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Bacteraemia caused by non-aeruginosa Pseudomonas species in a cancer centre
Journal of Hospital Infection (1992) 22, 307-316
Bacteraemia Pseudomonas M. Aoun,
caused by non-aeruginosa species in a cancer centre
P. Van der Auwera”, C. Devleeshouwer*, N. Seraj, F. Meunier and J. Gerain
D. Daneau,
Clinique des Maladies Infectieuses et Laboratoire de Microbiologic, Service de Me’decine Interne et Laboratoire d’Investigation Clinique H. J. Tagnon, and * Unite’ d’Hygit?ne Hospital&e, Institut Jules Bordet, Centre des Tumeurs de I’Universite’ Libre de Bruxelles, yue Hkger-Bordet, 1; B-1000 Brussels, Belgium Accepted for publication
18 September 1992
Summary:
Fifty-one episodes of bacteraemia due to Pseudomonas species other than Pseudomonas aeruginosa occurring between 1980 and 1990 in a Belgian cancer centre were reviewed. This corresponded to an incidence of 0.62/1000 admissions, or 1.5% of all bacteraemic episodes. Twenty-nine episodes, each with several positive blood culture sets were considered clinically significant, including six patients belonging to a well-documented outbreak of pseudobacteraemia with Xanthomonas maltophilia and associated with contaminated blood sampling tubes. The respiratory tract was the source in six (20.7%), an infected intravenous catheter in 10 (34.5%) and the source was unknown in seven (24.1%). Seven patients died from infection (24.1%). Twenty-three episodes with a single positive blood culture set were considered clinically not significant, although four of them were considered significant by the Centers for Disease Control (CDC) criteria because of the presence of symptoms and specific antibiotic treatment being administered. None of the patients with a single isolate died from infection despite the fact that 17 of 22 did not receive an effective antimicrobial agent. All isolates were susceptible to co-trimoxazole.
Keywords: Pseudobacteraemia; cancer
Xanthomonas maltophilia;
Pseudomonas spp;
patients.
Introduction Infections caused by Xanthomonas maltophilia and Pseudomonas spp. other than P. aeruginosa are rare and have usually been observed as isolated cases or in small clusters of nosocomial infections.’ The reservoir of these organisms is considered to be the environment including soil, water and plants. Aqueous solutions have been the source of infections with these bacterial species as well as the cause of pseudobacteraemia. They have also Correspondence 0195-6701/92/120307+10
to: P. Van der Auwera. SOS.OO/O
0 1992 The Hospital
307
Infection
Society
M. Aoun et al.
308
been isolated from blood products, povidone iodine and chlorhexidine solutions, heparinized saline solution, anaesthetics, intravenous catheters and contaminated automatic peritoneal dialysis instruments, humidifiers and respiratory assistance instruments.’ In contrast to P. aeruginosa, neither the pathogenic potential of these organisms nor the appropriate therapeutic strategy in debilitated and immunosuppressed patients is well defined. Therefore, we have reviewed all cases of bacteraemia due to such species occurring in the period 198&90 at the Institut Jules Bordet, Belgium, a 156-bed university cancer centre.
Materials During
an 1 l-year
period
and methods
(1980-90),
57 episodes
of bacteraemia
due to
Pseudomonas spp. other than P. aeruginosa (but including Xanthomonas maltophilia) occurred, for which 52 medical records were recovered and analysed. Each blood sample was cultured in a pair of blood culture vials including tryptic soy broth with the Septicheck agar slant system (Roche, Switzerland) for aerobic culture and brain-heart infusion broth for anaerobic culture (Gibco, Belgium). Each febrile episode (> 38*5”C) was usually documented with three sets of blood cultures. Identification of non-fermenting Gram-negative bacilli was performed using the API 20 NE system (API, France). Antibiotic susceptibility testing was performed by disk diffusion on Mueller-Hinton 2 agar and according to the National Committee for Clinical Laboratory Standards (NCCLS) published at the time of isolation.2’” The following data were collect.ed from the medical records: age, sex, underlying disease, circulatory neutrophil count, presence of venous central or arterial catheters, the possible source of the bacteraemia. the antimicrobial treatment given empirically, its eventual modification in the course of the treatment and outcome. Bacteraemia was considered to be clinically significant when the same ,organism was isolated from at least two blood culture bottles from different sets. In additi,on, the Centers for Disease Control (CDC) criteria for nosocomial bacteraemia4 were applied to define clinically significant bacteraemia: fever and two positive blood culture sets, or fever, one positive blood culture and specific antibiotic treatment. Other episodes were considered not to be clinically significant. Bacteraemia was considered to be vascular catheter-related when local signs of infection were present (cellulitis, pus discharge at the exit site) or when the removed catheter was positive at culture. Occasionally, a bacteraemic episode was considered to be catheter-related in the presence of persisting positive blood cultures ( > 3 days) despite optimal antimicrobial therapy (based on in-vitro susceptibility tests), and in the absence of another focus of infection. Among the patients with several blood culture sets positive for X. maltophilia and no obvious source of infection, four were considered to be of possible clinical significance because they
