Eur J Clin Microbiol Infect Dis DOI 10.1007/s10096-014-2079-x
REVIEW
Mycobacterium chelonae peritonitis in peritoneal dialysis. Literature review M. Kunin & A. Knecht & E. J. Holtzman
Received: 16 December 2013 / Accepted: 4 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Non-tuberculous mycobacteria are a rare but serious cause of peritoneal dialysis-related peritonitis. There are no clear guidelines for treating non-tuberculous mycobacteria peritoneal dialysis-associated infections. It has been recommended that at least two antibiotics be given for a prolonged period and peritoneal catheter should be removed. This paper describes the clinical course and treatment of a patient with M. chelonae peritoneal dialysis-related peritonitis and reviews the previously published cases.
Introduction Bacterial peritonitis is the most common complication of peritoneal dialysis (PD) and often is the reason for discontinuing PD. The vast majority of PD-associated peritonitis cases are caused by common gram-positive and gramnegative bacteria, such as coagulase-negative staphylococci, Staphylococcus aureus, and Pseudomonas aeruginosa. However, in the presence of clinical evidence of peritonitis and negative routine dialysate culture, mycobacteria and fungi (other than the Candida species, which grow readily in routine cultures) are potential pathogens. Nontuberculous mycobacteria (NTMs) are defined as Mycobacterium species other than M. tuberculosis and M. leprae [1, 2]. The International Society for Peritoneal Dialysis (ISPD) guidelines for PD-related infections [3] provide little information on non-tuberculous mycobacterial peritonitis. The treatment protocol for this type of infection is not well established [3]. M. Kunin (*) : A. Knecht : E. J. Holtzman Nephrology and Hypertension Institute, Sheba Medical Center and Sackler Faculty of Medicine, Tel-Hashomer, Israel e-mail: [email protected]
M. chelonae belong to the group of rapidly growing nontuberculous mycobacteria. Skin, bone, and soft tissue disease are the most common clinical manifestations of M. chelonae infection. Disseminated M. chelonae disease can also occur in immunocompromised patients and presents with characteristic skin lesions. Epidemic and sporadic cases of keratitis caused by M. chelonae have been associated with contact lens wear and ocular surgery, particularly laserassisted in situ keratomileusis (LASIK) [1]. The optimum type and duration of therapy has yet to be defined. M. chelonae appears to be more resistant to antimicrobial agents than M. fortuitum, with unpredictable antibiotic susceptibility. For serious skin, bone, and soft tissue disease, a minimum of 4 months of a combination drug therapy is necessary. Removal of foreign bodies, such as breast implants and percutaneous catheters, is important, or even essential, to recovery [1]. In this paper we described the case of M. chelonae PDrelated peritonitis and reviewed the previously published cases.
Case report A 54-year-old man with a history of hypertension, hyperlipidemia, gout, nephrolitiasis and hepatitis B infection was diagnosed with end-stage renal disease (ESRD) caused by chronic glomerulonephritis. He had been on peritoneal dialysis for 3 years. The patient practiced continuous ambulatory peritoneal dialysis. He used conventional low pH 2.5 % dextrose dialysis solution—four exchanges of two liters each per day. Ten months before his current presentation the patient was treated with oral amoxicillin due to bronchitis and a week later received prednisone 10 mg per day with tapering off for 2 weeks due to gouty arthritis. Since then he had no history of infections, including PD-associated infections, and did not take immunosuppressive drugs.
Eur J Clin Microbiol Infect Dis
The patient presented to the peritoneal dialysis facility with cloudy dialysate. Dialysate effluent analysis revealed a total white blood cell (WBC) count of 400 cells/mm³, with 70 % granulocytes. Peritonitis was suspected and the patient was treated empirically with intraperitoneal cefuroxime and ceftazidime. A day later, he was hospitalized due to fever and abdominal pain. Physical examination found abdominal tenderness, body temperature was 38.0°, blood pressure 141/90 mmHg and pulse 91 per minute. Laboratory studies revealed a peripheral WBC count of 10,290 K/microL with 80 % polymorphonuclear leukocytes (PMN); serum hemoglobin was 12.2 g/dl and serum C-reactive protein (CRP) 48 mg/l. Peritoneal fluid analysis returned with 490 cells/ mm³ WBC and with 30 % granulocytes. Tenckhoff catheter exit site was unremarkable. A computed tomography (CT) scan of the abdomen revealed no abscess or bowel obstruction. The empirical treatment for bacterial peritonitis was continued. During the following days of hospitalization the patient complained of abdominal pain and the abdomen remained tender on palpation. Peritoneal effluent white blood cell count continued to rise (Fig. 1a). On the fourth treatment day intraperitoneal vancomycin was added to antibiotic regimen. Two days later intravenous ceftazidime and vancomycin were started. After 7 days of empirical antibiotic treatment the patient did not improve clinically, peritoneal effluent white blood cell count was high (Fig. 1a), and serum C-reactive protein (CRP) continued to increase (Fig. 1b). Peritoneal culture tests remained negative. The peritoneal catheter was removed on the seventh day after the initial presentation and hemodialysis (HD) was started. The patient continued treatment with intravenous ceftazidime and vancomycin. After Tenckhoff catheter removal the patient’s clinical condition started to improve. Serum CRP decreased (Fig. 1b). Nine days after the patient’s presentation culture of the peritoneal fluid yielded a rapidly growing mycobacterium. Five days later gene sequencing by polymerase chain reaction of the isolate identified it to be Mycobacterium chelonae. The patient was doing well, therefore, the decision was made to wait for in vitro antimicrobial susceptibility results before specific antibiotic treatment initiation. Since in vitro antimicrobial sensitivities results were pending, oral clarithromycin of 500 mg per day on day 23 and intravenous amikacin in dose 5 mg/kg after hemodialysis session on day 27 were eventually started. Four days later the result showing resistance to amikacin arrived, therefore it was stopped. Additional 3 days took to complete all the sensitivities. Final antimicrobial sensitivities of the isolate demonstrated sensitivity only to clarithromycin. The bacterium was resistant to imipenem, ciprofloxacin, amikacin, cefoxitin, doxycycline and trimetoprim/sulfamethoxazole and showed intermediate sensitivity to tobramycin. Abdominal and pelvic CT searching for
