Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical patterns. (Research).

We initiated a worldwide collaborative study, including 455 episodes of bacteremia, to elucidate the clinical patterns of Klebsiella pneumoniae. Historically, community-acquired pneumonia has been consistently associated with K. pneumoniae. Only four cases of community-acquired bacteremic K. pneumoniae pneumonia were seen in the 2-year study period in the United States, Argentina, Europe, or Australia; none were in alcoholics. In contrast, 53 cases of bacteremic K. pneumoniae pneumonia were observed in South Africa and Taiwan, where an association with alcoholism persisted (p=0.007). Twenty-five cases of a distinctive syndrome consisting of K. pneumoniae bacteremia in conjunction with community-acquired liver abscess, meningitis, or endophthalmitis were observed. A distinctive form of K. pneumoniae infection, often causing liver abscess, was identified, almost exclusively in Taiwan.

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Klebsiella pneumoniae is among the most common gram-negative bacteria encountered by physicians worldwide. It is a common hospital-acquired pathogen, causing urinary tract infections, nosocomial pneumonia, and intraabdominal infections. K. pneumoniae is also a potential community-acquired pathogen. In this international collaborative study, we evaluated geographic differences and trends in three prominent presentations of community-acquired Klebsiella infection.

First, K. pneumoniae has been a recognized pulmonary pathogen since its discovery >100 years ago. The classic clinical presentation is dramatic: toxic presentation with sudden onset, high fever, and hemoptysis (currant jelly sputum). Chest radiographic abnormalities such as bulging interlobar fissure and cavitary abscesses are prominent. However, the incidence of community-acquired Klebsiella pneumonia has apparently declined in the United States (l,2). In studies from the 1920s to the 1960s, K. pneumoniae was considered an important cause of community-acquired pneumonia (2); however, in the last decade K. pneumoniae accounted for <1% of cases of pneumonia requiring hospitalization in North America (3,4).

Second, a striking clinical finding concerning a new manifestation of community-acquired K. pneumoniae infections has been documented. An unusual invasive presentation of K. pneumoniae infection, primary bacteremic liver abscess, has been described by numerous investigators in Asia; >900 patients with Klebsiella liver abscess have been reported from Taiwan in the last 10 years (5-22). In addition, case reports and small series from Korea, Singapore, Japan, India, and Thailand have been published (23-32). The Taiwanese patients with K. pneumoniae Diver abscess have no history of hepatobiliary disease. Seventy percent of such patients have diabetes mellitus (5,13,18,19); 11% to 12% of the reported patients with Klebsiella liver abscess have other septic metastatic lesions, including pulmonary emboli or abscess, brain abscess, pyogenic meningitis, endophthalmitis, prostatic abscess, osteomyelitis, septic arthritis, or psoas abscess (5,13,19).

The third striking clinical observation is the preponderance of K. pneumoniae as a cause of community-acquired bacterial meningitis in adults in Taiwan, even in the absence of liver abscess or other sites of infection. The proportion of cases of culture-proven bacterial meningitis due to K. pneumoniae in one Taiwanese hospital increased from 8% during 1981 and 1986 to 18% during 1987 to 1995 (33). In contrast, in a recent large review only 3 (1.2%) of 253 cases of community-acquired bacterial meningitis from the Massachusetts General Hospital were due to K. pneumoniae (34).

Given these empiric observations, we established an international collaboration of researchers from each of the world's populated continents. These investigators worked in large tertiary-care hospitals or hospitals serving veterans. One of our aims was to delineate in a single time period, with a consistent set of definitions, global differences in the clinical manifestations of serious K. pneumoniae infections. We also examined the influence of prior antibiotic use on these differences in K. pneumoniae infections.

Methods

A prospective study of consecutive patients with community-acquired K. pneumoniae bacteremia was performed in 12 hospitals. (1) The study period was January 1, 1996, to December 31, 1997. Records of patients >16 years of age with positive blood cultures for K. pneumoniae were reviewed, and a 188-item study form was completed. All items on the form were objective criteria, allowing standardization among medical centers. The study was observational in that administration of antimicrobial agents and other therapeutic management were controlled by the patient's physician, not the investigators.

Community-acquired bacteremia was defined as a positive blood culture taken on or within 48 hours of admission. Severity of acute illness at the time of positive blood cultures was assessed by a previously validated scoring system, based on mental status, vital signs, need for mechanical ventilation, and recent cardiac arrest (Pitt bacteremia score) (35). Type of infection was defined as pneumonia, urinary tract infection, meningitis, incisional wound infection, other soft tissue infection, intraabdominal infection, and primary bloodstream infection, according to Centers for Disease Control and Prevention definitions (36). In addition, distinctive sites of K. pneumoniae bacteremia were further defined as liver abscess, meningitis, or endophthalmitis. Liver abscesses were defined by the coexistence of blood cultures positive for K. pneumoniae and evidence of an intrahepatic abscess cavity by ultrasonography or computed tomography. Meningitis was defined as culture of K. pneumoniae from cerebrospinal fluid, and endophthalmitis was defined as decreased visual acuity, pain, hypyon, or severe anterior uveitis in a patient concurrently bacteremic with K. pneumoniae. Death was defined as including deaths from all causes within 14 days of the date the first positive blood culture for K. pneumoniae was obtained.