Pseudomonas
bacteraemia
in cancer
309
responded favourably to specific antimicrobial treatment (co-trimoxazole); three of them had multiple positive sets of blood cultures. Results
During the 11 -year study period, the number of admissions ranged from 3250 to 5989 per year (mean of 4523), representing a total of 49 760 patients. The rate of isolation of Pseudomonas spp. and X. maltophilia was 0.62 per 1000 admissions (range: O-2.08) or zero to eight episodes per year. The mean number of bacteraemic episodes was 177 per year (42 of 1000 admissions, range: 30-53), therefore these species accounted for 15% (range: O-+8%) of all bacteraemic episodes overall. In 1989-90 an outbreak of pseudobacteraemia occurred due to X. maltophilia. Apart from this outbreak, the other bacteraemic episodes were sporadic throughout the years without evident clustering. They were not attributed to a common source of contamination, although systematic cultures of the environment were not obtained. Bacteraemic episodes were differentiated into categories according to the number of positive blood culture samples (1 and 22). Fifteen patients identified in an outbreak of pseudobacteraemia due to X. maltophilia were analysed separately. Table I compares the characteristics of the 29 patients who had at least two positive sets of blood culture bottles to those of 23 patients with one positive set of blood cultures only. The characteristics of the two groups were not different except for patients with haematological malignancies who were more likely to be neutropenic in the group with significant bacteraemia. Of the 29 patients (56.8%) considered to have significant bacteraemia (including patients l-6 from Table III), 27 had an active malignancy at the time of bacteraemia and most were not neutropenic (68.9%). Xanthomonas maltophilia was predominant, followed by Pseudomonas cepacia and other species of pseudomonads. An intravenous catheter was considered as the source of bacteraemia in 10 patients and the respiratory tract in six patients. In seven patients the origin of bacteraemia remained unknown. In 10 catheter-related bacteraemias, the iv device had to be removed for persisting or recurrent bacteraemia. All patients treated adequately (causative strain susceptible to the treatment given empirically) recovered clinically (Table II). Among seven patients who died from infection, four did not receive an antimicrobial agent. Of 23 patients with bacteraemia deemed not to be significant, five patients received an active 1 week after isolation of the antimicrobial agent. None died within presumably contaminating strain, three died within 1 month from underlying disease. All strains were susceptible to co-trimoxazole. Among Xanthomonas maltophilia, resistance to imipenem was the rule, half of them were resistant to ceftazidime, other third generation cephalosporins and amikacin. Six strains were susceptible to ticarcillin: four Pseudomonas spp., one P. cepacia, and one P. stutzeri.
M. Aoun et al.
310 Table
I. Characteristics
of the patients with bacteraemia due to non-aeruginosa Pseudomonas spp. and Xanthomonas maltophilia Bacteraemia clinically significant
No. of patients Underlying diseases Non-malignant disease Malignant disease Solid tumour with neutropenia (< 1 X IO9 1-l) without neutropenia Haematological malignancy with neutropenia without neutropenia Age (years) median range Sex males females Causative organisms
Pseudomonas cepacia Xanthomonas maltophilia Pseudomonas spp. Source of bacteraemia Central venous catheter Respiratory tract Acute cholangitis Unknown Unknown and associated pseudobacteraemia
P value for a single-tailed
Table
P
Bacteraemia not clinically significant
29
(56.8%)
23
(43.2%)
2 27
(3.9%) (96.1%)
3 20
(13.0%) (87.0%)
1 14
;:
8’ 3 10 55 13-83 10 13
8 5: 15-83 :;
7
(24.1%)
15 7
(51.7%) (24.1%)
10 6 2 7
14
4
9
-=c0.05
with
chi* test. NS= not statistically
significant
II. Treatment and outcome in patients with clinically Pseudomonas spp.
(P>O.OS).
significant bacteraemia due to
Treatment/outcome
No. of patients
Patients who received antibiotic therapy Recovered Death from underlying disease within
22 22 5
1 month
of bacteraemia
(%)
(100) (22.7)
Patients who did not receive antibiotic therapy Recovered Death from infection (all within 48 h)
7 3 4*
(57.1)
No. of cases of septic shock Total deaths from infection
2 4
(13.8)
Total
patients
with
bacteraemia
* Two from septic shock (one with pneumonia), tography acute cholangitis.