Fig. 1 Peritoneal fluid white blood cell (WBC) count (a) and serum Creactive protein (CRP) concentration (b) during patient’s follow-up
possible intraabdominal complications was performed. Compared to CT examination at admission, it demonstrated prominent omentum infiltration and moderate amount of ascites. Peritoneal punction and centesis for WBC count and culture were considered. However, the patient refused this invasive procedure. The patient continued doing well. Follow-up CT performed 6 weeks later demonstrated improvement in omentum infiltration and disappearance of peritoneal fluid. The patient completed a 6-month clarithromycin course and remained free of ascites or signs and symptoms of peritonitis. He chose to stay on hemodialysis. After the completion of the antibiotic course he was return to the waiting list for kidney transplantation.
Literature review Ten cases of PD peritonitis due to M. chelonae were reported in English literature [4–11]. One of those reports, a population-based cohort study from Australia [11], did not provide detailed patient information. There are also few reports of M. chelonae infection at the catheter exit site, without peritonitis [12–15]. Those cases are not reviewed here. The geographic spread of PD peritonitis due to M. chelonae included reports from North America (4 patients), Asia (2 patients), Europe (2 patients) and Australia (2 patients) with none from the Middle East.
Bowel perforation Abdominal abscess No NM NM No Yes Yes Yes Yes No Yes 6 6 1.5 NM NM 6
Adhesion, ileus Yes 4.5
No No Yes Yes 6 2
No Yes Yes NM NM No
19 14 11 NM NM 23 82, male 34, female 58, male 68, male 51, male 54, male Rho Rho Renaud Jiang Jiang Our case
Yes
7 45, female Lee
NM not mentioned
No α-hemolytic streptococcus (dialysate) No Corynebacterium, S.epidermidis (drainage from catheter sinus) MRSA, Corynebacterium (exit site discharge) No No No NM NM No
No Yes
12 NM 63, male 61, female Merlin Hevia
Doxycycline, Amikacin Ciprofloxacin, Clarithromycin, Amikacin Imipenem, Tobramycin, Clarithromycin Moxifloxacin, Linezolid Amikacin, Cefoxitin, Clarithromycin Ciprofloxacin, Clarithromycin Ticarcillin + clavulanic acid Clarithromycin Clarithromycin
Abscess, adhesions No Yes Yes 2 2 Kanamycin, Erythromycin Erythromycin No No 35, female 35, male Selgas Poisson
14 13
Exit-site Time from disease onset to Mycobacteriuminfection anti-NTM treatment (days) specific treatment
It is important to maintain a high level of suspicion for NTM peritonitis when PD-associated peritonitis is culture negative, persistent or recurrent, or unresponsive to standard empirical antibiotic treatment. The failure to consider mycobacterial infection in the differential diagnosis of peritonitis can lead to delayed diagnosis and treatment and life-threatening complications. Neither clinical findings nor cell count or its differential in PD fluid and peripheral blood can be used to differentiate between NTM peritonitis and peritonitis caused by other bacteria. Rapidly growing NTM grow on nonselective bacteriologic media, but commonly require a minimum of
Reference Age, gender Other pathogens
Discussion
Table 1 Patients characteristics of reported M. chelonae PD-associated peritonitis
The clinical characteristics of patients with PD-related M. chelonae peritonitis and our case are summarized in Table 1. The average age of the patients was 52.3 years (range 34–82 years). Seven (64 %) of the NTM peritonitis cases occurred in males. ESRD was secondary to diabetes mellitus in three patients, to glomerulonephritis in two patients, to lupus nephritis in two patients and one case was of undetermined etiology. Exit site infection was diagnosed in four cases. One patient experienced simultaneous bacterial peritonitis [7] and two others demonstrated bacterial growth from exit site discharge [4, 5]. All cases in which the clinical picture was provided (8 from 11 cases) demonstrated a triad: abdominal pain, cloudy fluid and increased white blood cell count in peritoneal effluent. Most of the cases reported neutrophil-predominant peritoneal fluid cytology [5–9]. One patient [10] presented with 32 % neutrophils in his peritoneal fluid. Only in three patients acid-fast bacilli were identified from a smear from peritoneal effluent and exit site [8, 9]. Mean duration of time from disease onset to anti-NTM treatment start was 14.1±4.9 days. All patients received empirical antibacterial therapy prior to M. chelonae infection diagnosis: first generation cephalosporin (cefazolin, cefalotine or cephradin), vancomycin, gentamicin and ceftazidime. Drugs that were used for the treatment of M. chelonae infection included aminoglycosides, macrolides, imipenem, cefoxitin, fluoroquinolones, linezolid, ticarcillin/clavulanic acid and macrolides. The mean treatment duration was 4± 2.1 months, with two cases with unknown duration of treatment. In 10 of 11 cases the Tenckhoff catheter was also removed. One patient from an Australian report [11] was successfully treated without catheter removal. Data are not available to describe the clinical course of this patient. After peritoneal catheter removal patients have been switched to hemodialysis. In one, subsequent renal transplantation was successful [8]. Complications developed in four patients. Adhesions, abscess, ileus and bowel perforation have been reported [5, 6, 9]. No death from infection was reported in this patient group.
