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 BACTEREMIA AND SEPTICEMIA

Kenneth B. Roberts and Olakunle B. Akintemi

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Fever and (Occult) Bacteremia
Laboratory Diagnosis
Treatment of Presumed Sepsis
Pneumococcus
Haemophilus influenzae Type b
Meningococcus
Salmonella
Septic Shock
For bacteria to infect the bloodstream, they must first bypass the defenses of the skin and mucous membranes and then escape phagocytosis in the extravascular tissues; they travel via the lymphatics to regional lymph nodes and, if not contained by the nodes, gain access to the venous circulation. The liver and spleen play a major role in “filtering” bacteria from the blood; the spleen is predominant if there is no preexisting circulating antibody to the organism. This filtering process can be overwhelmed by a large inoculum of bacteria; residual organisms are phagocytized by white blood cells in the circulation, at alveolar capillary sites in the lungs, and in the tissues. Therefore, the following factors (with examples of disorders) predispose the host to bacteremia: (1) loss of integrity of the external defenses (e.g., major burns, gastrointestinal ulceration, intravenous catheter); (2) inadequate phagocytic or immune function (e.g., immunosuppressive drugs, neutropenia, immune deficiency disorders); (3) impaired reticuloendothelial function (e.g., splenectomy, sickle cell disease); and (4) an overwhelming inoculum (e.g., perforated intestine). Bacteremia is a dynamic process, a balance between multiplication, invasion, and clearance of organisms; in most patients, host defenses predominate, and bacteremia is a transient phenomenon.
Bacteremia and septicemia are not synonymous. Bacteremia refers only to the presence of organisms in the blood; septicemia adds the connotation of severe illness. The distinction was highlighted in the 1970s by studies demonstrating that more than 3% of febrile infants have bacteremia while not appearing “toxic.” (Rates as high as 13% were documented in “nonseptic-appearing” infants, with fever, leukocytosis, and no apparent focus of bacterial infection.) The causative organism in the majority of infants with “occult” bacteremia was and continues to be Streptococcus pneumoniae (the pneumococcus). Haemophilus influenzae type b (Hib) was the next most frequent, but is now rare since the introduction of vaccines that are effective in infants. Neisseria meningitidis (the meningococcus) and salmonellae can also circulate in the bloodstream without causing clinical septicemia. These organisms are capable of causing focal complications or sepsis; there is no way at present to determine whether septicemia or a serious focus of infection (e.g., meningitis) will develop in a given child with bacteremia.
The clinical signs of septicemia are nonspecific and difficult to define. Generally, the child has high fever and is quite ill; the words toxic and septic are often used to describe the child's appearance. The white blood cell count is usually elevated (or markedly decreased), and there may be vacuoles or “toxic granulations” in the polymorphonuclear leukocytes. In neonates and very young infants, the signs of septicemia may be considerably more subtle (see Chap. 48).
When septicemia is suspected, treatment must be instituted immediately, prior to bacteriologic confirmation. The age and condition of the patient provide reasonable guides to the pathogens most likely to be responsible for clinical disease. In newborns, group B streptococci and gram-negative bacilli are the most frequent bacteria, followed by staphylococci. In immunocompromised hosts, gram-negative bacilli predominate, particularly Pseudomonas, Escherichia coli, and Klebsiella strains; Staphylococcus aureus is also common. In children with inadequate splenic function (congenital or operative absence of the spleen, or “functional asplenia,” as in children with sickle cell disease), the pneumococcus is the usual cause of sepsis. Certain bacteria are associated with specific foci of infection, as discussed in later chapters: pneumonia (Chap. 64), meningitis (Chap. 3), infections of the bones and joints (Chap. 106), urinary tract infection (Chap. 77), and bacterial endocarditis (Chap. 57). Skin lesions suggest infection with specific organisms: petechiae/purpura (N. meningitidis), pustules (S. aureus), small lesions with necrotic centers (Neisseria gonorrhoeae, the gonococcus), ecthyma gangrenosum (Pseudomonas), and rose spots (Salmonella typhosa).
A gram-stained specimen of pus from any source or an aspirate from a skin lesion may demonstrate the organism. Rapid techniques, such as latex agglutination, may detect organism-specific antigen in body fluids such as urine or cerebrospinal fluid; these tests have not been rewarding when applied to specimens of blood or serum, however.