29 one with pneumonia, one with post-cholangiopancrea-
Pseudomonas
bacteraemia
in cancer
311
Table III shows the characteristics of the 15 patients who had positive blood cultures with Xunthomonas maltophilia during an outbreak of pseudobacteraemia involving two hospitals (Hopital St-Pierre and Institut J. Bordet) supplied with the same batch of tubes used for blood matching and containing citrate buffer as anticoagulant. The citrate buffer was heavily contaminated with a strain of Xanthomonas maltophilia and a strain of AZcaZigenes denitrificans. Surprisingly, only one patient not included in the present study developed bacteraemia with A. denitri&ans. Two of the 15 patients had a totally implantable catheter (‘Portacath’, Pharmacia, Sweden) which was superinfected with the contaminating strain of X. maltophilia as evidenced by persisting bacteraemia and culture-positivity of the catheter after removal. In four other patients, CDC criteria strongly indicated that the episode was clinically significant. Treatment with co-trimoxazole was associated with resolution of fever. An additional patient received co-trimoxazole but had a well-documented bacteraemia with a coagulase-negative staphylococcus and Corynebacterium jekeium related to a central venous catheter which had to be removed for persisting bacteraemia. The eight remaining patients were not treated as they were considered to have pseudobacteraemia, despite multiple positive blood cultures in two instances. Discussion The most common non-fermenting Gram-negative rod causing bacteraemia in cancer patients continues to be P. aeruginosa. Species of non-aeruginosa pseudomonads, including X. maltophilia are rarely isolated. Our study reviewed 52 episodes of bacteraemia of which 29 were considered to be significant (at least two blood cultures positive from different sets). Using the CDC criteria for significant bacteraemia,4 four additional episodes with a single positive blood culture set were thought to be significant because treatment seemed to be effective. Review of the medical records could exclude the clinical relevance of the bacteraemic isolate in the febrile illness of these four patients. Based on this review, the CDC criteria had a sensitivity of 100% and a specificity of 82%. There are only a few reports of bacteraemia due to Pseudomonas spp. other than P. aeruginosa and Xunthomonas in cancer patients. During 5 years, Pseudomonas putida was recovered from 15 patients with cancer.5 Eight were considered to have true bacteraemia using criteria similar to ours, of whom six had haematological malignancy. Five had polymicrobial bacteraemia and three had catheter-related bacteraemia, requiring removal of the vascular device in two of them. Third-generation cephalosporins, imipenem and ciprofloxacin were active in vitro. Kim et aZ.‘j reported four patients (during a 12-month period) and reviewed seven others from the literature with bacteraemia due to Pseudomonas putrefuciens. Two of them had cancer, of whom one had polymicrobial bacteraemia and died of sepsis.
F8)
(F54)
E,
:;‘o,
clinical
rj:8)
carcinoma
CML (+I
ALL (+I
Gastric (-)
significance CML (+I
cancer
Head and neck cancer f-1
Colon C-1
112
S/16
618
112
314
4/g
318
No. of positive blood culture bottles/total obtained
ND
ND
ND
ND
ND
not treated
Co-trimoxazole (9 days)
Co-trimoxazole (10 days)
Co-trimoxazole (7 days)
Co-trimoxazole (12 days)
Co-trimoxazole (8 days)
Port-a-Cath
days)
Co-trimoxazole (9 days)
Treatment (duration,
Port-a-Cath
Source
due to Xanthomonas maltophilia occurred during an outbreak contaminated blood sampling tubes (May 1989-ranuary 1990)
Underlying disease (+ / - ; neutropenia”)
whose bacteraemia
Not clinically significant M ALL 7 (40) (+)
6
5
4
Possible 3
2
F4)
significant
Clinically 1
Patients
Sex (age, years)
III.
Patient
Table
Recovered
Recovered
Recovered
recovered
removed,
associated
arrythmia
removed,
Died of cardiac (day 8)
Recovered
Catheter
Relapse, catheter recovered
Outcome
of pseudobacteraemia
with
k 9 2 3 rb ii 5
Pseudomonas
bacteraemia
in cancer
313
314
M. Aoun et al.
Xanthomonas maltophilia has only occasionally been associated with significant infection in humans with the exception of cystic fibrosis patients. Recently, ecthyma gangrenosum was reported in a patient with acute leukaemia.7 Elting et aZ.* reviewed 149 episodes, in 13 1 patients, of clinically significant bacteraemia due to Pseudomonas other than P. aeruginosa and X. maltophilia over 15 years. Xanthomonas maltophilia occurred in 46% followed by P. stutzeri, P. putida (11% each) and other species. The incidence increased from a range of one to four of 10 000 admissions before 1979 to a plateau of eight of 10 000 admissions for Xanthomonas and six of 10 000 admissions for Pseudomonas spp. The most common sites of infection associated with bacteraemia were pulmonary (40%), as in our study, and soft-tissue infection (12%). The relation between appropriate treatment and favourable outcome was as strong as observed here with 86% response in 108 patients treated appropriately and 59% in 27 who received inappropriate antibiotics. Catheter-related infection was proven in 57 patients, of whom 12 had relapse until the catheter was removed. This review deserves several comments. None of the bacteraemic episodes seemed to be associated with an outbreak although water faucets and drains from a medical intensive care unit were colonized by X. maltophilia. Pseudobacteraemia was not considered despite the high number of ‘non-significant’ isolates, in contrast with several reports from the literature and the present report that includes an outbreak of pseudobacteraemia. In addition to P. aeruginosa, P. cepacia and P. putida have the capacity to colonize the condensate that accumulates in ventilator circuits.’ Beside the risk of direct contamination of various devices from the environment, cancer patients may be colonized in the digestive tract, a secondary reservoir for further infection. Major factors for intestinal colonization may be antibiotics given orally or iv when biliary excretion of the drug is high, as well as anticancer chemotherapy. During myelosuppressive chemotherapy, non-fermenting Gram-negative bacilli may proliferate in the gut, including P. aeruginosa but mainly P. pickettii, P. stutzeri, P. cepacia and X. maltophilia.” We found that contamination of blood sampling tubes by X. maltophilia could result in an outbreak of pseudobacteraemia but also in true contamination of iv lines during the manipulation of the device. Although it was not possible to prove by microbiological investigation, we believe that contamination of the iv lines may have arisen from heavily colonized hands or gloves of staff. Nurses from the laboratory sampling team occasionally collected blood both for laboratory tests and blood cultures. Some of these nurses used to open the blood collection tubes after skin disinfection and before sampling, allowing the possibility of colonization of hands with the contaminated citrate buffer. It was possible to demonstrate that the isolate from the citrate buffer and those recovered from the 15 patients were indistinguishable by polyacrylamide gel electrophoresis of whole cell proteins (H. Goossens, Microbiology Laboratory, University Hospital
Pseudomonas
bacteraemia
in cancer
315
Saint-Pierre, Brussels). ‘i By contrast, unrelated endemic strains had a variety of different patterns. The outbreak ended when all contaminated tubes were replaced by gamma-ray sterilized tubes and the techniques of blood culture sampling and catheter-care had improved. A similar outbreak was reported by Henderson et aZ.‘* where P. cepacia contaminated a blood gas analyser, resulting in two cases of pseudobacteraemia and 14 genuine cases of bacteraemia. All X. maltophilia are resistant to imipenem by virtue of a zinc-containing penicillinase. i3 In addition, this sp ecies contains a class I j3-lactamase enzyme similar to that present in P. aeruginosa. All strains from the several species isolated by us were susceptible to co-trimoxazole which is considered to be the first-line antimicrobial agent. Most strains were susceptible to the third-generation cephalosporins and amikacin, which is the most common combination used for the empirical treatment of Gram-negative bacteraemia. All strains (except Xanthomonas) were susceptible to imipenem. Our study demonstrates the emergence of these unusual species of pseudomonads as a cause of clinically significant bacteraemia in cancer patients whether neutropenic or not. Interestingly, several infections were catheter-related, and despite effective antibiotic treatment the infected catheters had to be removed. Mortality associated with these episodes was 14%, most occurring within 2448 h. Our study shows also that contamination of blood sampling tubes, in addition to being responsible for pseudobacteraemia, may result in clinically significant bacteraemia through contamination of an iv catheter.
References 1. Sanford JP. Pseudomonas species (including Melioidosis and Glanders). In: Mandell GL, Douglas RG, Bennett JE, Ed. Principles and Practice of Infectious Diseases, 3rd edn. London: Churchill Livingstone 1990; 1692-l 695. 2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests, 3rd edn (M2-A3). 771 East Lancaster Ave, Villanova, PA 19085, USA 1984. 3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests (M2-T4). 771 East Lancaster Av, Villanova, PA 19085, USA 1988. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988 J Infect Control 1988; 16, 128-140. Anaissie E, Fainstein V, Miller P et al. Pseudomonas putida: newly recognized pathogen in patients with cancer. Am J Med 1987; 82: 1191-l 194. Kim JH, Cooper RA, Welty-Wolf KE, H arrell LJ, Zwadyk P, Klotman ME. Pseudomonas putrefaciens bacteremia. Rev Infect Dis 1989; 11: 97-104. Muder RR, Yu VL, Dummer JS, Vinson C, Lumish RM. Infections caused by Pseudomonas maltophilia. Expanding clinical spectrum. Arch Intern Med 1987; 147: 167221674. due to Xanthomonas species and non-aeruginosa 8. Elting LS, Bodey GP. Septicemia Pseudomonas species: increasing incidence of catheter-related infections. Medicine 1990; 69: 296-306.
316
M. Aoun et al.
B, Kennedy, C, Ross B. Microbial burdens in disposable and 9. Malecka-Griggs nondisnosable ventilator circuits used for 24 and 48 h in intensive care units. .Y Clin Micro&o1 1989; 27: 495-503. CD, Depaola LG, Suzuki JB. Oral 10. Minah GE, Rednor JL, Peterson DE, Overholser succession of gram-negative bacilli in myelosuppressed cancer patients. J Clin Microbial 1986; 24: 210-213. 11. De Mol P, Taca F, Vaneste R et al. Epidemic of pseudobacteremia in a general hospital. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, GA, USA. (Abstr. 1028) 1990; 257. DK, Baptiste R, Parrillo J, Gill VJ. Indolent epidemic of Pseudomonas 12. Henderson cepacia bacteremia and pseudobacteremia in an intensive care unit traced to a contaminated blood gas analvzer. Am 7 Med 1988: 84: 75-81. 13. Dufresne J, VCzina-G, Levesque RC. Cloning’ and expression of the imipenemhydrolyzing P-lactamase operon from Pseudomonas maltophilia in Escherichia coli. Antimicrob Agents Chemother 1988; 32: 819-826.