Duration of Catheter removal Complications antibiotics (months)
Eur J Clin Microbiol Infect Dis
Eur J Clin Microbiol Infect Dis
3–5 days to produce any visible growth. Our review demonstrated that the time from symptoms/signs onset to diagnosis and initiation of appropriate treatment was approximately two weeks. Although a smear of acid-fast bacilli from peritoneal effluent should be performed for rapid detection of mycobacteria, this test was helpful in only a small proportion of patients. NTM organisms appear fragmented and beaded on Gram’s stain and may be dismissed as debris or diphtheroids by unfamiliar examiners [7, 8, 16]. Colonies on bacterial media grossly resemble colonies of Corynebacterium species. There are no clear guidelines for treating NTM PD-related infections. In order to reduce the risk of acquired mutational resistance, it has been recommended that at least two antibiotics to which the organism is sensitive be given for a prolonged period [1, 16]. The only clinical treatment trial for M. chelonae skin disease, as a manifestation of disseminated M. chelonae infection, used clarithromycin alone [17]. Of patients treated with monotherapy at 500 mg twice a day for 6 months, all were cured except for one patient (8 %) who relapsed with an isolate that developed mutational resistance to clarithromycin [17]. One of the PD-associated infection cases reported in Rho et al. [9] was treated with a prolonged course of clarithromycin for an M. chelonae exit site infection and the catheter was not removed. This regimen failed to eradicate the infection. Poisson et al. [7] gave their patient erythromycin—intravenously and intraperitoneally, later orally. This patient’s clinical course was complicated by relapse of peritonitis. Jiang et al. [11] presented two patients with M. chelonae peritonitis, one was successfully treated with ticarcillin + clavulanic acid, another with clarithromycin alone. Our patient was successfully treated with clarithromycin for 6 months after receiving a single dose of intravenous amikacin at the beginning of the treatment and in fact received monotherapy. There is ongoing debate about the role of in vitro susceptibility testing for managing patients with NTM disease [1]. It is recommended that the clinician should use in vitro susceptibility data with an appreciation of its limitations and with the awareness that some NTM disease may not be eradicated in a given patient with therapy based on in vitro susceptibility results [1]. In most reported cases of NTM peritonitis, PD catheters were removed [18] and experience with non-removal was limited. In cases of NTM peritonitis reported three decades ago, patients who received antimicrobial therapy without removal of catheter experienced treatment failure or relapse of peritonitis [7, 19]. The most common indication for catheter removal in NTM peritonitis in the systematic review [18] was refractory PD peritonitis. In only four patients (7.1 %) the peritoneal catheter was not removed [18]. The authors demonstrated that the time from symptoms/signs onset to diagnosis and initiation of appropriate anti-NTM treatment averaged 4 weeks [18]. ISPD guidelines for PD related infections [3]
recommended to consider removal of peritoneal catheter after 5 days of treatment failure in refractory peritonitis. It can be assumed that in most of the cases reported by Song et al. peritoneal catheter was removed before anti-NTM treatment initiation [18]. In one of the three NTM peritonitis cases treated without peritoneal catheter removal [11] successful treatment with ciprofloxacin and clarithromycin as first-line therapy without Tenckhoff catheter removal was demonstrated. The authors assumed that this patient had a milder clinical presentation so antibiotics were not administered immediately. Unfortunately, there is no information on clinical course of an additional two patients [11] and in four cases from systematic review [18] who were treated without catheter removal. We can speculate that if diagnosed earlier, at least some atypical mycobacteria peritonitis cases, perhaps the milder ones, could be managed without catheter removal. Our case demonstrated that peritoneal catheter removal alone, before the beginning of antibiotics to which the organism is sensitive, caused rapid improvement of inflammation. The exact environmental link as to where the reviewed patients contracted M. chelonae remains unknown. Atypical mycobacteria are ubiquitous in soil, dust and water as well as much of the natural environment [1, 16]. In addition, municipal water supplies and tap water can harbor these organisms [1, 20, 21]. They have also been found to colonize medical equipment (endoscopes) and surgical solutions [1]. An outbreak of NTM bacteremia was reported