Blood cultures of K. pneumoniae were sent by participating hospitals on nutrient agar slants to a central study laboratory in Pittsburgh, where the identity of each isolate as K. pneumoniae was confirmed by the Vitek GNI system (Biomerieux Vitek, Hazelwood, MO). Extended-spectrum beta-lactamase (ESBL) production was defined phenotypically by broth dilution as a [greater than or equal to] 3 twofold concentration decrease in MIC for either cefotaxime or ceftazidime tested in combination with clavulanic acid compared with the MIC when tested alone. The protocol was reviewed and approved by Institutional Review Boards according to local requirements.

All data were entered into a central database (PROPHET version 5.1; BBN Systems and Technologies Corporation, Cambridge, MA). Contingency data were analyzed by two-tailed chi-square or Fisher's exact tests, and continuous data were analyzed by Student t test or Mann-Whitney U test.

Results

Two hundred two (44.4%) of 455 episodes of K. pneumoniae bacteremia during the study period were community-acquired cases. The percentage of cases of K. pneumoniae bacteremia that were community acquired in each study country differed strikingly: 96 (68%) of 142 in Taiwan, 25 (43%) of 68 in the United States, 28 (39%) of 71 in Australia, 40 (34%) of 116 in South Africa, 6 (22%) of 27 in Europe, and 7 (17%) of 41 in Argentina. K. pneumoniae bacteremia in Taiwan was significantly more likely to be community acquired than was bacteremia in the other countries combined (68% vs. 36%, p=0.0001).

The characteristics of patients with community-acquired K. pneumoniae bacteremia from Taiwan, South Africa, and the rest of the world were compared (Table 1). The source of bacteremia in community-acquired cases was geographically distinctive (Table 2). Pneumonia was the most common infection worldwide, accounting for 57 (28%) of 202 cases. However, 53 (93%) of 57 of all cases of community-acquired K. pneumoniae pneumonia occurred in Taiwan and South Africa.

Antibiotics had been used for >24 hours before admission in 21 (10%) of 202 patients. Prior antibiotic use was significantly lower in Taiwan (4 [4%] of 96 patients) and South Africa (2 [5%] of 40) than in the other countries (15 [23%] of 66) (p=0.0003). In four patients, the prior antibiotic was an oxyimino-containing cephalosporin (two in South Africa, one in Argentina, and one in Taiwan).

ESBL production was detected in 7 (3.5%) of 202 community-acquired strains compared with 78 (30.8%) of 253 hospital-acquired strains (p<0.00001). None of the patients with community-acquired ESBL-producing strains had recently received an oxyimino-containing cephalosporin. However, of the seven patients with community-acquired ESBL-producing K. pneumoniae bacteremia, only one (a patient with pneumonia from Africa) had no recent hospital exposure. The countries from which community-acquired ESBL-producing K. pneumoniae isolates were collected included Africa (three isolates), Turkey (two), the United States (one), and Australia (one). Twenty-five bloodstream isolates were ciprofloxacin resistant, of which 7 (28%) of 25 were community acquired. All these seven patients had serious underlying disease and frequent hospitalizations or nursing home admissions, and none had received a quinolone in the 14 days before hospital admission. Five of seven patients with community-acquired, ciprofloxacin-resistant K. pneumoniae bacteremia were from Taiwan.

Community-Acquired Pneumonia

Community-acquired pneumonia due to K. pneumoniae was significantly associated with alcoholism (p=0.007); 18% of patients with pneumonia were alcoholics as defined by their physicians, compared with 4% with other sources of K. pneumoniae bacteremia (Table 3). However, no patient with community-acquired K. pneumoniae bacteremic pneumonia outside South Africa or Taiwan was an alcoholic; of these patients, one was neutropenic, two were nursing home residents with neurologic impairment (ages 81 and 90), and one was a Vietnamese immigrant to Australia with no underlying illness.

Community-acquired pneumonia due to K. pneumoniae was significantly associated with HIV infection on univariate evaluation (p=0.002). Of the seven patients with HIV infection and K. pneumoniae bacteremia (all from Africa), six had community-acquired pneumonia. Community-acquired pneumonia due to K. pneumoniae was not associated with underlying liver disease, chronic renal failure, receipt of chemotherapy for malignant disease, or receipt of corticosteroids.

Multivariate analysis showed that residing in Africa (p=0.0001) or Taiwan (p=0.0046) and being an alcoholic (p=0.04) were significantly associated with community-acquired K. pneumoniae pneumonia. HIV infection was not independently associated with pneumonia (p=0.23). The death rates from community-acquired pneumonia due to K. pneumoniae were 54% in Taiwan and 56% in South Africa.

A Distinctive K. pneumoniae Bacteremia Syndrome

Twenty-five patients had a distinctive syndrome of K. pneumoniae bacteremia, which was defined by the presence of K. pneumoniae bacteremia in conjunction with liver abscess, endophthalmitis, or meningitis. Of these patients, 88% (16 with liver abscess, 4 with meningitis, 1 with liver abscess and meningitis, and 1 with endophthalmitis) were from Taiwan, compared with 12% from the other countries combined (2 with meningitis from South Africa and 1 with liver abscess from Belgium) (p=0.0001).

