Epidemiology of Klebsiella bacteraemia: a case control study using Escherichia coli bacteraemia as control

Journal

of Hospitul

Injection

Epidemiology control study

D. Schroder

(1998)

38,

11 O-1 32

of KZebsieZZa bacteraemia: a case using Escherichia coli bacteraemia as control Hansen*,

A. Gottschauf

and H. Jern

Kolmos$

*The International Escherichia and Klebsiella Centre (WHO), Statens Serum Institut, Copenhagen; j-Department of Biostatistics, Statens Serum Institut, Copenhagen, and Institute of Preventive Medicine, Copenhagen Universit_\. Hospital; and $Department of Clinical Microbiology, Hvidovre Hospital, University of Copenhagen, Denmark Received 9 May

1997; revised manuscript accepted 3 September 1997

Summary: Epidcmiological data from 117 cpisodcs of Klehsiellu bactcracmia were compared bvith those from matched controls with Bscherichiu coli hacteraemia. Cases and controls \yere obtained from 20 631 blood cultures taken from patients in Hvidovre Hospital between 1990 and 1992. The data studied included: sex and age, risk factors, portal of entry, outcome, nosocomial acquisition and distribution within the hospital. The incidence of Klehsiella hacteraemia was 9.3/10 000 admissions (76% Klehsiella pneumoniur; 24% Klehsielln oxytoca). Patients with Klebsiella and E. roli hacteraemia had many common features, including a high incidence of neoplastic disease, hiliary tract disease, and renal failure. Many had undergone surgery or received therapy with steroids, antacids or antibiotics. Klebsida hacteraemia was more often found in males, in patients with hospital contact within the previous month, and polymicrohial infection. Logistic regression analysis showed that use of invasive plastic devices and diabetes bvere significantI> associated with Klebsiellu hacteraemia. The urinary tract was the commonest source, followed by the hiliary tract; 27% of patients had no obvious focus of infection, and in many of these an invasive device may have been involved. Forty-tive K-serotypes were found-the largest number being nine strains of type K3; only a few strains had acquired resistance characters to antimicrobial agents. ‘rhere bvvere no differences between communityand hospitalacquired strains; indicating that our hospital docs not have a resident strain of Klebsiellu. Keywords: Klrb.siel/u nosocomial infection; fection; serotyping.

bacteraemia; epidemiology;

E.

co/i hacteraemia; diabetes mellitus;

case-control device-associated

study; in-

Introduction Klebsiella is an important cause of hospital-acquired infections, accounting for 16.7 episodes per 10 000 patient discharges.’ After Escherichia coli, it is C’orrcspondencc Statcns Strum

to: I>r I>. S. Hansen, ‘I’hti Intcrnaticmal Eschcrichia and Klchsiclla lnstitut, Artillcrivej 5, DK-2300 Copcnhagcn S. Denmark.

Ccntrr

(\VI IO).

120

D. Schreder

Hansen

et al.

the commonest cause of Gram-negative septicaemia with a case fatality rate of 25~50%.*-~ Klebsiella may acquire resistance to many different antimicrobial agents, and multiply resistant strains give rise to therapeutic problems worldwide.‘s9 Despite its major role in nosocomial infections, the clinical characteristics of Klebsiella infection are only partly elucidated. Epidemiological data cannot easily be compared because it is difficult to differentiate between data that are characteristic of Klebsiella and those that reflect local conditions. One way to overcome this problem is to undertake a case-control study, using a well-known organism as a control. To our knowledge studies of this kind have not been performed for Klebsiella bacteraemia. The purpose of this investigation was to study the epidemiology of Klebsiella bacteraemia in a case-control design, using E. coli bacteraemia as the control. The data studied included sex and age of patients, risk factors, portal of entry, outcome, nosocomial acquisition and distribution in hospital. We also wanted to investigate whether nosocomial Klebsiella strains differed from community-acquired strains with regard to serotype and antimicrobial resistance patterns. Patients

