. One took twice the stated dose on the second and third days of treatment and withdrew on the fourth day because of nausea. Three took slightly fewer tablets than had been prescribed but were cured. One other patient took extra tablets but failed. We could not ascribe any adverse changes in clinical, haematological or biochemical parameters to pefloxacin treatment. Eight female and four male patients of the 22 entered (55%) experienced 16 side effects (Table II). Muscle and joint reactions were reported by seven patients (32%), presenting as aching leg muscles in two and Achilles tendonitis in five. All were mild to moderate in severity, resolving during pefloxacin treatment in two and after completing treatment in the other five. Four patients (18%) had skin reactions. None were photosensitivity reactions. Two were bullous eruptions: one was pseudoporphyria cutanea tarda which is a common skin lesion in dialysis patients and probably not pefloxacin-related: the other was a severe exacerbation of an SLE rash. This latter patient stopped pefloxacin because of this rash (although she was failing treatment as well) as did one of the two other patients with pruritis (although this patient was cured). Three patients had nausea and vomiting: in two the dose was decreased successfully but the third had taken excessive doses in error and withdrew because of this symptom. Two patients had minor central nervous system side effects, headache and tinnitus.
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of these infections, 25% (one of four) of those due to Staph. aureus and 14% (one of seven) of those due to Staph. epidermidis. This was a surprising result in view of the known efficacy of pefloxacin and other quinolones in staphylococcal infections and the ability of these drugs to enter both normal and inflamed tissue. In the pharmacokinetic phase of this study (Rose et al., 1990), we showed that pefloxacin reached concentrations well above these MICs in peritoneal dialysate within 4 h of initial dosing. We also knew that these concentrations persisted throughout treatment and that our patients were compliant Others have reported quinolones to be effective in staphylococcal CAPD peritonitis. Scott et al. (1987) cured all six episodes (one due to Staph. aureus and five due to Staph. epidermidis) with oral ciprofloxacin. Chan, Chu & Chan (1988) cured all six episodes of Staph. epidermidis CAPD peritonitis and three of four due to Staph. aureus with oral ofloxacin. Denis et al. (1987) cured three of four Staph. aureus and three of four Staph. epidermidis infections using an initial intravenous and subsequent oral dosing regimen of pefloxacin 400 mg daily for ten days. All these groups also showed effective penetration of the quinolone into peritoneal dialysate. The reasons for the apparently lower success rate for staphylococcal infection in this study are unknown, although there are several potential explanations for our poor results. Perhaps the most compelling is the recent demonstration (Weissauer-Condon, Engels & Daschinen, 1987) that the MICs of many organisms to quinolones (in particular pefloxacin, enoxacin, ciprofloxacin and ofloxacin) are raised, often to resistant levels, when measured in peritoneal dialysis fluid. They are also raised, but to a lesser extent, when measured in the fluid recovered at the end of dialysis. This latter fluid presumably represents most closely that in which antibiotics work for most of the time in the peritoneal cavity of patients with CAPD peritonitis. These in-vitro trends were generally most pronounced with pefloxacin, enoxacin and ofloxacin and least with ciprofloxacin. For all drugs the effect was most dramatic with Staph. epidermidis and Staph. aureus, so that these drugs might be ineffective against staphylococci. In contrast, however, all of them, and especially ciprofloxacin, should usually be effective against Gram-negative bacteria (with the probable exception of Pseudomonas aeruginosa), as we found. An alternative or perhaps additional explanation lies in the ability of Staph. epidermidis to become embedded in dense accumulations of extracellular slime on the peritoneal catheters (Evans & Holmes, 1987). Currently most episodes of peritonitis are treated with intraperitoneal antibiotic instilled through the peritoneal catheter there will certainly be antibiotic in the catheter lumen during treatment using this method. In contrast, oral treatment may result in little or no antibiotic in the catheter lumen. The dialysate might then be cleared of infection during oral antibiotic treatment, but once treatment was discontinued peritoneal reinfection would occur from sequestered Staph. epidermidis. Our relapse rate after treatment of Staph. epidermidis infection would be compatible with this explanation. Finally, development of resistance would obviously cause failure. It is interesting to note that all five staphylococci which persisted during pefloxacin treatment had increased MICs on reisolation. Two became frankly resistant, while the other three isolates had twofold increases. While we acknowledge the small numbers, of the four relapsed isolates only one had an MIC increase, and that only twofold, while the other three had MICs identical with pre-treatment values. If this observation were confirmed by others in larger series, it would provide support for the idea that the original