Twelve (67%) of 18 patients with liver abscess had diabetes mellitus. On univariate analysis, residing in Taiwan (p=0.0001) and having diabetes mellitus (p=0.001) were significantly associated with community-acquired K. pneumoniae liver abscess. Patients with liver abscess were more likely to have renal failure, but this association was not statistically significant (p=0.09). There was no association between liver abscess and gender, age, previous antibiotic use, or presence of underlying liver disease. Multivariate analysis showed that residence in Taiwan (p=0.0034), diabetes mellitus (p=0.0058), and renal failure (p=0.0178) were significantly associated with the presence of liver abscess.

Patients with any of the distinctive manifestations of K. pneumoniae (liver abscess, meningitis, or endophthalmitis) were compared with patients with other community-acquired infections (Table 4). These complications were significantly associated with diabetes mellitus (60% vs. 28%, p=0.0015) and living in Taiwan (88% vs. 42%, p=0.0001).

Discussion

When pneumonia due to Klebsiella was first described by Friedlander in 1882, he believed it to be the most common cause of bacterial pneumonia (37). Although this concept was soon refuted in favor of pneumococcus, from the 1930s through the 1960s, 10 to 50 cases of Klebsiella pneumonia were reported each year by large hospitals in the United States (2). U.S. textbooks of medicine continue to list K. pneumoniae as an important cause of community-acquired pneumonia (38,39).

In our prospective study, we found only four cases of community-acquired K. pneumoniae pneumonia in 2 years in nine large hospitals from the United States, Australia, Europe, and Argentina. The hospitals surveyed included an inner-city veterans hospital in the United States and two large inner-city public hospitals in Australia. These three centers care for large numbers of indigent and alcoholic patients.

Recently published reports from the United States, Israel, and Europe support our observations, Neither Vergis et al. (40) from the United States nor Lieberman et al. (41) from Israel found a single case of K. pneumoniae pneumonia in large multicenter studies of community-acquired pneumonia in the 1990s. Nine European studies published since 1990 show that only 14 (2.3%) of 621 patients admitted with severe community-acquired pneumonia requiring intensive-care unit admission had K. pneumoniae as the presumptive etiologic agent (42-50). In contrast, K. pneumoniae continues to be associated with community-acquired pneumonia in Africa and Asia. In our study, we observed 28 cases in Taiwan and 25 in South Africa, accounting for 29% and 62% of all cases of community-acquired K. pneumoniae bacteremia in Taiwan and South Africa, respectively (Table 2). Recent studies from Taiwan, Singapore, and South Africa corroborate these findings. In a Taiwanese study, K. pneumoniae accounted for 34% of 41 cases of community-acquired bacteremic pneumonia (51). K. pneumoniae was the cause of 15% of community-acquired pneumonia requiring intensive-care unit admission in Singapore (52). K. pneumoniae was found to be the cause of pneumonia in 32% of African patients with severe community-acquired pneumonia requiring intensive-care unit admission in Johannesburg (53) and 11% of patients requiring intensive-care unit admission in Cape Town (54).

In our study, 18% of patients with community-acquired K. pneumoniae pneumonia were alcoholics (p=0.007) (Table 3). Alcoholics in Africa and Asia may have limited access to health care (perhaps including reduced access to antibiotics) compared with those in the Americas, Europe, and Australia, and may have respiratory symptoms later. A weakness of our study is that we were not able to ascertain the duration of symptoms before each patient was hospitalized. However, a recent study of aborigines from rural northern Australia (35% of whom were alcoholics and most of whom had suboptimal access to health-care facilities) showed that none of 90 admitted to hospital with community-acquired pneumonia had K. pneumoniae infection (55). The hypothesis that Klebsiella pneumonia is related to poor primary health care for alcoholics may therefore be less plausible.

Bacteremic K. pneumoniae liver abscess occurred almost exclusively in patients from Taiwan (Table 2), consistent with a growing number of reports from Asia describing this distinctive type of infection. K. pneumoniae was the most common cause of liver abscesses in Taiwan, Singapore, and Korea in reports from 1990 to 1999 (5,9,24,31,32); similarly, numerous reports of liver abscess have recently been published from Hong Kong, Thailand, and Japan (23,25-30). In total, >900 patients with K. pneumoniae liver abscess have been reported from Asian countries in the last 10 years; in contrast, reports of only 23 patients with this condition have been published from regions outside Asia in this same period (56-63).

K. pneumoniae meningitis in adults has also been infrequently reported from North America, Europe, and Australia, in contrast to Taiwan. In our study, five cases of bacteremic K. pneumoniae meningitis were in Taiwanese patients and two in African patients (Table 2). Four (57%) of 7 patients with meningitis had prior diabetes mellitus. Meningitis caused by K. pneumoniae in the United States, Australia, and Europe is most often hospital acquired and associated with prior neurosurgical procedures or instrumentation. However, of 115 cases of K. pneumoniae meningitis reported from Taiwan (33,64,65), 84% were community acquired, and 64% of cases had concurrent Klebsiella bacteremia. Unlike pyogenic liver abscess, the clinical course was fulminant, with a death rate of 57% (33,64,65). The death rate from bacteremic K. pneumoniae meningitis in our series was 71%.

We found only one patient (an alcoholic from Taiwan) with K. pneumoniae bacteremia and endophthalmitis. K. pneumoniae endophthalmitis is also likely to be far more common in Asia than elsewhere; >50 cases have been reported in the last 10 years from Asia (6,10,11,19,27,66-70) compared with only 10 from the United States, Europe, and Australia (57,60,62,7176). More than 50% of previously reported Asian patients with K. pneumoniae endophthalmitis have had concurrent liver abscess (6,10,11,19,27,66-70).