Bacteraemia Pseudomonas M. Aoun,
caused by non-aeruginosa species in a cancer centre
P. Van der Auwera”, C. Devleeshouwer*, N. Seraj, F. Meunier and J. Gerain
D. Daneau,
Clinique des Maladies Infectieuses et Laboratoire de Microbiologic, Service de Me’decine Interne et Laboratoire d’Investigation Clinique H. J. Tagnon, and * Unite’ d’Hygit?ne Hospital&e, Institut Jules Bordet, Centre des Tumeurs de I’Universite’ Libre de Bruxelles, yue Hkger-Bordet, 1; B-1000 Brussels, Belgium Accepted for publication
18 September 1992
Summary:
Fifty-one episodes of bacteraemia due to Pseudomonas species other than Pseudomonas aeruginosa occurring between 1980 and 1990 in a Belgian cancer centre were reviewed. This corresponded to an incidence of 0.62/1000 admissions, or 1.5% of all bacteraemic episodes. Twenty-nine episodes, each with several positive blood culture sets were considered clinically significant, including six patients belonging to a well-documented outbreak of pseudobacteraemia with Xanthomonas maltophilia and associated with contaminated blood sampling tubes. The respiratory tract was the source in six (20.7%), an infected intravenous catheter in 10 (34.5%) and the source was unknown in seven (24.1%). Seven patients died from infection (24.1%). Twenty-three episodes with a single positive blood culture set were considered clinically not significant, although four of them were considered significant by the Centers for Disease Control (CDC) criteria because of the presence of symptoms and specific antibiotic treatment being administered. None of the patients with a single isolate died from infection despite the fact that 17 of 22 did not receive an effective antimicrobial agent. All isolates were susceptible to co-trimoxazole.
Keywords: Pseudobacteraemia; cancer
Xanthomonas maltophilia;
Pseudomonas spp;
patients.
Introduction Infections caused by Xanthomonas maltophilia and Pseudomonas spp. other than P. aeruginosa are rare and have usually been observed as isolated cases or in small clusters of nosocomial infections.’ The reservoir of these organisms is considered to be the environment including soil, water and plants. Aqueous solutions have been the source of infections with these bacterial species as well as the cause of pseudobacteraemia. They have also Correspondence 0195-6701/92/120307+10
to: P. Van der Auwera. SOS.OO/O
0 1992 The Hospital
307
Infection
Society
M. Aoun et al.
308
been isolated from blood products, povidone iodine and chlorhexidine solutions, heparinized saline solution, anaesthetics, intravenous catheters and contaminated automatic peritoneal dialysis instruments, humidifiers and respiratory assistance instruments.’ In contrast to P. aeruginosa, neither the pathogenic potential of these organisms nor the appropriate therapeutic strategy in debilitated and immunosuppressed patients is well defined. Therefore, we have reviewed all cases of bacteraemia due to such species occurring in the period 198&90 at the Institut Jules Bordet, Belgium, a 156-bed university cancer centre.
Materials During
an 1 l-year
period
and methods
(1980-90),
57 episodes
of bacteraemia
due to
Pseudomonas spp. other than P. aeruginosa (but including Xanthomonas maltophilia) occurred, for which 52 medical records were recovered and analysed. Each blood sample was cultured in a pair of blood culture vials including tryptic soy broth with the Septicheck agar slant system (Roche, Switzerland) for aerobic culture and brain-heart infusion broth for anaerobic culture (Gibco, Belgium). Each febrile episode (> 38*5”C) was usually documented with three sets of blood cultures. Identification of non-fermenting Gram-negative bacilli was performed using the API 20 NE system (API, France). Antibiotic susceptibility testing was performed by disk diffusion on Mueller-Hinton 2 agar and according to the National Committee for Clinical Laboratory Standards (NCCLS) published at the time of isolation.2’” The following data were collect.ed from the medical records: age, sex, underlying disease, circulatory neutrophil count, presence of venous central or arterial catheters, the possible source of the bacteraemia. the antimicrobial treatment given empirically, its eventual modification in the course of the treatment and outcome. Bacteraemia was considered to be clinically significant when the same ,organism was isolated from at least two blood culture bottles from different sets. In additi,on, the Centers for Disease Control (CDC) criteria for nosocomial bacteraemia4 were applied to define clinically significant bacteraemia: fever and two positive blood culture sets, or fever, one positive blood culture and specific antibiotic treatment. Other episodes were considered not to be clinically significant. Bacteraemia was considered to be vascular catheter-related when local signs of infection were present (cellulitis, pus discharge at the exit site) or when the removed catheter was positive at culture. Occasionally, a bacteraemic episode was considered to be catheter-related in the presence of persisting positive blood cultures ( > 3 days) despite optimal antimicrobial therapy (based on in-vitro susceptibility tests), and in the absence of another focus of infection. Among the patients with several blood culture sets positive for X. maltophilia and no obvious source of infection, four were considered to be of possible clinical significance because they