In practice, it is often necessary to administer broad-spectrum antibiotic coverage until the bacterium is identified. The combination of vancomycin and a third generation cephalosporin (e.g., cefotaxime or ceftriaxone) may be used to treat invasive infections caused by the organisms that commonly colonize the skin or respiratory tract. Although the third generation cephalosporins are effective against many gram-negative organisms, an aminoglycoside is generally added to initial coverage if gram-negative sepsis is suspected. Once sensitivity testing is completed, the spectrum of antibiotic coverage can be narrowed. Penicillin is the drug of choice for sepsis resulting from meningococci or penicillin-sensitive pneumococci; a penicillinase-resistant penicillin (e.g., nafcillin, methicillin, oxacillin) for the staphylococcus; ceftriaxone or cefotaxime for b-lactamase–producing strains of H. influenzae (ampicillin can be used if the strain does not produce b-lactamase); and an aminoglycoside (e.g., gentamicin, tobramycin) for the commonly isolated gram-negative bacilli, excluding Salmonella. Pseudomonas infection, particularly if the host is immunosuppressed, is best treated with the synergistic combination of an aminoglycoside and a penicillin with anti-Pseudomonas activity (e.g., piperacillin). Current cephalosporins (e.g., ceftriaxone, cefotaxime) have been developed with characteristics that make them particularly attractive: excellent activity against the pneumococcus, Hib, and the meningococcus, even in the central nervous system, coupled with the safety characteristic of older cephalosporins. Ceftazidime is notable for its anti-Pseudomonas activity.
The most serious complication of bloodstream infection is the syndrome of septic shock, characterized by the hypoperfusion of vital organs. Metabolic acidosis and tissue starvation may be profound, resulting from an inadequate blood supply and mitochondrial injury. Endothelial cells are damaged, leading to edema and acting as a nidus for thrombus formation; platelets adhere to the damaged cells, fibrin is deposited, and a cycle is established that can lead to disseminated intravascular coagulation (DIC). In addition, both pathways of complement are activated, and there is potent stimulation for both vasodilatation and vasoconstriction, producing the characteristic findings of hypotension and poor peripheral circulation. Poor perfusion and DIC, in some cases complicated by adrenal hemorrhage, may result in the clinical state of purpura fulminans, with 40–80% mortality. The meningococcus is the most frequent cause of septic shock in normal hosts, but an identical syndrome may be caused by gram-negative bacilli and, particularly in patients with deficient splenic function, by the pneumococcus.
The high morbidity and mortality associated with septicemia and its complications are improved but by no means eliminated by early recognition and aggressive therapy. Antibiotic therapy must be initiated promptly; consideration is often given to the administration of corticosteroids along with (or just prior to) antibiotics, but clinical data to support steroid use are lacking. Supportive therapy is critical and includes the intravenous infusion of fluids, oxygen, and pressors, such as dopamine, when necessary. Respiratory failure is a major mode of death.
Approaches to prevention of bacteremia and septicemia include chemoprophylaxis and immunization. Rifampin chemoprophylaxis, for example, is generally prescribed for close contacts of patients with meningococcal disease, and is recommended for some contacts of patients with invasive H. influenzae disease; however, the ability of chemoprophylaxis to prevent septicemia on a large scale is obviously limited. Vaccination against Hib has been remarkably successful since the introduction of conjugate vaccines, i.e., those that couple the carbohydrate moiety of the organism to a protein; the protein permits the infantile immune system to “recognize” the antigen and develop protective antibodies. Since the introduction of the Hib vaccine, the incidence of Hib infection has declined by 95%. Similar technology has been applied to creating a pneumococcal vaccine for use during infancy; it is expected to be effective but may not be quite as successful as the vaccines against Hib because of the greater number of pneumococcal serotypes capable of producing invasive disease. Vaccines against meningococci (groups A, C, W-135, and Y) are available for children older than 2 years in high-risk groups, but these polysaccharide vaccines are of limited effectiveness in infants younger than 2 years. Immunization against N. meningitidis is further limited since there is no effective vaccine against certain strains, such as group B, that are common causes of meningococcal disease in the United States.
Fever and (Occult) Bacteremia

1.
Baraff, L., et al. Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Pediatrics 92:1–12, 1993.
Definitely the place to start your reading. Includes the key references, a compilation of the findings, expert analysis, and recommendations. Note, however, that the prevalence of occult bacteremia in the post–Haemophilus influenzae type b (Hib) era is now about 1.6%. (See also Arch. Pediatr. Adolesc. Med. 152:624–628, 1998.)