and

methods

One hundred and seventeen consecutive cases of Klebsiella bacteraemia, which occurred in patients admitted to Hvidovre Hospital between 1990 and 1992, were studied along with 117 cases of E. coli bacteraemia in a one-to-one matched case-control study. The blood culture register of the clinical microbiological department from the three years was reviewed, and data from patients who had at least one blood culture positive for Klebsiella were registered. Each case was matched by the nearest preceding patient with E. coli bacteraemia. The matching thus took account of a possible time trend. Case records were obtained for all the patients and clinical and laboratory data were registered electronically. Blood culture was performed using a two-bottle system with 10 mL in each bottle (Colorbacts, Statens Serum Institut, Copenhagen, Denmark).‘” Identification of Klebsiella strains as K. pneumoniae or K. oxytoca was made with an enzyme test panel (MinibactR, Statens Serum Institut, Copenhagen, Denmark).” Serotyping was done by counter current immuno-electrophoresis (CCIE) using a modification of the method described by Palfreyman.12 An extractI was used as antigen instead of a whole cell suspension, with the modification that it was only heated once for 1 h at 100°C before centrifugation. All strains with negative or doubtful reactions in CCIE were investigated by the classical quellung reaction.14 Antibiotic susceptibility was tested by the agar diffusion method using Neo-sensitabs (Rosco Diagnostica, Denmark) on Danish Blood Agar.”

Epidemiology

of

Klebsiella

bacteraemia

121

DeJinitions An episode was defined as at least one positive blood culture. Positive blood cultures with other organisms that occurred within two weeks before or after the index blood culture were assigned to the episode. Bacteraemia was classified as polymicrobial if micro-organisms other than the index organism were isolated from the index blood culture or from other blood cultures taken during the episode. The bacteraemia was considered confirmed if the same species with a similar resistance pattern was isolated from two separate blood culture sets or from one blood culture set and at least one other type of specimen. The bacteraemia was considered probable if the organism was isolated in one, when only one blood culture set was taken, and doubtful if the organism was isolated from one of several blood culture sets. The bacteraemia was defined as nosocomial if the organism was isolated from blood cultures obtained at least 48 h after admission, or if the patient had been hospitalized or had undergone invasive procedures in an outpatient clinic during the previous four vveeks. All other episodes were considered community-acquired. The presence of one or more of the following conditions was recorded: a major underlying disease (MUD): cancer (N= SC;), alcoholic liver cirrhosis (N= 23), human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (N= 5), renal failure with need of dialysis (N= 9), intracranial haemorrhage (N= 3), >30% burns (N= 2), multiple trauma (N= 2), gastrotomy sequela with several stomas (N= 2), myocardial infarction (N= l), Crohn’s disease (N= l), meconium aspiration (N= 1) and chronic aggressive hepatitis (N= 1). In\-asive plastic devices (IPD) included one or more of the following: endotracheal tube, biliary tract prosthesis, central venous catheters (CVC) and nephrostomy, ureteral, biliary and pleural catheters. A microbiologically verified focus was defined as a clinically evident focus, from which the same organism was isolated at the time of bacteraemia (e.g., urine, sputum, pus, tip of venous catheter). A lower respiratory tract focus was defined as the presence of clinical signs of pneumonia and infiltrates on chest X-ray. Microbiological verification demanded both microscopic demonstration and culture of the organism in relevant material from the lower airways. Shock was defined as the presence of clinical signs of impaired circulation and at least one of the following conditions: systolic blood pressure ~90 mm Hg, drop in blood pressure by >70 mm Hg, or treatment with sympathomimetic agents. Statistical methods As a result of a literature survey, 39 variables were studied (those 30 variables shown in Table III and sex, age, detection time, nosocomial cases, previous hospital contact, polymicrobial cases, clinical significance, focus

122

D. Schreder Table

I. Distribution

Hansen

et al.

in hospital of Klebsiella teraemia

Department

and

E. coli

Klebsiella

E. coli

0(12) m*

Infectious diseases Medical gastroenterology Surgical gastroenterology Rheumatology Nephrology Urology Neonatal intensive care Endocrinology Other departments

14 14 8 10 15

Total

bac-

9 18 18 4 8 15 1

(7) (3)

(6) (13)

(6) (12) (12) (3) (7) (8) (1)

6 (2)

z (‘:I 28 (24)

21 (15)

100 (72)

100 (66)

The number of episodes in the six most common departments organism have been included. * Number of nosocomial cases according to definition.