The reason for the geographic preponderance of these severe manifestations of K. pneumoniae infections in Asia is unknown. The geographic diversity of Klebsiella infections possibly results from interaction between bacterial variables, host variables (for example, defects in host defense caused by diabetes mellitus or alcoholism), socioeconomic factors, and possibly genetic susceptibility in different racial groups. We are studying the phenotypic and genotypic differences in K. pneumoniae causing different disease manifestations in different countries. Because no more than three hospitals from each country were included in our study, our results may not necessarily be generalizable to hospitals in other regions. In addition, other countries in the same continent (e.g., other countries in Asia or eastern Europe) were not studied but may have different clinical patterns compared with the study country.

In summary, our results challenge the classic view of serious Klebsiella infections. In the United States, Europe, Argentina, and Australia, we have observed that hospital-acquired K. pneumoniae infections predominate, with community-acquired bacteremia being caused by urinary tract infection, vascular catheter infection, and cholangitis. Classic community-acquired pneumonia is no longer an important entity in these regions. In South Africa, pneumonia (especially in alcoholics) continues to be an important community-acquired infection. In Taiwan, community-acquired pneumonia persists, and distinctive infections such as liver abscess, endophthalmitis, and meningitis have emerged as substantial public health problems.

Table 1. Clinical characteristics of patients with
community-acquired Klebsiella pneumoniae bacteremia from Taiwan,
South Africa, and other countries

                                             South
                                Taiwan       Africa
Clinical characteristics        (n=96)       (n=40)

Age (mean, years)                58.8         47.2

Female, n (%)                  35 (38%)     17 (42%)

Underlying diseases, n (%)

  Diabetes mellitus            38 (40%)     8 (20%)

  Liver disease                33 (34%)     6 (15%)

  Alcoholism                   12 (12%)      3 (8%)

  Malignancy                   15 (16%)      3 (8%)

  HIV infection                 0 (0%)      7 (18%)

  Chronic renal failure         6 (6%)       2 (5%)

  Organ transplant              0 (0%)       0 (0%)

  Corticosteroid use            5 (5%)       1 (3%)

No underlying                  22 (23%)     21 (52%)
disease

Critically ill (b)             30 (31%)     12 (30%)

Death rate at 14 days,         30 (31%)     24 (60%)
n (%)

                                Other
                              countries
Clinical characteristics        (n=66)    p value (a)

Age (mean, years)                59.9         0.014

Female, n (%)                  24 (36%)         NS

Underlying diseases, n (%)

  Diabetes mellitus            19 (29%)        0.06

  Liver disease                12 (18%)        0.02

  Alcoholism                    1 (2%)         0.08

  Malignancy                   25 (38%)       0.0002

  HIV infection                 0 (0%)        0.0001

  Chronic renal failure         6 (9%)          NS

  Organ transplant             7 (11%)        0.0006

  Corticosteroid use           7 (11%)          NS

No underlying                  24 (36%)       0.003
disease

Critically ill (b)              2 (3%)        0.0001

Death rate at 14 days,         8 (12%)        0.0001
n (%)

(a) p values refer to differences between the three regions;
NS = not significant at p >0.20.

(b) Critically ill defined as Pitt bacteremia score [less than or
equal to] 4.
Table 2. Worldwide differences in the sites of infection associated
with community-acquired Klebsiella pneumoniae bacteremia

                                   South      Other
                    Taiwan (a)    Africa    countries
Infection site       (n=96)       (n=40)      (n=66)   p value (b)

Pneumonia            28 (29%)    25 (62%)     4 (6%)      0.0001

Liver abscess        17 (18%)        0        1 (2%)      0.0002

Endophthalmitis       1 (1%)         0          0           NS

Meningitis            5 (5%)      2 (5%)        0          0.06

Urinary tract        14 (15%)     4 (10%)    25 (38%)     0.0003
infections

Acute cholangitis    13 (14%)        0       12 (18%)      0.02

Intravascular            0        2 (5%)     11 (17%)        0
catheter-related
infections

Skin and soft         5 (5%)      1 (3%)      4 (6%)        NS
tissue
infections

Spontaneous           7 (7%)         0        1 (2%)       0.06
bacterial
peritonitis

Intraabdominal        2 (2%)      2 (5%)      2 (3%)        NS
abscess

Other                 1 (1%)         0        2 (3%)        NS

No primary site       7 (7%)      5 (12%)     4 (6%)        NS
evident

(a) Four Taiwanese patients had more than one site of infection:
pneumonia and liver abscess (2), liver abscess and meningitis (1)
and pneumonia and endophthalmitis (1). One South African patient
had both pneumonia and meningitis.