2.
Kramer, M., and Shapiro, E. Management of the young febrile child. A commentary on recent practice guidelines. Pediatrics 100:128–133, 1997.
A scholarly and thought-provoking commentary on the “practice guidelines” (Ref. 1 above). The authors question the utility of diagnostic testing (i.e., blood culture, bladder catheterization, suprapubic aspiration), and empiric antibiotic for febrile “nontoxic” children without a source of infection. See also pp. 133–138 for commentaries on the commentary.

3.
Kuppermann, N. Occult bacteremia in young febrile children. Pediatr. Clin. North Am. 46:1073–1109, 1999.
A well-documented (230 references) review of the epidemiology, natural history and “basic science” of occult bacteremia. For a more basic and practical overview, see Contemp. Pediatr. 14:53–65, 1997.

4.
Baraff, L., Oslund, S., and Prather, M. Effect of antibiotic therapy and etiologic microorganism on the risk of bacterial meningitis in children with occult bacteremia. Pediatrics 92:140–143, 1993.
The only failures of oral therapy were in children with Hib infection; no failures of ceftriaxone were identified in 139 children.

5.
Harper, M., Bachur, R., and Fleisher, G. Effect of antibiotic therapy on the outcome of outpatients with unsuspected bacteremia. Pediatr. Infect. Dis. J. 14:760–767, 1995.
A retrospective study of 550 consecutive febrile children with unsuspected bacteremia to determine the efficacy of empiric antibiotic therapy. At follow-up, patients who received empiric antibiotic therapy (oral or parenteral) during the initial visit were afebrile; improved; and had fewer focal complications, persistent bacteremia, and admissions. (For a focus on meningococcal disease, see Arch. Pediatr. Adolesc. Med. 154:556–560, 2000.)

6.
Rothrock, S., et al. Do oral antibiotics prevent meningitis and serious bacterial infections in children with Streptococcus pneumoniae occult bacteremia? A meta-analysis. Pediatrics 99:438–444, 1997.
This study confirms that, while oral antibiotics reduce the risk of serious bacterial infections in children with occult Streptococcus pneumoniae bacteremia, they do not prevent meningitis. (See also Acad. Emerg. Med. 5:599–606, 1998.)

7.
Wittler, R., Cain, K., and Bass, J. A survey about management of febrile children without source by primary care physicians. Pediatr. Infect. Dis. J. 17:271–277, 1998.
A survey of primary care practitioners to determine their practice patterns since the publication of the 1993 practice guidelines. Most practitioners would admit the 3- and 7-week-old infants. But more pediatricians would use empiric outpatient antibiotics for the febrile 7-week-old infant. Clearly, the publication of guidelines on the management of febrile children has made little impact. See accompanying commentary, pp. 277–279. (For the result of the 1993 survey prior to the publication of the guidelines, see Pediatr. Infect. Dis. J. 12:179–183, 1993.)

8.
McCarthy, P. Infants with fever. N. Engl. J. Med. 329:1493–1494, 1993.
A perspective editorial accompanying a report of outpatient management of febrile “low-risk” infants without antibiotics (p. 1437).

9.
Baker, M., Bell, L., and Avner, J. The efficacy of routine outpatient management without antibiotics of fever in selected infants. Pediatrics 103:627–631, 1999.
The authors confirm the safety of the Philadelphia protocol for outpatient management (without antibiotics) of febrile infants 29–60 days at “low risk” for serious bacterial illness (SBI). (See also Clin. Pediatr. Emerg. Med. 7:102–108, 2000.)