for each

of bacteraemia and outcome). First, all 39 variables were tested in an univariate analysis using McNemar’s test. Second, a conditional logistic regression analysis for the matched observations was made using the seven variables in which a statistically significant difference had been found in the univariate analysis, and those variables that could be suspected to be dependent of each other from a clinical point of view (e.g., operation and the use of CVC).‘” A stepwise procedure was used to eliminate nonsignificant variables. The significance level was 5%. Results

Over the three-year period, 117 episodes of Klebsiella bacteraemia were identified among 20 631 blood cultures. No obvious outbreaks were encountered. The average incidence was 9.3 episodes per 10 000 admissions. K. pneumoniae accounted for 89 (76%) and K. oxytoca for 28 episodes (24%). Seventeen patients with Klebsiella also had E. coli isolated from blood cultures within the period defining the episode. They were, therefore, together with their controls, excluded from the following calculations, which thus included 100 cases (77 K. pneumoniae, 23 K. oxytoca) and 100 controls. As no differences could be found between bacteraemia with K. pneumoniae and bacteraemia with K. oxytoca, Klebsiella bacteraemia will refer to both. Distribution in hospital Table I shows the distribution of cases and controls in hospital. Generally there was no difference in the distribution of cases and controls between

Epidemiology

of

Klebsiella

bacteraemia

123

departments, except for the department of infectious diseases where no Klehsiella cases were found. The proportion of nosocomial cases did not differ significantly between the departments. Sex and age distribution There were significantly more males among patients with Klebsiella (58%) than E. coli (42%). On the whole, there was no difference in age between the two groups (median age 71 years vs. 72 years). However, in the I?‘. co/i group females tended to be older than males (median age 75 years vs. 64 years), whereas in the Klebsiella group the two sexes were of similar age (median age 71 years vs. 70 years). Detection time for positive blood cultures For the blood cultures with Klebsiella 64% were positive after one day and 88% after two days of incubation. For the blood cultures with R. coli the corresponding figures were 71 and 90X, respectively (NS). Nosocomial cases and previous hospital contact In 56 of the Klebsiella cases, blood cultures had been taken >48 h after admission to hospital. In addition, 16 patients had been hospitalized or had undergone invasive procedures in an outpatient clinic during the previous four weeks. For E. coli the corresponding figures were 53 and 13. ‘l’hus, 72% of the Klebsiella cases and 66% of the E. coli controls were nosocomial according to the definition (NS). However, more patients in the Klebsiella group had been hospitalized or had undergone invasive procedures during the previous four vveeks (50 vs. 34%; P=O.O2). Polymicrobial cases From the first blood culture set defining a case of Klebsiella bacteraemia, bacteria other than Klebsiella were isolated on 18 occasions. Among the E. coli controls other bacteria were isolated in 10 cases (P=O.O8). From other blood cultures taken during the episode other bacteria were isolated in seven Klebsiella cases and five E. coli controls. Thus, a total of 25% of Klebsiella bacteraemia episodes were polymicrobial, versus 15% of E. coli episodes (P= 0.05). Clinical significance The number of confirmed, probable, and doubtful cases in the Klebsiella group were 36, 46 and 18, respectively. For the B. coli group the corresponding numbers were 65, 27 and 8. Thus there were fewer cases of confirmed bacteracmia in the Klebsiella group (WO.00002). This was primarily due to a lower number of cases with a microbiologically verified primary focus in the Klebsiella group (29 vs. 54; P=O.O004).

124

D. Schreder Table

II.

than

et al.

Portal of entry in 100 cases of Klebsiella and 100 cases of E. coli bacteraemia

Lower respiratory tract Urinary tract Central venous catheter Wound and abscess Biliary tract Other foci No known focus Numbers * More

Hansen

bacteraemia

Klebsiella

E. coli

5* 45 4 7 I7 1 27

5 69 1 7 I3 7 18

in brackets indicate microbiologically one focus can occur in each patient.

(1) (21) (4) (3) (1) (1)

documented

(1) (44) (1) (7) (1) (5)

cases.