(b) p values refer to the differences between the three regions;
NS = not significant at p >0.20.
Table 3. Comparison of the characteristics of patients with
community-acquired bacteremic pneumonia due to Klebsiella
pneumoniae and other patients with community-acquired K.
pneumoniae bacteremia: association between pneumonia and alcoholism
and residence in South Africa

                                          Bacteremia
                             Bacteremic    without
                              pneumonia   pneumonia
Characteristic                  (n=57)     (n=145)    p value (a)

Resides in South Africa       25 (44%)    15 (10%)        <0.001

Age (years)                     53.6        58.6            0.07

Serum creatinine (b) (mg/        2.1         2.3            0.2
dL)

Blood urea nitrogen (b)         34.8        37.9             NS
(mg/dL)

Liver function tests (b,c)

Serum albumin (g/mL)             2.8         3.1           0.05

Serum bilirubin (mg/dL)          2.8         2.9            NS

AST (IU/mL)                      174         303            NS

ALT (IU/mL)                      115         189            NS

Underlying disease

Diabetes mellitus (%)         12 (21%)    53 (37%)         0.03

Alcoholism (%)                10 (18%)     6 (4%)          0.01

Malignancy (%)                 7 (12%)    36 (25%)         0.05

HIV infection (%)              6 (10%)     1 (1%)         0.002

No underlying disease         23 (40%)    44 (30%)      NS (0.17)

Critically ill                21 (37%)    23 (16%)        0.001

Death rate at 14 days (%)     31 (54%)    32 (22%)        0.0001

(a) NS = not significant at p > 0.20; AST = aspartate
aminotransferase; ALT = alanine aminotransferase.

(b) Laboratory values are those taken on first visit to a
health-care provider; for continuous variables, the figures in the
table are mean values.

(c) Bacteremic patients with liver cirrhosis, acute cholangitis,
and liver abscess were excluded from the analysis of liver function
tests.
Table 4. Comparison of the characteristics of patients with
distinctive infections associated with community-acquired
Klebsiella pneumoniae bacteremia (liver abscess, meningitis,
and endophthalmitis) and other patients with community-acquired
K. pneumoniae bacteremia: association with diabetes mellitus
and residence in Taiwan

                                            Other
                        Liver abscess,    community-
                        endophthalmitis    acquired
                         or meningitis    bacteremia
Characteristic              (n=25)         (n=177)    p-value (a)

Resides in Taiwan          22 (88%)        74 (42%)       0.0001

Age (years)                  55.5            57.4           NS

Serum creatinine (b)          2.2            2.2            NS
(mg/dL)

Blood urea nitrogen          35.7            37.2           NS
(mg/dL)

Underlying disease

Diabetes mellitus (%)      15 (60%)        50 (28%)       0.0015

Chronic renal               3 (12%)        11 (6%)          NS
failure (%)

Underlying liver            5 (20%)        46 (26%)         NS
disease (%)

Chronic hepatitis B            0            9 (5%)          NS
virus infection

Hepatitis C virus           1 (4%)          8 (5%)          NS
infection (%)

Alcoholism (%)              2 (8%)         14 (8%)          NS

Malignancy (%)                 0           43 (24%)       0.006

No underlying disease       6 (24%)        61 (34%)         NS

Critically ill (c)          9 (36%)        35 (20%)        0.07

Death rate at 14            8 (32%)        54 (31%)         NS
days (%)

(a) NS = p > 0.20.

(b) Laboratory values are those taken on first visit to a
health-care provider; for continuous variables, the figures in the
table are mean values.

(c) Critically ill defined as Pitt bacteremia score [greater than
or equal to] 4.

Acknowledgments

We thank Marilyn Wagener for the statistical analyses and Shirley Brinker for secretarial assistance.

(1) United States: Pittsburgh Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, and Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois; Taiwan: National Cheng Kung University Medical College, Tainan; Australia: Royal Brisbane Hospital, Mater Adults Hospital, and Greenslopes Private Hospital, all in Brisbane; South Africa: Hillbrow Hospital and Baragwanath Hospital, both in Johannesburg; Turkey: Marmara University Hospital, Istanbul; Belgium: University Hospital, Antwerp; and Argentina: San Lucas Hospital and Comunidad Olives Hospital, both in Buenos Aires.

References

(1.) Korvick JA, Hackett AK, Yu VL, Muder RR. Klebsiella pneumonia in the modem era: clinicoradiographic correlations. South Med J 1991;84:2004.

(2.) Carpenter JL. Klebsiella pulmonary infections: occurrence at one medical center and review. Rev Infect Dis 1990;12:672-82.

(3.) Fang G, Fine MJ, Orloff JJ, Arisumi D, Yu VL, Kapoor W, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy. A prospective multicenter study of 359 cases. Medicine (Baltimore) 1990;69:307-16.

(4.) Marrie TJ, Durant H, Yates L. Community-acquired pneumonia requiring hospitalization: 5-year prospective study. Rev Infect Dis 1989;11:586-99.

(5.) Wang JH, Liu YC, Lee SS, Yen MY, Chen YS, Wann SR, et al. Primary liver abscess due to Klebsiella pneumoniae in Taiwan. Clin Infect Dis 1998;26:1434-8.

(6.) Lee CC, Chen CY, Chen FH, Zimmerman RA, Hsiao HS. Septic meta-static endophthalmitis from Klebsiella pneumoniae liver abscess: CT and MR imaging characteristics--report of three cases. Radiology 1998;207:411-6.

(7.) Yeh TS, Jan YY, Jeng LB, Hwang TL, Chao TC, Chien RN, et al. Pyogenic liver abscesses in patients with malignant disease: a report of 52 cases treated at a single institution. Arch Surg 1998;133:242-5.

(8.) Jan YY, Yeh TS, Chen MF. Cholangiocarcinoma presenting as pyogenic liver abscess: is its outcome influenced by concomitant hepatolithiasis? Am J Gastroenterol 1998;93:253-5.