in a Louisiana hemodiaysis centre related to contamination of dialysers processed from contaminated water supplies [22]. Similar reports of water contamination and NTM have been reported since then [23, 24]. Touch contamination as well as exposure to contaminated water may pose a threat to exposed PD patients. Infection can also result from contaminated automated peritoneal dialysis (APD) machines [25]. Poisson et al. [7] mentioned that a titanium adapter from Tenckhoff detached from its junction and fell on the humid floor of the bathroom several days before M. chelonae peritonitis started. Our patient denied any exposure to contaminated water or touching contamination and he did not use an APD machine. Patients with ESRD have a relative defect in cell-mediated immunity, which may contribute to NTM infections [26]. Some studies have demonstrated that PD may hinder both phagocytic and lymphocytic activity in peritoneal fluid, which allows infection by a smaller inoculum of microorganisms [26, 27]. Diabetes, which is known to include depressed antibacterial immunity, was the cause of ESRD in three of the reviewed patients. In addition, two NTM peritonitis patients have an autoimmune disease (e.g. SLE). Prior topical gentamycin has been cited as a risk factor for rapidly growing NTM exit site infection [15]. None of the reviewed patients was treated with topical gentamycin before the diagnosis of M. chelonae peritonitis. This is the first case of M. chelonae PD-peritonitis reported in the Middle East. Our case demonstrated that a prolonged
Eur J Clin Microbiol Infect Dis
therapy with a single antimicrobial agent to which the organism is sensitive accompanied by catheter Tenckhoff removal led to cure of the infection. Peritoneal catheter removal alone could probably be sufficient to treat the infection.
Conflict of interest The authors declare that they have no conflict of interest.
References 1. Griffith DE, Aksamit T, Brown-Elliott BA et al (2007) An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 175:367–416 2. Jarzembowski JA, Young MB (2008) Nontuberculous mycobacterial infections. Arch Pathol Lab Med 132:1333–1341 3. Li PK-T, Szeto CC, Piraino B, Bernardini J, Figueiredo AE, Gupta A, Johnson DW, Kuijper EJ, Lye W-C, Salzer W, Schaefer F, Dirk G, Struijk DG (2010) Peritoneal dialysis-related infections recommendations: 2010 update. Perit Dial Int 30:393–423 4. Hevia C, Bajo MA, Sanchez-Tomero JA, del Peso G, FernandezPerpen A, Millan I, Aguilera A, Selgas R (2000) Peritoneal catheter exit-site infections caused by rapidly-growing atypical mycobacteria. Nephrol Dial Transplant 15:1458–1460 5. Lee KF, Chen HH, Wu CJ (2008) Mycobacterium chelonae peritonitis in a patient on peritoneal dialysis. Ren Fail 30:335–338 6. Selgas R, Munoz J, Aquella A, Huarte E, Fonseca E, Escuin F, Contreras F (1987) Mycobacterium chelonei peritonitis due to hematogenous dissemination in a continuous ambulatory peritoneal dialysis patient. Am J Kidney Dis 10:144–146 7. Poisson M, Beroniade V, Falardeau P, Vega C, Morisset R (1983) Mycobacterium chelonei peritonitis in a patient undergoing continuous ambulatory peritoneal dialysis (CAPD). Perit Dial Bull 3:86–88 8. Merlin TL, Tzamaloukas AH (1989) Mycobacterium chelonae peritonitis associated with continuous ambulatory peritoneal dialysis. Am J Clin Pathol 91:717–720 9. Rho M, Bia F, Brewster UC (2007) Nontuberculous mycobacterial peritonitis in peritoneal dialysis patients. Semin Dial 20:271–276 10. Renaud CJ, Subramanian S, Tambyah PA, Lee E (2011) The clinical course of rapidly growing nontuberculous mycobacterial peritoneal dialysis infections in Asians: a case series and literature review. Nephrology (Carlton) 16:174–179 11. Jiang SH, Roberts DM, Clayton PA, Jardine M (2013) Nontuberculous mycobacterial PD peritonitis in Australia. Int Urol Nephrol 45:1423–1428
12. Gehr TW, Walters BA (1994) Catheter-related Mycobacterium chelonei infection in a CAPD patient. Perit Dial Int 14:278–279 13. Siu YP, Leung KT, Tong MK, Lee MK (2005) Mycobacterium chelonae exit site infection in a patient on peritoneal dialysis. Clin Nephrol 63:321–324 14. Kleinpeter MA, Krane NK (2001) Treatment of mycobacterial exitsite infections in patients on continuous ambulatory peritoneal dialysis. Adv Perit Dial 17:172–175 15. Tse KC, Lui SL, Cheng VCC, Yip TPS, Lo WK (2007) A cluster of rapidly growing mycobacterial peritoneal dialysis catheter exit-site infections. Am J Kidney Dis 50:1–5 16. Wallace RJ, Swenson JM, Silcox VA, Good RC, Tschen JA, Stone MS (1983) Spectrum of disease due to rapidly growing mycobacteria. Rev Infect Dis 5:657–679 17. Wallace RJ Jr, Tanner D, Brennan PJ, Brown BA (1993) Clinical trial of clarithromycin for cutaneous (disseminated) infection due to Mycobacterium chelonae. Ann