Focus of bacteraemia Table II shows the portals of entry. The urinary tract was the most important focus in both groups. However, a bacteriologically verified urinary tract focus occurred less often among Klebsiella patients (P= 0.004). For 27 cases and 18 controls no demonstrable focus could be found (NS, P=O.19). Outcome The overall mortality four weeks after detection of bacteraemia was 19% in Klebsiella cases and 20% in E. coli controls (NS). Mortality was the same for both organisms among confirmed, probable and doubtful cases (Klebsiella: 19.4, 17.4 and 22.2%, E. coli: 21.5, 18.5 and 12.5%). Underlying conditions The distribution of underlying conditions in patients with Klebsiella and E. coli bacteraemia is shown in Table III. Diabetes mellitus occurred with a higher frequency in the Klebsiella group, whereas patients with HIV or AIDS were more common in the E. coli group. Most patients in both groups had at least one major underlying disease (MUD)-only 19 cases and 33 controls were without. Monotherapy with ampicillin tended to be more common among patients with Klebsiella bacteraemia. Four of the six patients in the control group who had received monotherapy with ampicillin had bacteraemia with an ampicillin-resistant E. coli strain. Operations or other invasive therapeutic procedures during the previous four weeks tended to be more common among Klebsiella patients. However these patients were also more likely to have had a CVC and to have been given iv nutrition (data not shown). The number of patients with various invasive plastic devices was too low to show significant differences (except for CVC), but in toto patients with

Epidemiology ‘Table

III.

The

distrihzction

of

Klebsiella

bacteraemia

125

of ruzder~yingconditionsin patients with

Klebsiella

and

E.

coli

hacteraemia Klehsiella Clinical conditions Diabetes mellitus Neoplastic disease III\‘-infected or AIDS Biliary tract morbiditv Alcoholic liver cirrhosis Renal failure Urinary tract obstruction Pancrwtitis Prematurity Major underlying disease Leukocyte ~3.8 x lO”/I, Ixukocyte >I 1 .O x 1 o”/L Shock Smoking Alcoholism, not cirrhosis

21 29 0 35 9 34 26 6 8: 7 61 16 42 10

(‘XI)

E. coli (‘XI)

9 27 0 26 14 35 22 6 1 67 II 61 10 36 0

0.01

0~07 0.04

‘I’herapeutic factors Operation Iv nutrition Antimicrobial treatment Ampicillin monotherapy Antacids Steroid treatment Cytostatic treatment Hlood transfusion

49 11 57 14 17 10 6 35

36 4 54

I>evices Ilndotracheal tube Central venous catheter Peripheral venous cath. Biliary tract prosthesis Nephro/bile/pleural cath. Indwelling urinary cath. Invasive plastic device

8 27 I”, 11 0 20 43

4 1-F 22 5 5 IX 23

* \Vithin

precetling

P-value

0.03

0.12 I:: I3 6 30

0.03

a.01

4 weeks

Klehsiella bacteraemia had a higher frequency of invasive plastic devices (IPD). In the conditional regression analysis the outcome was the proportion of Klebsiella bacteraemias. The explanatory variables included were: sex, age, diabetes mellitus, operation, iv nutrition, IPD and MUD. Table IV shows the proportion of patients with Klebsiella bacteraemia according to presence or absence of each of the seven variables for all 200 patients. Five variables were excluded in a step-by-step procedure as they had no statistically significant effect of their own. First MUD was excluded (P=O.65), then age (P= 0.46), operation (P= 0.41), iv nutrition (P=O.30) and finally sex (P=O.O9). Only diabetes mellitus and IPD had a significant effect of their

126

D. Schreder Table IV. Proportion of patients with or absence of each of the seven variables

Hansen Klebsiella included analysis

et al. bacteraemia according to presence in the conditional logistic regression

Variable

Patients Number

5L ex

Diabetes Operation Iv

nutrition

Invasive

plastic

Major

Table

device

underlying

V. Percentage

disease

resistance

to nine antibiotics among the listed breakpoints

Minimum concentration

*

Number

of tested

inhibitory (mg/mL) >l >6 >2 ,2 >4 >4 >3 22 >l

Tetracycline Chloramphenicol Ampicillin Mecillinam Gentamicin Netilmicin Cefuroxime Cefotaxime Ciprofloxacin