(9.) Chou FF, Sheen-Chen SM, Chen YS, Chen MC. Single and multiple pyogenic liver abscesses: clinical course, etiology, and results of treatment. World J Surg 1997;21:384-8. [discussion 388-9].

(10.) Yarng SS, Hsieh CL, Chen TL. Vitrectomy for endogenous Klebsiella pneumoniae endophthalmitis with massive subretinal abscess. Ophthalmic Surg Lasers 1997;28:147-50.

(11.) Chou FF, Kou HK. Endogenous endophthalmitis associated with pyogenic hepatic abscess. J Am Coll Surg 1996;182:33-6.

(12.) Ni YH, Chang MH, Hsu HY, Lee CY. Ultrasound-guided percutaneous drainage of liver abscess in children. Chung-Hua Min Kuo Hsiao Erh Ko'i Hsueh Hui Tsa Chih 1995;36:336-41.

(13.) Chang FY, Chou MY. Comparison of pyogenic liver abscesses caused by Klebsiella pneumoniae and non-K, pneumoniae pathogens. J Formos Med Assoc 1995;94:232-7.

(14). Chou FF, Sheen-Chen SM, Lee TY. Rupture of pyogenic liver abscess. Am J Gastroenterol 1995;90:767-70.

(15). Chou FF, Sheen-Chen SM, Chen YS, Lee TY. The comparison of clinical course and results of treatment between gas-forming and non-gas-forming pyogenic liver abscess. Arch Surg 1995;130:401-5;[discussion 406].

(16.) Hwang CF, Lee CY, Lee PI, Chen JM, Lli KH, Lin DT, et al. Pyogenic liver abscess in beta-thalassemia major--report of two cases. Chung-Hua Min Kuo Hsiao Erh Ko'i Hsueh Hui Tsa Chih 1994;35:466-70.

(17.) Kong MS, Lin JN. Pyogenic liver abscess in children. J Formos Med Assoc 1994;93:45-50.

(18). Yang CC, Chen CY, Lin XZ, Chang TT, Shin JS, Lin CY. Pyogenic liver abscess in Taiwan: emphasis on gas-forming liver abscess in diabetics. Am J Gastroenterol 1993;88:1911-5.

(19.) Cheng DL, Liu YC, Yen MY, Liu CY, Wang RS. Septic metastatic lesions of pyogenic liver abscess. Their association with Klebsiella pneumoniae bacteremia in diabetic patients. Arch Intern Med 1991;151:1557-9.

(20.) Wang LS, Lee FY, Cheng DL, Liu CY, Hinthorn DR, Jost PM. Klebsiella pneumoniae bacteremia: analysis of 100 episodes. J Formos Med Assoc 1990;89:756-63.

(21). Cheng DL, Liu YC, Yen MY, Liu CY, Shi FW, Wang LS. Pyogenic liver abscess: clinical manifestations and value of percutaneous catheter drainage treatment. J Formos Med Assoc 1990;89:571-6.

(22.) Cheng DL, Liu YC, Yen MY, Liu CY, Shi FW, Wang LS. Causal bacteria of pyogenic liver abscess. J Formos Med Assoc 1989;88:1008-11.

(23.) Dylewski JS, Dylewski I. Necrotizing fasciitis with Klebsiella liver abscess [letter]. Clin Infect Dis 1998;27:1561-2.

(24.) Yeoh KG, Yap I, Wong ST, Wee A, Guan R, Kang JY. Tropical liver abscess. Postgrad Med J 1997;73:89-92.

(25.) Yokoyama T, Hiyama E, Imamura Y. Pyogenic liver abscess. Ryoikibetsu Shokogun Shirizu 1995;7:39-42.

(26.) Higashi T, Makino Y, Katsurada K. A case of gas-containing liver abscess with multiple metastatic lesions (in Japanese). Kansenshogaku Zasshi - J Japanese Assoc Infect Dis 1995;69:1017-20.

(27.) Chee SP, Ang CL. Endogenous Klebsiella endophthalmitis--a case series. Ann Acad Med Singapore 1995;24:473-8.

(28). Assantachai P, Luengrojanakul P, Phimolsamti R, Charoenlarp K, Ratanarapee S. Liver abscess in polycystic liver disease. J Med Assoc Thailand 1995;78:210-6.

(29.) Lee KH, Hui KP, Tan WC, Lim TK. Klebsiella bacteraemia: a report of 101 cases from National University Hospital, Singapore. J Hosp Infect 1994;27:299-305.

(30.) Shimada H, Ohta S, Maehara M, Katayama K, Note M, Nakagawara G. Diagnostic and therapeutic strategies of pyogenic liver abscess, Int Surg 1993;78:40-5.

(31.) Chung DR, Kang JM, Hong SS, Cho YK, Kim EO, Kim YS, et al. Epidemiologic study of pyogenic liver abscess in Korea, 1989-1998. Clin Infect Dis 1998;27:950.

(32.) Chung DR, Kang JM, Hong SS, Cho YK, Kim EO, Kim YS, et al. Risk factors associated with Klebsiella pneumoniae liver abscess: a case-control study using Escherichia coli liver abscess as control. Clin Infect Dis 1998;27:950.

(33.) Tang LM, Chen ST, Hsu WC, Chen CM. Klebsiella meningitis in Taiwan: an overview. Epidemiol Infect 1997;119:135-42.