Intern Med 119:482–486 18. Song Y, Wu J, Yan H, Chen J (2012) Peritoneal dialysis-associated nontuberculous mycobacterium peritonitis: a systematic review of reported cases. Nephrol Dial Transplant 27:1639–1644 19. Pulliam JP, Vernon DD, Alexander SR, Hartstein AI, Golper TA (1983) Nontuberculous mycobacterial peritonitis associated with continuous ambulatory peritoneal dialysis. Am J Kidney Dis 2: 610–614 20. Falkinham JO 3rd, Norton CD, LeChevallier MW (2001) Factors influencing numbers of Mycobacterium avium, Mycobacterium intracellulare, and other Mycobacteria in drinking water distribution systems. Appl Environ Microbiol 67:1225–1231 21. Goslee S, Wolinsky E (1976) Water as a source of potentially pathogenic mycobacteria. Am Rev Respir Dis 113(3):287–292 22. Bolan G, Reingold AL, Carson LA et al (1985) Infections with Mycobacterium chelonei in patients receiving dialysis and using processed hemodialyzers. J Infect Dis 152:1013–1019 23. Kline S, Cameron S, Streifel A, Yakrus MA, Kairis F, Peacock K, Besser J, Cooksey RC (2004) An outbreak of bacteremias associated with Mycobacerium mucogenicum in a hospital water supply. Infect Control Hosp Epidemiol 25:1042–1049 24. Wallace RJ Jr (1987) Nontuberculous mycobacteria and water: A love affair with increasing clinical importance. Infect Dis Clin North Am 1:677–686 25. Band JD, Ward JI, Fraser DW, Peterson NJ, Silcox VA, Good RC, Ostroy PR, Kennedy J (1987) Peritonitis due to a mycobacterium chelonei-like organism associated with intermittent chronic peritoneal dialysis. Infect Dis Clin North Am 1:677–686 26. Rubin J, Lin LM, Lewis R, Cruse J, Bower JD (1983) Host defense mechanisms in continuous ambulatory peritoneal dialysis. Clin Nephrol 20:140–144 27. Kazancioglu R (2009) Peritoneal defense mechanisms—the effects of new peritoneal dialysis solutions. Perit Dial Int 29(Suppl 2):S198– S201
REVIEW
Mycobacterium chelonae peritonitis in peritoneal dialysis. Literature review M. Kunin & A. Knecht & E. J. Holtzman
Received: 16 December 2013 / Accepted: 4 February 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Non-tuberculous mycobacteria are a rare but serious cause of peritoneal dialysis-related peritonitis. There are no clear guidelines for treating non-tuberculous mycobacteria peritoneal dialysis-associated infections. It has been recommended that at least two antibiotics be given for a prolonged period and peritoneal catheter should be removed. This paper describes the clinical course and treatment of a patient with M. chelonae peritoneal dialysis-related peritonitis and reviews the previously published cases.
Introduction Bacterial peritonitis is the most common complication of peritoneal dialysis (PD) and often is the reason for discontinuing PD. The vast majority of PD-associated peritonitis cases are caused by common gram-positive and gramnegative bacteria, such as coagulase-negative staphylococci, Staphylococcus aureus, and Pseudomonas aeruginosa. However, in the presence of clinical evidence of peritonitis and negative routine dialysate culture, mycobacteria and fungi (other than the Candida species, which grow readily in routine cultures) are potential pathogens. Nontuberculous mycobacteria (NTMs) are defined as Mycobacterium species other than M. tuberculosis and M. leprae [1, 2]. The International Society for Peritoneal Dialysis (ISPD) guidelines for PD-related infections [3] provide little information on non-tuberculous mycobacterial peritonitis. The treatment protocol for this type of infection is not well established [3]. M. Kunin (*) : A. Knecht : E. J. Holtzman Nephrology and Hypertension Institute, Sheba Medical Center and Sackler Faculty of Medicine, Tel-Hashomer, Israel e-mail: [email protected]
M. chelonae belong to the group of rapidly growing nontuberculous mycobacteria. Skin, bone, and soft tissue disease are the most common clinical manifestations of M. chelonae infection. Disseminated M. chelonae disease can also occur in immunocompromised patients and presents with characteristic skin lesions. Epidemic and sporadic cases of keratitis caused by M. chelonae have been associated with contact lens wear and ocular surgery, particularly laserassisted in situ keratomileusis (LASIK) [1]. The optimum type and duration of therapy has yet to be defined. M. chelonae appears to be more resistant to antimicrobial agents than M. fortuitum, with unpredictable antibiotic susceptibility. For serious skin, bone, and soft tissue disease, a minimum of 4 months of a combination drug therapy is necessary. Removal of foreign bodies, such as breast implants and percutaneous catheters, is important, or even essential, to recovery [1]. In this paper we described the case of M. chelonae PDrelated peritonitis and reviewed the previously published cases.
