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Etiologic Agents
Clinical Approach

When the microbiology laboratory reports that a blood culture is positive for a gramnegative bacillus, it must be assumed that the patient is bacteremic and a life-threatening infection is present. The history and physical examination will usually strongly suggest the source of infection. Specific identification of the gram-negative bacillus will also sometimes be helpful in identifying a primary infection.
Etiologic Agents
Several studies have classified gram-negative bacteremia according to most common etiologic agent and most frequent source of infection. Kreger and associates, for example, reviewed 612 episodes of gram-negative bacteremia during a 10-year period. Table 68-1 shows the distribution of etiologic agents. Escherichia coli was the most common gram-negative rod causing bacteremia, being responsible for 31% of cases. Table 68-2 shows the sources of gram-negative bacteremia. Urinary tract infection is by far the most common source, with infection of the gastrointestinal and biliary tract second. The respiratory tract (i.e., bacteremic pneumonia) was the source in only 9% of cases, and skin and soft tissue in 6.5%.

Table 68-1. Etiologic agents in gram-negative bacteremia

Table 68-2. Primary sources of gram-negative bacteremia

The gram-negative organism most likely to cause bacteremia varies with several factors. If the bacteremia is acquired in the community, E. coli is the most common organism. Organisms such as Pseudomonas aeruginosa and Serratia marcescens are most likely to occur in the hospital. The longer the length of stay, the more likely it is that these relatively antimicrobial-resistant organisms will be found. The population studied will also affect the distribution of etiologic agents in gram-negative bacteremia. P. aeruginosa is more likely to occur in the neutropenic patient, whereas E. coli is by far the most common agent in the healthy young patient. Each hospital has its own profile of etiologic agents. Some organisms, such as Acinetobacter species, may be common in one hospital and unusual in another. The site of infection may also predict the etiologic agent. For example, Proteus mirabilis or Providencia species isolated from blood cultures suggest urinary tract infection. In bacteremic pneumonia, Klebsiella pneumoniae and P. aeruginosa are much more common than Proteus species, Providencia, or even E. coli. Bacteroides bacteremia suggests anaerobic infection of the colon or female genital tract, a liver abscess, or postoperative wound infection.
The pattern of gram-negative bacteremia has been changing with the introduction of new antimicrobials. For example, Xanthomonas maltophilia (formerly Pseudomonas maltophilia) infection has been increasing because of the aminoglycoside resistance of this organism. Isolates can be cultured from the hospital environment, and common-source outbreaks can occur. Pseudomonas cepacia has also caused an increasing incidence of bacteremia and outbreaks associated with hospital devices, such as a blood gas analyzer. Pseudomonas fluorescens has caused bacteremia in association with blood transfusion. An increasing number of Pseudomonas species have been implicated in bacteremia.
Enterobacter bacteremia has also been caused by contaminated blood products, but Enterobacter is reported to contaminate IV fluids more frequently. Compared with K. pneumoniae bacteremia, Enterobacter bacteremia appears to carry a higher mortality rate, is more often associated with surgery or infection of unknown source, and is more likely to be associated with polymicrobial bloodstream infection.
Acinetobacter species are causing more cases of nosocomial bacteremia, in part because of their relative resistance to third-generation cephalosporins. Bacteremia is frequently associated with an IV catheter or is secondary to pneumonia. The organism, on Gram’s stain, frequently appears as a gram-negative coccus or diplococcus rather than as a rod.
A gram-negative bacillus on smear may represent bacteremia from a nonenteric gram-negative rod. For example, a group of slow-growing gram-negative bacilli, including Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species (HACEK group), can cause a picture of subacute bacterial endocarditis. These organisms are often difficult to grow, requiring prolonged incubation and subculturing to chocolate agar. Haemophilus influenzae can cause bacteremia secondary to pneumonia, otitis media, meningitis, or epiglottitis. These small, gram-negative coccobacilli can usually be distinguished from the larger enteric gram-negative rods on smear.
Dysgonic fermenter-2, now called Capnocytophaga canimorsus, is a slow-growing gram-negative bacillus that causes a zoonotic infection acquired through dog bites. It can cause fulminating bacteremia in splenectomized and alcoholic patients.