1:: 88

Male Female <70 years > 70 years No Yes No Yes No Yes No Yes No Yes

Age

N*

96 113 116 69 114 117 117 94 112

Klebsiella bacteraemia

:; 53 47 47 70 44

112 170

1:: 85 185

2; 73 43

1:: 66 52 148

117 Klebsiella

Nosocomial

3 1:: 35 0 0 :, 1

i:: 55

bacteraemia

strains

Community

at

acquired

7 9 100 30 0 z 0 3

strains

own, whereas sex was on the borderline of significance. The odds ratio for diabetes was 2.51 (95% confidence interval 1*04-6.10), for IPD the odds ratio was 2.42 (9.5% confidence interval 1.23-4.76). Antimicrobial resistance characters Table V shows the individual antimicrobial resistance characters for all 117 Klebsiella bacteraemia isolates. The only acquired resistance character of numeral importance was resistance to mecillinam. There were no differences in antibiotic resistance between nosocomial and community-acquired isolates.

Epidemiology ‘I’able

VI.

K-type

of Klebsiella

bacteraemia

of 102 Klebsiella

hacteraemia

Number K-type

Nosocomial

1 2 3 6 16 18 21 2-C

1 3 5 2 2 2 1 2

30 31 35 39. 46 43’ 52 5S 61 h4 b8 74 7’1 Xl N’l’

2 3

strains

of each

Community

type acquired

1 0 1 1 0 1 2 2

0 0 3 2 3

2 2 3

K-types, *K-type: 47, 4x,

of strains

127

single

53,

isolates*

7, 8, 9, 10, 10, 61, il, 57, 62, 63.

17 11,

15, 20,

25,

.59, 26,

32,

33,

31,

37,

RX,

Serological typing Of the 117 Klebsiella bacteraemia isolates, 102 were available for K-typing. The total number of K-types was 45 and the largest number of any Ktype was nine of K-type K3 (Table VI). S ix isolates were non-typeable (NT), and a few strains showed association to more than one K-type (K10, 61, K25,59 and K39,46). There were no differences in K-types between nosocomial and community-acquired cases. Three patients had Klebsiellu bacteraemia twice with the same K-type (K79, K3 and K3). The intervals between the first and the second episode were three, eight and 31 weeks, respectively. Discussion

Th epidemiology of Klebsiella infections has been described in several studies, but to our knowledge only three have used a case-control, and none of them had bacteraemia as the study object.“-‘” The lack of a control

128

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et al.

makes it difficult to evaluate whether the epidemiological characteristics that are reported characterize Klebsiella bacteraemia as such, or reflect the characteristics of the hospital, in which the study took place. Klebsiella bacteraemia has been found to be associated with malignancy,6 hepatobiliary diseases,‘” prior surgery,” alcoholism and alcoholic liver cirrhosis,22 steroid therapy,23 previous antibiotic therapy,6 chemotherapy,23 neutropenia24 and measles.25 The portal of entry has most often been the urinary tract,21724but the respiratory tract6,22,23and the biliary trac? have been reported as the most common foci. Using E. coli bacteraemia as baseline, it was possible to identify epidemiological features characteristic for Klebsiella bacteraemia. E. coli was chosen as a control because it is a well-characterized organism and the commonest cause of nosocomial and community acquired Gram-negative bacteraemia; in our hospital E. coli bacteraemia is three-times more frequent than Klebsiella bacteraemia.’ Like others we found that the group of patients with Klebsiella bacteraemia had a high prevalence of neoplastic diseases, biliary tract morbidity and renal failure. Furthermore, a high proportion of the patients had undergone surgery or had been treated with steroids, antacids or antibiotics. But so had the group of patients with E. coli bacteraemia. When tested by a conditioned logistic regression analysis, only the presence of diabetes mellitus and IPD differed significantly between the two groups, while male sex showed borderline significance. Diabetes has been mentioned as a predisposing factor in several previous studies. 20,22,23,26,27 However, as a result of the study design, this is the first time that such a clear connection between diabetes and Klebsiella bacteraemia has been found. Lee2’ suggests that the association could be due to the impaired phagocytic function of leucocytes seen in diabetic patients. Another explanation could be a potential association between plasma or urine glucose level and production of capsular material. Artificial growth media with excess carbohydrates enhance the production of capsular substance in vitro.2y,30 An elevated plasma glucose level might lead to enhanced capsule production in Go. As the capsule is a well-known virulence factor this could explain the increased incidence of Klebsiella bacteraemia in diabetics.31-33 Since 0rskov34 described the importance of instrumentation and catheterization of the urinary tract for urinary tract infection, in 1952, several others have confirmed this finding.‘7*‘y*26.35The importance of endotracheal intubation for colonization/infection is well known.‘7,3h,37 An increased incidence of Klebsiella infections has also been associated with iv catheterization.38 Our finding that the presence of a IPD was associated with a greater risk of Klebsiella bacteraemia, strengthens the association between biomaterials and Klebsiella, and points at the ability of this organism to colonize biomaterial surfaces. The general trend that hospitalized patients become older, more immunocompromised and receive more intensive