Case report A 54-year-old man with a history of hypertension, hyperlipidemia, gout, nephrolitiasis and hepatitis B infection was diagnosed with end-stage renal disease (ESRD) caused by chronic glomerulonephritis. He had been on peritoneal dialysis for 3 years. The patient practiced continuous ambulatory peritoneal dialysis. He used conventional low pH 2.5 % dextrose dialysis solution—four exchanges of two liters each per day. Ten months before his current presentation the patient was treated with oral amoxicillin due to bronchitis and a week later received prednisone 10 mg per day with tapering off for 2 weeks due to gouty arthritis. Since then he had no history of infections, including PD-associated infections, and did not take immunosuppressive drugs.
Eur J Clin Microbiol Infect Dis
The patient presented to the peritoneal dialysis facility with cloudy dialysate. Dialysate effluent analysis revealed a total white blood cell (WBC) count of 400 cells/mm³, with 70 % granulocytes. Peritonitis was suspected and the patient was treated empirically with intraperitoneal cefuroxime and ceftazidime. A day later, he was hospitalized due to fever and abdominal pain. Physical examination found abdominal tenderness, body temperature was 38.0°, blood pressure 141/90 mmHg and pulse 91 per minute. Laboratory studies revealed a peripheral WBC count of 10,290 K/microL with 80 % polymorphonuclear leukocytes (PMN); serum hemoglobin was 12.2 g/dl and serum C-reactive protein (CRP) 48 mg/l. Peritoneal fluid analysis returned with 490 cells/ mm³ WBC and with 30 % granulocytes. Tenckhoff catheter exit site was unremarkable. A computed tomography (CT) scan of the abdomen revealed no abscess or bowel obstruction. The empirical treatment for bacterial peritonitis was continued. During the following days of hospitalization the patient complained of abdominal pain and the abdomen remained tender on palpation. Peritoneal effluent white blood cell count continued to rise (Fig. 1a). On the fourth treatment day intraperitoneal vancomycin was added to antibiotic regimen. Two days later intravenous ceftazidime and vancomycin were started. After 7 days of empirical antibiotic treatment the patient did not improve clinically, peritoneal effluent white blood cell count was high (Fig. 1a), and serum C-reactive protein (CRP) continued to increase (Fig. 1b). Peritoneal culture tests remained negative. The peritoneal catheter was removed on the seventh day after the initial presentation and hemodialysis (HD) was started. The patient continued treatment with intravenous ceftazidime and vancomycin. After Tenckhoff catheter removal the patient’s clinical condition started to improve. Serum CRP decreased (Fig. 1b). Nine days after the patient’s presentation culture of the peritoneal fluid yielded a rapidly growing mycobacterium. Five days later gene sequencing by polymerase chain reaction of the isolate identified it to be Mycobacterium chelonae. The patient was doing well, therefore, the decision was made to wait for in vitro antimicrobial susceptibility results before specific antibiotic treatment initiation. Since in vitro antimicrobial sensitivities results were pending, oral clarithromycin of 500 mg per day on day 23 and intravenous amikacin in dose 5 mg/kg after hemodialysis session on day 27 were eventually started. Four days later the result showing resistance to amikacin arrived, therefore it was stopped. Additional 3 days took to complete all the sensitivities. Final antimicrobial sensitivities of the isolate demonstrated sensitivity only to clarithromycin. The bacterium was resistant to imipenem, ciprofloxacin, amikacin, cefoxitin, doxycycline and trimetoprim/sulfamethoxazole and showed intermediate sensitivity to tobramycin. Abdominal and pelvic CT searching for
Fig. 1 Peritoneal fluid white blood cell (WBC) count (a) and serum Creactive protein (CRP) concentration (b) during patient’s follow-up
possible intraabdominal complications was performed. Compared to CT examination at admission, it demonstrated prominent omentum infiltration and moderate amount of ascites. Peritoneal punction and centesis for WBC count and culture were considered. However, the patient refused this invasive procedure. The patient continued doing well. Follow-up CT performed 6 weeks later demonstrated improvement in omentum infiltration and disappearance of peritoneal fluid. The patient completed a 6-month clarithromycin course and remained free of ascites or signs and symptoms of peritonitis. He chose to stay on hemodialysis. After the completion of the antibiotic course he was return to the waiting list for kidney transplantation.