(34.) Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness VS, et al. Acute bacterial meningitis in adults: a review of 493 episodes. N Engl J Med 1993;328:21-8.

(35.) Chow JW, Yu VL. Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: a commentary. Int J Antimicrob Agents 1999;11:7-12.

(36.) Garner JS, Jarvis WR, Emori TG Horan TC, Hughes JM. CDC definitions for nosocomial infections. Am J Infect Control 1988;16:128-40.

(37.) Friedlander C. Uber die scizomyceten bei der acuten fibrosen pneumonie. Arch Pathol Anat Physiol Klin Med 1882:87:319-24.

(38.) Eisenstein BI, Watkins V. Diseases caused by Gram-negative bacilli. In: Fauci AS, Braunwald E, Isselbacher KJ, Kasper DL, Hauser SL, Longo DL, et al., editors. Harrison's principles of internal medicine. 14th ed. New York: McGraw-Hill; 1998.

(39.) Johanson WG. Pneumonia caused by aerobic Gram-negative bacilli. In: Bennett JC, Plum F, editors. Cecil textbook of medicine. 20th ed. Philadelphia: WB Saunders Co.; 1996.

(40.) Vergis EN, Phillips J, Bates JH, File TM, Tan JS, Sarosi GA, et al. A prospective, randomized, multicenter trial of azithromycin versus cefuroxime plus erythromycin for community-acquired pneumonia in hospitalized patients. Arch Intern Med 2000;160:1294-300.

(41.) Lieberman D, Lieberman D, Porath A. Seasonal variation in community-acquired pneumonia. Eur Respir J 1996;9:2630-4.

(42.) Rello J, Rodriguez R, Jubert P, Alvarez B. Severe community-acquired pneumonia in the elderly: epidemiology and prognosis. Clin Infect Dis 1996;23:723-8.

(43.) Cosentini R, Blasi F, Raccanelli R, Rossi S, Arosio C, Tarsia P, et al. Severe community-acquired pneumonia: a possible role for Chlamydia pneumoniae. Respiration 1996;63:61-5.

(44.) Moine P, Vercken JB, Chevret S, Gajdos P. Severe community-acquired pneumococcal pneumonia. Scand J Infect Dis 1995;27:201-6.

(45.) Almirall J, Mesalles E, Klamburg J, Parra O, Agudo A. Prognostic factors of pneumonia requiring admission to the intensive-care unit. Chest 1995;107:511-6.

(46.) Rello J, Quintana E, Ausina V, Net A, Prats G. A three-year study of severe community-acquired pneumonia with emphasis on outcome. Chest 1993;103:232-5.

(47.) The British Thoracic Society Research Committee and the Public Health Laboratory Service. The aetiology, management and outcome of severe community-acquired pneumonia on the intensive-care unit. Respir Med 1992;86: 7-13.

(48.) Torres A, Serra-Batlles J, Ferrer A, Jimenez P, Cells R, Cobo E, et al. Severe community-acquired pneumonia. Epidemiology and prognostic factors. Am Rev Respir Dis 1991;144:312-8.

(49.) Pachon J, Prados MD, Capote F, Cuello JA, Garnacho J, Verano A. Severe community-acquired pneumonia. Etiology, prognosis and treatment. Am Rev Respir Dis 1990;142:369-73.

(50.) Alkhayer M, Jenkins PF, Harrison BD. The outcome of community acquired pneumonia treated on the intensive-care unit. Respir Med 1990;84:13-6.

(51.) Chen CW, Jong GM, Shiau JJ. Adult bacteremic pneumonia: bacteriology and prognostic factors. J Formos Med Assoc 1992;91:754-9.

(52.) Lee KH, Hui KP, Tan WC, Lim TK. Severe community-acquired pneumonia in Singapore. Singapore Med J 1996;37:374-7.

(53.) Feldman C, Ross S, Mahomed AG, Omar J, Smith C. The aetiology of severe community-acquired pneumonia and its impact on initial empiric, antimicrobial chemotherapy. Respir Med 1995;89:187-92.

(54.) Potgieter PD, Hammond JMJ. Etiology and diagnosis of pneumonia requiring ICU admission. Chest 1992;101:199-203.

(55.) Thomson JE. Community-acquired pneumonia in northeastern Australia--a hospital based study of aboriginal and non-aboriginal patients. Aust N Z J Med 1997;27:59-61.

(56.) Brook I, Frazier EH. Microbiology of liver and spleen abscesses. J Med Microbiol 1998;47:1075-80.

(57.) Lindstrom ST, Healey PR, Chen SC. Metastatic septic endophthalmitis complicating pyogenic liver abscess caused by Klebsiella pneumoniae [letter]. Aust N Z J Med 1997;27:77-8.

(58.) Aguilar J, Cruz A, Ortega C. Multiple hepatic and pulmonary abscesses caused by Klebsiella pneumoniae [letter]. Enfermedades Infecciosas y Microbiologia Clinica 1994;12:270-1.

(59.) Hansen N, Vargish T. Pyogenic hepatic abscess: a case for open drainage. Am Surg 1993;59:219-22.

(60.) Couez D, Libon E, Wasteels M, Derue G, Gilbeau JP. Klebsiella pneumoniae liver abscess with septic endophthalmitis. The role of computed tomography. Journal Belge de Radiologie 1991;74:41-4.