Salmonella bacteremia has become an increasing problem in patients with AIDS. Recurrent episodes of fever and chills and positive blood cultures are common. Campylobacter may also cause disease with bacteremia. Shigella species, rarely a cause of bacteremia, have been more commonly reported, particularly in AIDS patients.
Flavobacterium species, particularly F. meningosepticum, are nonmotile, catalase-positive, gram-negative bacilli that have become ubiquitous in some hospital environments. Hospital outbreaks of bacteremia can occur. The organism has an unusual sensitivity pattern, generally being sensitive to trimethoprim-sulfamethoxazole and vancomycin but resistant to aminoglycosides.
New genera and species of Enterobacteriaceae continue to emerge. In 1972, there were 11 genera and 26 species; in 1995, there were 28 genera and 115 species. Newer genera, which may cause episodes of urinary tract infection, wound infection, or bacteremia, include Hafnia, Edwardsiella, Ewingella, Kluyvera, and Cedecea. Many of these newer genera are particularly antibiotic-resistant.
Clinical Approach
An internal medicine or infectious disease consultant will often be asked to assess a patient when the laboratory calls with the positive blood culture report. A history and physical examination should be directed at the most likely sources of infection (a urinary tract infection; gastrointestinal infection; pneumonia; skin, soft-tissue, or catheter infection). Urine Gram’s stain and culture should be obtained. Chest roentgenography and sputum Gram’s stain are necessary if pneumonia is suspected. A complete physical examination will include a pelvic examination in a woman in whom no other definite source of infection can be defined. IV lines should be removed, and the patency of indwelling Foley catheters or nephrostomy tubes should be checked. Abdominal tenderness in the setting of gram-negative bacteremia will usually require a surgical consult and appropriate imaging examination.
Most patients reported to have gram-negative rods in a blood culture will require therapy with an antimicrobial that has a broad spectrum of gram-negative activity. In the case of a patient who appears well at the time of the report, blood cultures can be repeated while the patient is being closely observed. However, few blood cultures positive for gram-negative bacilli represent contamination. The great majority of such cases require rapid antimicrobial therapy. When infection caused by H. influenzae, endocarditis-causing organisms of the HACEK group, dysgonic fermenter-2, or anaerobes is suspected, a different approach to antimicrobial therapy will be required than in infection with the more common enteric gram-negative bacilli. (S.L.B.)
Baltch AL, Griffin PE. Pseudomonas aeruginosa bacteremia: a clinical study of 75 patients. Am J Med Sci 1977;274:119.
P. aeruginosa bacteremia is nosocomial, arising from a urinary tract, respiratory tract, or intravascular focus of infection.
Bisbe J, et al. Pseudomonas aeruginosa bacteremia: univariate and multivariate analyses of factors influencing the prognosis in 133 episodes. Rev Infect Dis 1988;10:629.
Pseudomonas bacteremia represented 25% of all cases of gram-negative bacteremia. Appropriate antimicrobial therapy is critical to survival.
Bouza E, et al. Enterobacter bacteremia: an analysis of 50 episodes. Arch Intern Med 1985;145:1024.
Describes particular clinical characteristics of Enterobacter bacteremia.
Bouza E, et al. Serratia bacteremia. Diagn Microbiol Infect Dis 1987;7:237.
Bacteremia caused by S. marcescens has become common in some institutions. Increasing resistance to gentamicin has developed.
Crowe HM, Levitz RE. Invasive Haemophilus influenzae disease in adults. Arch Intern Med 1987;147:241.
H. influenzae, usually nontypable, caused bacteremia in 29 adults. Pneumonia was the most common source.
DuPont HL, Spink WW. Infections due to gram-negative organisms: an analysis of 860 patients with bacteremia at the University of Minnesota Medical Center, 1958–1966. Medicine (Baltimore) 1969;48:307.
An analysis of the portal of entry in 655 adults with gram-negative bacteremia.
Edmondson EB, Sanford JP. The Klebsiella-Enterobacter (Aerobacter)-Serratia group: a clinical and bacteriological evaluation. Medicine (Baltimore) 1967;46:323.
The lung is an important focus for Klebsiella bacteremia.
Fainstein V, et al. Haemophilus species bacteremia in patients with cancer: a 13-year experience. Arch Intern Med 1989;149:1341.
Haemophilus bacteremia may occur in patients with cancer. Most isolates were nontypable.
Flynn DM, Weinstein RA, Kabins SA. Infections with gram-negative bacilli in a cardiac surgery intensive care unit: the relative role of Enterobacter. J Hosp Infect 1988;11(Suppl A): 367.
Enterobacter is a particularly important cause of bacteremia in surgical patients.
Freney J, et al. Postoperative infant septicemia caused by Pseudomonas luteola (CDC Group Ve-1) and Pseudomonas oryzihabitans (CDC Group Ve-2). J Clin Microbiol 1988;26:1241.