Literature review Ten cases of PD peritonitis due to M. chelonae were reported in English literature [4–11]. One of those reports, a population-based cohort study from Australia [11], did not provide detailed patient information. There are also few reports of M. chelonae infection at the catheter exit site, without peritonitis [12–15]. Those cases are not reviewed here. The geographic spread of PD peritonitis due to M. chelonae included reports from North America (4 patients), Asia (2 patients), Europe (2 patients) and Australia (2 patients) with none from the Middle East.
Bowel perforation Abdominal abscess No NM NM No Yes Yes Yes Yes No Yes 6 6 1.5 NM NM 6
Adhesion, ileus Yes 4.5
No No Yes Yes 6 2
No Yes Yes NM NM No
19 14 11 NM NM 23 82, male 34, female 58, male 68, male 51, male 54, male Rho Rho Renaud Jiang Jiang Our case
Yes
7 45, female Lee
NM not mentioned
No α-hemolytic streptococcus (dialysate) No Corynebacterium, S.epidermidis (drainage from catheter sinus) MRSA, Corynebacterium (exit site discharge) No No No NM NM No
No Yes
12 NM 63, male 61, female Merlin Hevia
Doxycycline, Amikacin Ciprofloxacin, Clarithromycin, Amikacin Imipenem, Tobramycin, Clarithromycin Moxifloxacin, Linezolid Amikacin, Cefoxitin, Clarithromycin Ciprofloxacin, Clarithromycin Ticarcillin + clavulanic acid Clarithromycin Clarithromycin
Abscess, adhesions No Yes Yes 2 2 Kanamycin, Erythromycin Erythromycin No No 35, female 35, male Selgas Poisson
14 13
Exit-site Time from disease onset to Mycobacteriuminfection anti-NTM treatment (days) specific treatment
It is important to maintain a high level of suspicion for NTM peritonitis when PD-associated peritonitis is culture negative, persistent or recurrent, or unresponsive to standard empirical antibiotic treatment. The failure to consider mycobacterial infection in the differential diagnosis of peritonitis can lead to delayed diagnosis and treatment and life-threatening complications. Neither clinical findings nor cell count or its differential in PD fluid and peripheral blood can be used to differentiate between NTM peritonitis and peritonitis caused by other bacteria. Rapidly growing NTM grow on nonselective bacteriologic media, but commonly require a minimum of
Reference Age, gender Other pathogens
Discussion
Table 1 Patients characteristics of reported M. chelonae PD-associated peritonitis
The clinical characteristics of patients with PD-related M. chelonae peritonitis and our case are summarized in Table 1. The average age of the patients was 52.3 years (range 34–82 years). Seven (64 %) of the NTM peritonitis cases occurred in males. ESRD was secondary to diabetes mellitus in three patients, to glomerulonephritis in two patients, to lupus nephritis in two patients and one case was of undetermined etiology. Exit site infection was diagnosed in four cases. One patient experienced simultaneous bacterial peritonitis [7] and two others demonstrated bacterial growth from exit site discharge [4, 5]. All cases in which the clinical picture was provided (8 from 11 cases) demonstrated a triad: abdominal pain, cloudy fluid and increased white blood cell count in peritoneal effluent. Most of the cases reported neutrophil-predominant peritoneal fluid cytology [5–9]. One patient [10] presented with 32 % neutrophils in his peritoneal fluid. Only in three patients acid-fast bacilli were identified from a smear from peritoneal effluent and exit site [8, 9]. Mean duration of time from disease onset to anti-NTM treatment start was 14.1±4.9 days. All patients received empirical antibacterial therapy prior to M. chelonae infection diagnosis: first generation cephalosporin (cefazolin, cefalotine or cephradin), vancomycin, gentamicin and ceftazidime. Drugs that were used for the treatment of M. chelonae infection included aminoglycosides, macrolides, imipenem, cefoxitin, fluoroquinolones, linezolid, ticarcillin/clavulanic acid and macrolides. The mean treatment duration was 4± 2.1 months, with two cases with unknown duration of treatment. In 10 of 11 cases the Tenckhoff catheter was also removed. One patient from an Australian report [11] was successfully treated without catheter removal. Data are not available to describe the clinical course of this patient. After peritoneal catheter removal patients have been switched to hemodialysis. In one, subsequent renal transplantation was successful [8]. Complications developed in four patients. Adhesions, abscess, ileus and bowel perforation have been reported [5, 6, 9]. No death from infection was reported in this patient group.