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Acknowledgements We thank Mrs Marianne Rendle of Rhone-Poulenc New Zealand Ltd for assistance with this trial and Rhone-Poulenc New Zealand Ltd for financial support. We thank the staff of the Clinical Microbiology Laboratory, Auckland Hospital, for organism identification and pefloxacin sensitivity data. Mrs Wignall typed the manuscript. References Blevins, R. D., Halstenson, C. E., Salem, N. G. & Matzke, G. R. (1984). Pharmacokinetics of vancomycin in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrobial Agents and Chemotherapy 25, 603-6. Boeschoten, E. W., Rietra, P. J. G. M., Krediet, R T., Visscr, M. J. & Arisz, L. (1985). CAPD peritonitis: a prospective randomized trial of oral versus intraperitoneal treatment with cephradine. Journal of Antimicrobial Chemotherapy 16, 789-97. Chan, M. K., Chau, P. Y. & Chan, W. W. N. (1988). Oral treatment of peritonitis in CAPD patients with two dosage regimens of ofloxacin. Journal of Antimicrobial Chemotherapy 22, 371-5. Denis, F., Mounier, M., Lagarde, C. & Benevent, D. (1987). Traitement des peritonites des insuffisants renaux en dialyse peritoneale continue ambulatoire par la pefloxacine. Resultats et pharmacocinetique. Pathologie Biologic 35, 652-5. Drew, P. J. T., Casewell, M. W., Desai, N., Houang, E. T., Simpson, C. N. & Marsh, F. P. (1984). Cephalexin for the oral treatment of CAPD peritonitis. Journal of Antimicrobial Chemotherapy 13, 153-9. Evans, R. C. & Holmes, C. J. (1987). Effect of vancomycin hydrochloride on Staphylococcus epidermidis biofilm associated with silicons elastomer. Antimicrobial Agents and Chemotherapy 31, 889-94. Fleming, L. W., Moreland, T. A., Scott, A. C , Stewart, W. K. & White, L. O. (1987). Ciprofloxacin in plasma and peritoneal dialysate after oral therapy in patients on continuous ambulatory peritoneal dialysis. Journal of Antimicrobial Chemotherapy 19, 493-503. Glcw, R. H., Pavuk, R. A., Shuster, A. & Alfred, H. J. (1982). Vancomycin pharmacokinetics in patients undergoing chronic intermittent peritoneal dialysis. International Journal of Clinical Pharmacology, Therapy and Toxicology 20, 559-63. Jungers, P., Gancval, D., Hannedouche, T., Prieur, B. & Montay, G. (1987). Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment. European Journal of Clinical Pharmacology 33, 463-7. Ligtvoet, E. E. J. & Wickerhoff-Minoggio, T. (1985). In-vitro activity of pefloxacin compared with six other quinolones. Journal of Antimicrobial Chemotherapy 16, 485-90.
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sensitive organisms, at relapse, have simply reinfected the peritoneal cavity from some sequestered antibiotic free site. Overall oral pefloxacin was not well tolerated by these patients with 55% recording some side effects and three patients having to stop the drug because of them. Seven developed aching calf muscles or frank Achilles tendonitis, a side effect not previously documented with pefloxacin. We acknowledge that open evaluations do not allow critical comparison. Nevertheless, we conclude that oral pefloxacin and probably most other quinolones are unlikely to be optimal agents for treating Gram-positive coccal peritonitis, despite their appealing pharmacokinetics. Oral pefloxacin could have a role as the Gram-negative component of combined treatments, or even as definitive treatment of proven Gramnegative infections, Nevertheless such an approach requires further evaluation and comparisons of efficacy and relative toxicity with presently used regimens.
Oral pefloxadn to CAPD peritonltfa
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{Received 23 November 1989, accepted 11 January 1990)
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Miller, T. E., Ormrod, D. & Collins, J. (1990). Host defences and infection in dialysis patients. In Clinical Dialysis, 2nd edn (Nissenson, A. R., Fine, R. N. & Gentile, D. E., Eds), pp. 559-78. Appleton & Lange, East Norwalk, CT. Montay, G., Jacquot, C , Bariety, J. & Cunci, R. (1985). Phannacokinetics of pefloxacin in renal insufficiency. European Journal of Clinical Pharmacology 29, 345-9. Prowant, B., Nolph, K., Ryan, L., Twardowski, Z. & Khanna, R. (1986). Peritonitis in continuous ambulatory peritoneal dialysis: analysis of an 8-year experience. Nephron 43, 105-9. Rose, T. F., Bremncr, D. A., Collins, J., Ellis-Pcgler, R., Isaacs, R., Richardson, R. et al. (1990). Plasma and dialysate levels of pefloxacin and its metabolites in patients on continuous ambulatory peritoneal dialysis with peritonitis. Journal of Antimicrobial Chemotherapy 25, 657-64. Rubin, J., Rogers, W. A., Taylor, H. M., Everett, E. D., Prowant, B. F., Fruto, L. V. et al. (1980). Peritonitis during continuous ambulatory peritoneal dialysis. Annals of Internal Medicine 92, 7-13. Scott, A. C, Fleming, L. W. & Stewart, W. K. (1987). Efficacy of ciprofloxacin in treatment of CAPD peritonitis. European Journal of Clinical Microbiology 6, 599. Somani, P., Shapiro, R. S., Stockard, H. & Higgins, J. T. (1982). Unidirectional absorption of gentamidn from the peritoneum during continuous ambulatory peritoneal dialysis. Clinical Pharmacology and Therapeutics 32, 113-21. Weissauer-Condon, C , Engels, I. & Deschner, F. D. (1987). In vitro activity of four new quinolones in Mueller-Hinton broth and peritoneal dialysis fluid. European Journal of Clinical Microbiology 6, 324-6.