Pseudomonas
bacteraemia
in cancer
309
responded favourably to specific antimicrobial treatment (co-trimoxazole); three of them had multiple positive sets of blood cultures. Results
During the 11 -year study period, the number of admissions ranged from 3250 to 5989 per year (mean of 4523), representing a total of 49 760 patients. The rate of isolation of Pseudomonas spp. and X. maltophilia was 0.62 per 1000 admissions (range: O-2.08) or zero to eight episodes per year. The mean number of bacteraemic episodes was 177 per year (42 of 1000 admissions, range: 30-53), therefore these species accounted for 15% (range: O-+8%) of all bacteraemic episodes overall. In 1989-90 an outbreak of pseudobacteraemia occurred due to X. maltophilia. Apart from this outbreak, the other bacteraemic episodes were sporadic throughout the years without evident clustering. They were not attributed to a common source of contamination, although systematic cultures of the environment were not obtained. Bacteraemic episodes were differentiated into categories according to the number of positive blood culture samples (1 and 22). Fifteen patients identified in an outbreak of pseudobacteraemia due to X. maltophilia were analysed separately. Table I compares the characteristics of the 29 patients who had at least two positive sets of blood culture bottles to those of 23 patients with one positive set of blood cultures only. The characteristics of the two groups were not different except for patients with haematological malignancies who were more likely to be neutropenic in the group with significant bacteraemia. Of the 29 patients (56.8%) considered to have significant bacteraemia (including patients l-6 from Table III), 27 had an active malignancy at the time of bacteraemia and most were not neutropenic (68.9%). Xanthomonas maltophilia was predominant, followed by Pseudomonas cepacia and other species of pseudomonads. An intravenous catheter was considered as the source of bacteraemia in 10 patients and the respiratory tract in six patients. In seven patients the origin of bacteraemia remained unknown. In 10 catheter-related bacteraemias, the iv device had to be removed for persisting or recurrent bacteraemia. All patients treated adequately (causative strain susceptible to the treatment given empirically) recovered clinically (Table II). Among seven patients who died from infection, four did not receive an antimicrobial agent. Of 23 patients with bacteraemia deemed not to be significant, five patients received an active 1 week after isolation of the antimicrobial agent. None died within presumably contaminating strain, three died within 1 month from underlying disease. All strains were susceptible to co-trimoxazole. Among Xanthomonas maltophilia, resistance to imipenem was the rule, half of them were resistant to ceftazidime, other third generation cephalosporins and amikacin. Six strains were susceptible to ticarcillin: four Pseudomonas spp., one P. cepacia, and one P. stutzeri.
M. Aoun et al.
310 Table
I. Characteristics
of the patients with bacteraemia due to non-aeruginosa Pseudomonas spp. and Xanthomonas maltophilia Bacteraemia clinically significant
No. of patients Underlying diseases Non-malignant disease Malignant disease Solid tumour with neutropenia (< 1 X IO9 1-l) without neutropenia Haematological malignancy with neutropenia without neutropenia Age (years) median range Sex males females Causative organisms
Pseudomonas cepacia Xanthomonas maltophilia Pseudomonas spp. Source of bacteraemia Central venous catheter Respiratory tract Acute cholangitis Unknown Unknown and associated pseudobacteraemia
P value for a single-tailed
Table
P
Bacteraemia not clinically significant
29
(56.8%)
23
(43.2%)
2 27
(3.9%) (96.1%)
3 20
(13.0%) (87.0%)
1 14
;:
8’ 3 10 55 13-83 10 13
8 5: 15-83 :;
7
(24.1%)
15 7
(51.7%) (24.1%)
10 6 2 7
14
4
9
-=c0.05
with
chi* test. NS= not statistically
significant
II. Treatment and outcome in patients with clinically Pseudomonas spp.
(P>O.OS).
significant bacteraemia due to
Treatment/outcome
No. of patients
Patients who received antibiotic therapy Recovered Death from underlying disease within
22 22 5
1 month
of bacteraemia
(%)
(100) (22.7)
Patients who did not receive antibiotic therapy Recovered Death from infection (all within 48 h)
7 3 4*
(57.1)
No. of cases of septic shock Total deaths from infection
2 4
(13.8)
Total
patients
with
bacteraemia
* Two from septic shock (one with pneumonia), tography acute cholangitis.