Duration of Catheter removal Complications antibiotics (months)
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3–5 days to produce any visible growth. Our review demonstrated that the time from symptoms/signs onset to diagnosis and initiation of appropriate treatment was approximately two weeks. Although a smear of acid-fast bacilli from peritoneal effluent should be performed for rapid detection of mycobacteria, this test was helpful in only a small proportion of patients. NTM organisms appear fragmented and beaded on Gram’s stain and may be dismissed as debris or diphtheroids by unfamiliar examiners [7, 8, 16]. Colonies on bacterial media grossly resemble colonies of Corynebacterium species. There are no clear guidelines for treating NTM PD-related infections. In order to reduce the risk of acquired mutational resistance, it has been recommended that at least two antibiotics to which the organism is sensitive be given for a prolonged period [1, 16]. The only clinical treatment trial for M. chelonae skin disease, as a manifestation of disseminated M. chelonae infection, used clarithromycin alone [17]. Of patients treated with monotherapy at 500 mg twice a day for 6 months, all were cured except for one patient (8 %) who relapsed with an isolate that developed mutational resistance to clarithromycin [17]. One of the PD-associated infection cases reported in Rho et al. [9] was treated with a prolonged course of clarithromycin for an M. chelonae exit site infection and the catheter was not removed. This regimen failed to eradicate the infection. Poisson et al. [7] gave their patient erythromycin—intravenously and intraperitoneally, later orally. This patient’s clinical course was complicated by relapse of peritonitis. Jiang et al. [11] presented two patients with M. chelonae peritonitis, one was successfully treated with ticarcillin + clavulanic acid, another with clarithromycin alone. Our patient was successfully treated with clarithromycin for 6 months after receiving a single dose of intravenous amikacin at the beginning of the treatment and in fact received monotherapy. There is ongoing debate about the role of in vitro susceptibility testing for managing patients with NTM disease [1]. It is recommended that the clinician should use in vitro susceptibility data with an appreciation of its limitations and with the awareness that some NTM disease may not be eradicated in a given patient with therapy based on in vitro susceptibility results [1]. In most reported cases of NTM peritonitis, PD catheters were removed [18] and experience with non-removal was limited. In cases of NTM peritonitis reported three decades ago, patients who received antimicrobial therapy without removal of catheter experienced treatment failure or relapse of peritonitis [7, 19]. The most common indication for catheter removal in NTM peritonitis in the systematic review [18] was refractory PD peritonitis. In only four patients (7.1 %) the peritoneal catheter was not removed [18]. The authors demonstrated that the time from symptoms/signs onset to diagnosis and initiation of appropriate anti-NTM treatment averaged 4 weeks [18]. ISPD guidelines for PD related infections [3]
recommended to consider removal of peritoneal catheter after 5 days of treatment failure in refractory peritonitis. It can be assumed that in most of the cases reported by Song et al. peritoneal catheter was removed before anti-NTM treatment initiation [18]. In one of the three NTM peritonitis cases treated without peritoneal catheter removal [11] successful treatment with ciprofloxacin and clarithromycin as first-line therapy without Tenckhoff catheter removal was demonstrated. The authors assumed that this patient had a milder clinical presentation so antibiotics were not administered immediately. Unfortunately, there is no information on clinical course of an additional two patients [11] and in four cases from systematic review [18] who were treated without catheter removal. We can speculate that if diagnosed earlier, at least some atypical mycobacteria peritonitis cases, perhaps the milder ones, could be managed without catheter removal. Our case demonstrated that peritoneal catheter removal alone, before the beginning of antibiotics to which the organism is sensitive, caused rapid improvement of inflammation. The exact environmental link as to where the reviewed patients contracted M. chelonae remains unknown. Atypical mycobacteria are ubiquitous in soil, dust and water as well as much of the natural environment [1, 16]. In addition, municipal water supplies and tap water can harbor these organisms [1, 20, 21]. They have also been found to colonize medical equipment (endoscopes) and surgical solutions [1]. An outbreak of NTM bacteremia was reported in a Louisiana hemodiaysis centre related to contamination of dialysers processed from contaminated water supplies [22]. Similar reports of water contamination and NTM have been reported since then [23, 24]. Touch contamination as well as exposure to contaminated water may pose a threat to exposed PD patients. Infection can also result from contaminated automated peritoneal dialysis (APD) machines [25]. Poisson et al. [7] mentioned that a titanium adapter from Tenckhoff detached from its junction and fell on the humid floor of the bathroom several days before M. chelonae peritonitis started. Our patient denied any exposure to contaminated water or touching contamination and he did not use an APD machine. Patients with ESRD have a relative defect in cell-mediated immunity, which may contribute to NTM infections [26]. Some studies have demonstrated that PD may hinder both phagocytic and lymphocytic activity in peritoneal fluid, which allows infection by a smaller inoculum of microorganisms [26, 27]. Diabetes, which is known to include depressed antibacterial immunity, was the cause of ESRD in three of the reviewed patients. In addition, two NTM peritonitis patients have an autoimmune disease (e.g. SLE). Prior topical gentamycin has been cited as a risk factor for rapidly growing NTM exit site infection [15]. None of the reviewed patients was treated with topical gentamycin before the diagnosis of M. chelonae peritonitis. This is the first case of M. chelonae PD-peritonitis reported in the Middle East. Our case demonstrated that a prolonged
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therapy with a single antimicrobial agent to which the organism is sensitive accompanied by catheter Tenckhoff removal led to cure of the infection. Peritoneal catheter removal alone could probably be sufficient to treat the infection.
Conflict of interest The authors declare that they have no conflict of interest.
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