Epidemiology

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bacteraemia

129

therapy, could lead to even more Klebsiella infections in future. The predominance of men among patients with Klebsiella bacteraemia has been found in most other studies. This is understandable in studies where the population studied is predominantly male,‘X,“‘x2” but the reason is more Lesions in the urinary tract following obscure in other studies. 6,17,2’,22,24 catheterization in males could play a role. The most common focus in this study was the urinary tract, whereas the respiratory tract was a rare focus. This may be due partly to the very strict criteria for a lower respiratory tract focus, and partly to the fact that the socio-economic conditions associated with primary K. pneumorziae pneumonia2’ are rarely found in Denmark. Another important focus w:as the biliary tract. Howev.er, the second most frequent tinding among both cases and controls was of an unknown focus. This was most evident among the Klebsiella cases, where one out of four patients had a unknown focus. With the demonstrated association of Klebsiella to IPD, one might speculate whether in a number of cases IPDs do in fact represent a clinically unrecognized focus. Twelve of the 27 cases without a known focus had a CVC. More Klebsiella bacteraemias were polymicrobial (25% vs. 15%). This number is an underestimate, as the 17 cases with both Klebsiella and E. coli bacteraemia were excluded. Thus, when looking at all 117 Klebsiella bacteraemia episodes, 36% were polymicrobial, with E. coli as the most frequent second micro-organism found. Klebsiella bacteraemia was associated with the same case fatality, whether bacteraemia was categorized as confirmed, probable or doubtful, according to our definition. ‘l‘his confirms previous observations that Klebsiella is a primary pathogen and that isolates from blood cultures should be regarded clinically relevant in all cases.2h.3” The six patients with HIV/AIDS included in this study all had E. coli bacteraemia. The reason for the absence of Klebsiella bacteraemia in these patients remains unclear, however, it could indicate that E. coli generally is more virulent than Klebsiella spp. or it may reflect that HIV/AIDS patients compared with other patients with an similar degree of immunosuppression have fewer invasive catheters. Serotyping disclosed 45 K-types among the 102 investigated isolates. Whether any of the small groups of patients with the same K-type include single cases or small clusters of cross infection cannot bc determined from this study. However, the results clearly show that no outbreaks took place in the study period. Three patients had bacteraemia twice with the same K-type, isolated with intervals of 3, 8, and 31 weeks, respectively. This underscores the well-known potential of Klebsiella to colonize patients ov’er a long time.“‘,“’ Klebsiella is often considered a typical nosocomial pathogen in contrast to E. coli which is predominantly thought to be community-acquired. We found that the proportion of nosocomial cases was the same for both organisms, although patients with Klebsiella bacteraemia had more often had hospital contact within the preceding four weeks. Furthermore, there

130

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were no differences in resistance characters and serotypes between nosocomial and community acquired Klebsiella strains. This indicates that no special hospital flora of Klebsiella exists in our hospital. The majority of isolates categorized as nosocomial according to our definition are probably selected from the patient’s endogenous flora, which they bring with them on admission to hospital. Similar observations have been made in our hospital with E. coli and Enterobacter cloacae.42’43The low frequency of acquired resistance characters found in our Klebsiella isolates is in striking contrast to the results from other parts of Europe, where up to 41% of isolates display resistance towards third generation cephalosporins.44,45 This low frequency of resistance may be ascribed to the low consumption of antibiotics in our country.46

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Epidemiology

1X.

1Y.

20.

21.

22. 23. 24. 25. 26. 27. 28. 2Y. 30.

31. 32. 33. 34. 35.

36. 37.

38. 3’).

40. 41. 42.

of Klebsiella

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