29 one with pneumonia, one with post-cholangiopancrea-
Pseudomonas
bacteraemia
in cancer
311
Table III shows the characteristics of the 15 patients who had positive blood cultures with Xunthomonas maltophilia during an outbreak of pseudobacteraemia involving two hospitals (Hopital St-Pierre and Institut J. Bordet) supplied with the same batch of tubes used for blood matching and containing citrate buffer as anticoagulant. The citrate buffer was heavily contaminated with a strain of Xanthomonas maltophilia and a strain of AZcaZigenes denitrificans. Surprisingly, only one patient not included in the present study developed bacteraemia with A. denitri&ans. Two of the 15 patients had a totally implantable catheter (‘Portacath’, Pharmacia, Sweden) which was superinfected with the contaminating strain of X. maltophilia as evidenced by persisting bacteraemia and culture-positivity of the catheter after removal. In four other patients, CDC criteria strongly indicated that the episode was clinically significant. Treatment with co-trimoxazole was associated with resolution of fever. An additional patient received co-trimoxazole but had a well-documented bacteraemia with a coagulase-negative staphylococcus and Corynebacterium jekeium related to a central venous catheter which had to be removed for persisting bacteraemia. The eight remaining patients were not treated as they were considered to have pseudobacteraemia, despite multiple positive blood cultures in two instances. Discussion The most common non-fermenting Gram-negative rod causing bacteraemia in cancer patients continues to be P. aeruginosa. Species of non-aeruginosa pseudomonads, including X. maltophilia are rarely isolated. Our study reviewed 52 episodes of bacteraemia of which 29 were considered to be significant (at least two blood cultures positive from different sets). Using the CDC criteria for significant bacteraemia,4 four additional episodes with a single positive blood culture set were thought to be significant because treatment seemed to be effective. Review of the medical records could exclude the clinical relevance of the bacteraemic isolate in the febrile illness of these four patients. Based on this review, the CDC criteria had a sensitivity of 100% and a specificity of 82%. There are only a few reports of bacteraemia due to Pseudomonas spp. other than P. aeruginosa and Xunthomonas in cancer patients. During 5 years, Pseudomonas putida was recovered from 15 patients with cancer.5 Eight were considered to have true bacteraemia using criteria similar to ours, of whom six had haematological malignancy. Five had polymicrobial bacteraemia and three had catheter-related bacteraemia, requiring removal of the vascular device in two of them. Third-generation cephalosporins, imipenem and ciprofloxacin were active in vitro. Kim et aZ.‘j reported four patients (during a 12-month period) and reviewed seven others from the literature with bacteraemia due to Pseudomonas putrefuciens. Two of them had cancer, of whom one had polymicrobial bacteraemia and died of sepsis.
F8)
(F54)
E,
:;‘o,
clinical
rj:8)
carcinoma
CML (+I
ALL (+I
Gastric (-)
significance CML (+I
cancer
Head and neck cancer f-1
Colon C-1
112
S/16
618
112
314
4/g
318
No. of positive blood culture bottles/total obtained
ND
ND
ND
ND
ND
not treated
Co-trimoxazole (9 days)
Co-trimoxazole (10 days)
Co-trimoxazole (7 days)
Co-trimoxazole (12 days)
Co-trimoxazole (8 days)
Port-a-Cath
days)
Co-trimoxazole (9 days)
Treatment (duration,
Port-a-Cath
Source
due to Xanthomonas maltophilia occurred during an outbreak contaminated blood sampling tubes (May 1989-ranuary 1990)
Underlying disease (+ / - ; neutropenia”)
whose bacteraemia
Not clinically significant M ALL 7 (40) (+)
6
5
4
Possible 3
2
F4)
significant
Clinically 1
Patients
Sex (age, years)
III.
Patient
Table
Recovered
Recovered
Recovered
recovered
removed,
associated
arrythmia
removed,
Died of cardiac (day 8)
Recovered
Catheter
Relapse, catheter recovered
Outcome
of pseudobacteraemia
with
k 9 2 3 rb ii 5
Pseudomonas
bacteraemia
in cancer
313
314
M. Aoun et al.
Xanthomonas maltophilia has only occasionally been associated with significant infection in humans with the exception of cystic fibrosis patients. Recently, ecthyma gangrenosum was reported in a patient with acute leukaemia.7 Elting et aZ.* reviewed 149 episodes, in 13 1 patients, of clinically significant bacteraemia due to Pseudomonas other than P. aeruginosa and X. maltophilia over 15 years. Xanthomonas maltophilia occurred in 46% followed by P. stutzeri, P. putida (11% each) and other species. The incidence increased from a range of one to four of 10 000 admissions before 1979 to a plateau of eight of 10 000 admissions for Xanthomonas and six of 10 000 admissions for Pseudomonas spp. The most common sites of infection associated with bacteraemia were pulmonary (40%), as in our study, and soft-tissue infection (12%). The relation between appropriate treatment and favourable outcome was as strong as observed here with 86% response in 108 patients treated appropriately and 59% in 27 who received inappropriate antibiotics. Catheter-related infection was proven in 57 patients, of whom 12 had relapse until the catheter was removed. This review deserves several comments. None of the bacteraemic episodes seemed to be associated with an outbreak although water faucets and drains from a medical intensive care unit were colonized by X. maltophilia. Pseudobacteraemia was not considered despite the high number of ‘non-significant’ isolates, in contrast with several reports from the literature and the present report that includes an outbreak of pseudobacteraemia. In addition to P. aeruginosa, P. cepacia and P. putida have the capacity to colonize the condensate that accumulates in ventilator circuits.’ Beside the risk of direct contamination of various devices from the environment, cancer patients may be colonized in the digestive tract, a secondary reservoir for further infection. Major factors for intestinal colonization may be antibiotics given orally or iv when biliary excretion of the drug is high, as well as anticancer chemotherapy. During myelosuppressive chemotherapy, non-fermenting Gram-negative bacilli may proliferate in the gut, including P. aeruginosa but mainly P. pickettii, P. stutzeri, P. cepacia and X. maltophilia.” We found that contamination of blood sampling tubes by X. maltophilia could result in an outbreak of pseudobacteraemia but also in true contamination of iv lines during the manipulation of the device. Although it was not possible to prove by microbiological investigation, we believe that contamination of the iv lines may have arisen from heavily colonized hands or gloves of staff. Nurses from the laboratory sampling team occasionally collected blood both for laboratory tests and blood cultures. Some of these nurses used to open the blood collection tubes after skin disinfection and before sampling, allowing the possibility of colonization of hands with the contaminated citrate buffer. It was possible to demonstrate that the isolate from the citrate buffer and those recovered from the 15 patients were indistinguishable by polyacrylamide gel electrophoresis of whole cell proteins (H. Goossens, Microbiology Laboratory, University Hospital
Pseudomonas
bacteraemia
in cancer
315
Saint-Pierre, Brussels). ‘i By contrast, unrelated endemic strains had a variety of different patterns. The outbreak ended when all contaminated tubes were replaced by gamma-ray sterilized tubes and the techniques of blood culture sampling and catheter-care had improved. A similar outbreak was reported by Henderson et aZ.‘* where P. cepacia contaminated a blood gas analyser, resulting in two cases of pseudobacteraemia and 14 genuine cases of bacteraemia. All X. maltophilia are resistant to imipenem by virtue of a zinc-containing penicillinase. i3 In addition, this sp ecies contains a class I j3-lactamase enzyme similar to that present in P. aeruginosa. All strains from the several species isolated by us were susceptible to co-trimoxazole which is considered to be the first-line antimicrobial agent. Most strains were susceptible to the third-generation cephalosporins and amikacin, which is the most common combination used for the empirical treatment of Gram-negative bacteraemia. All strains (except Xanthomonas) were susceptible to imipenem. Our study demonstrates the emergence of these unusual species of pseudomonads as a cause of clinically significant bacteraemia in cancer patients whether neutropenic or not. Interestingly, several infections were catheter-related, and despite effective antibiotic treatment the infected catheters had to be removed. Mortality associated with these episodes was 14%, most occurring within 2448 h. Our study shows also that contamination of blood sampling tubes, in addition to being responsible for pseudobacteraemia, may result in clinically significant bacteraemia through contamination of an iv catheter.
References 1. Sanford JP. Pseudomonas species (including Melioidosis and Glanders). In: Mandell GL, Douglas RG, Bennett JE, Ed. Principles and Practice of Infectious Diseases, 3rd edn. London: Churchill Livingstone 1990; 1692-l 695. 2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests, 3rd edn (M2-A3). 771 East Lancaster Ave, Villanova, PA 19085, USA 1984. 3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests (M2-T4). 771 East Lancaster Av, Villanova, PA 19085, USA 1988. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988 J Infect Control 1988; 16, 128-140. Anaissie E, Fainstein V, Miller P et al. Pseudomonas putida: newly recognized pathogen in patients with cancer. Am J Med 1987; 82: 1191-l 194. Kim JH, Cooper RA, Welty-Wolf KE, H arrell LJ, Zwadyk P, Klotman ME. Pseudomonas putrefaciens bacteremia. Rev Infect Dis 1989; 11: 97-104. Muder RR, Yu VL, Dummer JS, Vinson C, Lumish RM. Infections caused by Pseudomonas maltophilia. Expanding clinical spectrum. Arch Intern Med 1987; 147: 167221674. due to Xanthomonas species and non-aeruginosa 8. Elting LS, Bodey GP. Septicemia Pseudomonas species: increasing incidence of catheter-related infections. Medicine 1990; 69: 296-306.
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B, Kennedy, C, Ross B. Microbial burdens in disposable and 9. Malecka-Griggs nondisnosable ventilator circuits used for 24 and 48 h in intensive care units. .Y Clin Micro&o1 1989; 27: 495-503. CD, Depaola LG, Suzuki JB. Oral 10. Minah GE, Rednor JL, Peterson DE, Overholser succession of gram-negative bacilli in myelosuppressed cancer patients. J Clin Microbial 1986; 24: 210-213. 11. De Mol P, Taca F, Vaneste R et al. Epidemic of pseudobacteremia in a general hospital. 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Atlanta, GA, USA. (Abstr. 1028) 1990; 257. DK, Baptiste R, Parrillo J, Gill VJ. Indolent epidemic of Pseudomonas 12. Henderson cepacia bacteremia and pseudobacteremia in an intensive care unit traced to a contaminated blood gas analvzer. Am 7 Med 1988: 84: 75-81. 13. Dufresne J, VCzina-G, Levesque RC. Cloning’ and expression of the imipenemhydrolyzing P-lactamase operon from Pseudomonas maltophilia in Escherichia coli. Antimicrob Agents Chemother 1988; 32: 819-826.