Several unusual Pseudomonas species have caused bacteremia—in this case, in an infant after open heart surgery.
Glew RH, Moellering RC Jr, Kunz LJ. Infections with Acinetobacter calcoaceticus (Herellea vaginicola): clinical and laboratory studies. Medicine (Baltimore) 1977; 56:79.
The sources of bacteremia include intravascular cannulas and respiratory infections.
Gregory WJ, McNabb PC. Pseudomonas cepacia. Infect Control 1986;7:281.
Reviews the epidemiology and microbiology of P. cepacia.
Henderson DK, et al. Indolent epidemic of Pseudomonas cepacia bacteremia and pseudobacteremia in an intensive care unit traced to a contaminated blood gas analyzer. Am J Med 1988;84:75.
P. cepacia is a cause of nosocomial bacteremia, often associated with contamination of hospital devices.
Hicklin H, Verghese A, Alvarez S. Dysgonic fermenter-2 septicemia. Rev Infect Dis 1987;9:884.
Dysgonic fermenter-2 causes bacteremia after dog bites, particularly in splenectomized and alcoholic patients.
Isenberg HD, D’Amato RF. Enterobacteriaceae In: Gorbach SL, Bartlett JG, Blacklow NR, eds. In Infectious Disease. Philadelphia: WB Saunders, 1998.
Khabbaz RF, et al. Pseudomonas fluorescens bacteremia from blood transfusion. Am J Med 1984;76:62.
P. fluorescens caused bacteremia after proliferating in refrigerated whole blood.
Kreger BE, et al. Gram-negative bacteremia. III. Reassessment of etiology, epidemiology and ecology in 612 patients. Am J Med 1980;68:332.
Definitive study on the clinical picture of gram-negative bacteremia, including etiologic agents and sources of infection.
Levin DC, et al. Bacteremic Haemophilus influenzae pneumonia in adults: a report of 24 cases and a review of the literature. Am J Med 1977;62:219.
A review of the clinical features of H. influenzae bacteremia.
Lewis J, Fekety FR Jr. Proteus bacteremia. Johns Hopkins Med J 1969;124:151.
The urinary tract and cutaneous wounds were the most common primary sites of infection.
Mandell W, Neu HC. Shigella bacteremia in adults. JAMA 1986;255:3116.
A case of Shigella bacteremia in a patient with AIDS.
McCue JD. Improved mortality in gram-negative bacillary bacteremia. Arch Intern Med 1985;145:1212.
Compares etiologic agents in community-acquired versus hospital-acquired gram-negative bacteremia.
McGowan JE Jr. Changing etiology of nosocomial bacteremia and fungemia and other hospital-acquired infections. Rev Infect Dis 1985;7(Suppl 3):357.
Describes changing trends between 1935 and 1983.
Miller PJ, Wenzel RP. Etiologic organisms as independent predictors of death and morbidity associated with bloodstream infection. J Infect Dis 1987;156:471.
Compares mortality rates and incidence of shock associated with various etiologic agents in gram-negative bacteremia.
Morduchowicz G, et al. Shigella bacteremia in adults: a report of five cases and review of the literature. Arch Intern Med 1987;147:2034.
Report of five cases of Shigella bacteremia. Patients were malnourished but did not have AIDS.
Morrison AJ Jr, Hoffmann KK, Wenzel RP. Associated mortality and clinical characteristics of nosocomial Pseudomonas maltophilia in a university hospital. J Clin Microbiol 1986;24:52.
P. maltophilia is becoming an increasingly common cause of nosocomial bacteremia. The organism is resistant to aminoglycosides but sensitive to trimethoprimsulfamethoxazole.
Myerowitz RL, Medeiros AA, O’Brien TF. Recent experience with bacillemia due to gram-negative organisms. J Infect Dis 1971;124:239.
A blood culture that grows a gram-negative bacillus is virtually always significant.
Ratner H. Flavobacterium meningosepticum. Infect Control 1984;5:237.
This organism may cause hospital-acquired bacteremia. It has an unusual pattern of antimicrobial sensitivity.
Smego RA Jr. Endemic nosocomial Acinetobacter calcoaceticus bacteremia. Arch Intern Med 1985;145:2174.
A. calcoaceticus causes nosocomial bacteremia. The lungs and IV catheters are the most common primary sources.
Young LS, et al. University of California/Davis Interdepartmental Conference on gram-negative septicemia. Rev Infect Dis 1991;13:666.
Includes a good overview of empiric antimicrobial therapy.

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  1. My son is a 40 year old person with cerebral palsy and dystonia….he is progressively getting worse regards contractures and undesired muscle movements……in October 2011 he had bacterial spinal meniningitis……..he has a catheter…….and has benn hospitalized 3 xs since then with UTIs. He now has had gram-negative-rods grown from his blood cultyure (he has been in the hospital Critical Care for 2 days….he lost 1200 ccs of blood through his catheter, presumably from an injury during the irrigation/replacement of his catheter on Wednesday (3/31/2012)…….THIS DEVELOPMENT (THE gram-negative-rods) scares the bee-Jesus out of me and I want to know all I can about this “life threatening” (as presented in the first paragraph of this article) bug. ANY IDEAS OR HELP OR INFO APPRECIATED. 619 302-2825

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