(61.) Ridker PM, Enders GH, Lifton RP. False positive mononucleosis screening test results associated with Klebsiella hepatic abscess. Am J Clin Pathol 1990;94:222-3.

(62.) Martinez M, Castro F, Ocasio R, Vazquez G, Ramirez Ronda CH. Septic endophthalmitis associated with bacteremia and liver abscess caused by Klebsiella pneumoniae. Boletin Asociacion Medica de Puerto Rico 1991;83:485-6.

(63.) Barton EN, Daisley H, Gilbert DT, Roberts L. Diabetes mellitus and Klebsiella pneumoniae liver abscess in adults. Trop Geogr Med 1991;43:100-4.

(64.) Lu CH, Chang WN, Wu HS. Klebsiella pneumoniae meningitis: analysis on clinical features of thirty-two adult patients. Zhonghua Yi Xue Za Zhi (Taipei) 1997;60:296-302.

(65.) Jang TN, Wang FD, Wang LS, Yu KW, Liu CY. Gram-negative bacillary meningitis in adults: a recent six-year experience. J Formos Med Assoc 1993;92:540-6.

(66.) Ebisuno S, Miyai M. A case of Klebsiella pneumoniae endophthalmitis metastasized from prostatitis. Hinyokika Kiyo - Acta Urologica Japonica 1994;40:625-7.

(67.) Hung HC, Chen WC, Chao Y, Hou MC, Lin HC, Chang FY, et al. Klebsiella pneumoniae panophthalmitis: a possible complication of endoscopic variceal injection sclerotherapy. Am J Gastroenterol 1998;93:2603-4.

(68.) Liao HR, Lee HW, Leu HS, Lin BJ, Juang CJ. Endogenous Klebsiella pneumoniae endophthalmitis in diabetic patients. Can J Ophthalmol 1992;27:143-7.

(69.) Ram J, Sharma A, Gupta A. Multiple scleral abscesses with recurrent bacterial endophthalmitis eight months following cataract surgery. Acta Ophthalmologica 1990;68:615-6.

(70.) Hidaka T, Yokota T, Tamura K. A case of liver abscess associated with endophthalmitis caused by Klebsiella pneumoniae. Kansenshogaku Zasshi - J Japanese Assoc Infect Dis 1993;67:76-80.

(71.) Havunjian RH, Goldberg RA, Hepler RS. Bilateral endogenous endophthalmitis in a patient with diabetes and renal papillary necrosis [letter]. Am J Ophthalmol 1991;111:653-4.

(72.) Kremer I, Gaton DD, Baniel J, Servadio C. Klebsiella metastatic endophthalmitis--a complication of shock wave lithotripsy. Ophthalmol Surg 1990;21:206-8.

(73.) Margo CE, Mames RN, Guy JR. Endogenous Klebsiella endophthalmitis. Report of two cases and review of the literature. Ophthalmology 1994;101:1298-301.

(74.) Riss JM, Righini-Chossegros M, Paulo F, Escoffier P, Saracco JB. Endogenous bacterial endophthalmitis. Report of 3 cases. J Francais d Ophtalmologie 1990;13:327-3l.

(75). Sanchez A, Blazquez JC, Royo G, Cloquet E. Bacterial endophthalmitis caused by Klebsiella pneumoniae associated with urinary sepsis [letter]. Enfermedades Infecciosas y Microbiologia Clinica 1994;12:416-7.

(76.) Stotka JL, Rupp ME. Klebsiella pneumoniae urinary tract infection complicated by endophthalmitis, perinephric abscess, and ecthyma gangrenosum. South Med J 199l;84:790-3.

Address for correspondence: Victor L. Yu, Infectious Disease Section, VA Medical Center, University Drive C, Pittsburgh, PA 15240, USA; fax: [phone]; e-mail: [e-mail]

Wen-Chien Ko, * David L. Paterson, ([dagger]) ([double dagger]), Anthanasia J. Sagnimeni, ([double dagger]) Dennis S. Hansen, ([section]) Anne Von Gottberg, ([section]) Sunita Mohapatra, # Jose Maria Casellas, ** Herman Goossens, ([dagger]) ([dagger]) Lutfiye Mulazimoglu, ([double dagger]) ([double dagger]) Gordon Trenholme, # Keith P. Klugman, ([paragraph]) Joseph G. McCormack, ([double dagger]) Victor L. Yu ([dagger])

* National Cheng Kung University Medical College, Taiwan; ([dagger]) Veterans Administration Medical Center and University of Pittsburgh, Pittsburgh, Pennsylvania, USA; ([double dagger]) University of Queensland, Mater Adults Hospital, Brisbane, Australia; ([section]) Statens Serum Institut, Copenhagen, Denmark; ([paragraph]) South African Institute of Medical Research, Johannesburg, South Africa; # Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois, USA; ** Sanatorio San Lucas, Buenos Aires, Argentina; ([dagger]) ([dagger]) University Hospital, Antwerp, Belgium; and ([double dagger]) ([double dagger]) Marmara University, Istanbul, Turkey

Dr. Paterson's work was supported in part by the Cottrell Epidemiology Fellowship of the Royal Australasian College of Physicians.

Wen-Chien Ko is an infectious disease physician at National Cheng Kung University Medical Collete, Tainan, Taiwan. His research interests are in the pathogenesis of Klebsiella infections and the epidemiology and treatment of Aeromonas infections.