10.
Hoberman, A., et al. Prevalence of urinary tract infection in febrile infants. J. Pediatr. 123:17–23, 1993. And Shaw, K.N., et al. Prevalence of urinary tract infection in febrile young children in the emergency department. Pediatrics 102:e16, 1998. (Available at: http://www.pediatrics.org/cgi/content/full/102/2/e16.)
Just a reminder that bacteremia is not the only concern in febrile infants without apparent source of infection. White female infants have the highest prevalence of urinary tract infection. (Obtaining a chest x-ray in an infant with no respiratory signs and symptoms is unnecessary see Pediatrics 92:524, 199. But chest x-ray may be considered with a temperature of 39°C or higher and leukocytosis [WBC >20,000/mm3] see Ann. Emerg. Med. 33:166–173, 1999.)
Laboratory Diagnosis

11.
Rowley, A., and Wald, E. The incubation period necessary for detection of bacteremia in immunocompetent children. Clin. Pediatr. 25:485–489, 1986.
Of blood cultures containing any of the five most common pathogens, 98.5% were “positive” within 48 hours. (Rate is not as high when considering all pathogens, however. See Pediatr. Infect. Dis. 5:333, 1986.)

12.
Saez-Llorens, X., and Lagrutta, F. The acute-phase host reaction during bacterial infection and its clinical impact in children. Pediatr. Infect. Dis. J. 12:83–87, 1993.
Insight into the “acute-phase reactants” that form the basis of nonspecific tests (e.g., white blood cell count, erythrocyte sedimentation rate) frequently performed to assess the risk of bacteremia.
Treatment of Presumed Sepsis

13.
Klass, P., and Klein, J. Therapy of bacterial sepsis, meningitis and otitis media in infants and children: 1992 Poll of directors of programs in pediatric infectious diseases. Pediatr. Infect. Dis. J. 11:702–705, 1992.
In this periodic questionnaire regarding the treatment of presumed sepsis in 5-week-olds, 5-year-olds, and 12-year-olds, the favored treatment was the combination of ampicillin and a cephalosporin (cefotaxime) for 5-week-olds, and a cephalosporin (ceftriaxone, cefotaxime, or cefuroxime) alone in the older children.
Pneumococcus

14.
Klein, J. The epidemiology of pneumococcal disease in infants and children. Rev. Infect. Dis. 3:246–253, 1981.
Part of a 200-page symposium on the pneumococcus. For more on the pneumococcal vaccine, see M.M.W.R. 64:1–19, 1997.

15.
American Academy of Pediatrics Committee on Infectious Diseases. Therapy for children with invasive pneumococcal infections. Pediatrics 99:289–299, 1997.
Established therapy guidelines for both meningeal and nonmeningeal invasive pneumococcal infections.
Haemophilus influenzae Type b

16.
Centers for Disease Control and Prevention. Progress toward eliminating Haemophilus influenzae type b disease among infants and children. United States, 1987–1997. M.M.W.R. 47:993–998, 1998.
This report highlights the continuing decline in the incidence of Hib. Since 1988, when the Hib conjugate vaccines were first licensed for children aged 18–59 months, the number of cases of invasive Hib disease has declined by 99%. The end of Hib infection may be near. See Emerg. Infect. Dis. 4:229–237, 1998.

17.
Wenger, J., et al. Day care characteristics associated with Haemophilus influenzae disease: Haemophilus influenzae Study Group. Am. J. Public Health 80:1455–1458, 1990.
The only characteristic associated with protection against Hib was the use of handerkerchiefs. (Our mothers were right!)
Meningococcus

18.
Resenstein, N., et al. The changing epidemiology of meningococcal disease in the United States, 1992–1996. J. Infect. Dis. 180:1894–1901, 1999.
The recent epidemiology of meningococcal disease in the United States. The CDC estimates 2,400 cases annually, 22% of which are in children 2 years or younger. The highest age-specific incidence is in infants younger than 1 year, with a peak incidence in infants 4–5 months old. In 1996, 33% of cases were due to serotype Y. There have been increasing numbers of meningococcal infection outbreaks (mostly by serogroup C) (J.A.M.A. 273:383–389, 1995). For more on control and prevention of meningococcal disease, see M.M.W.R. 46:1–21, 1997.

19.
Sullivan, T., and LaScolea, L. Neisseria meningitidis bacteremia in children: Quantitation of bacteremia and spontaneous clinical recovery without antibiotic therapy. Pediatrics 80:63–67, 1987.
Meningococcal bacteremia can be associated with meningitis, meningococcemia, occult bacteremia, or spontaneous recovery.

20.
Towes, W., and Bass, J. Skin manifestations of meningococcal infection. Am. J. Dis. Child. 127:173–176, 1974.
No skin lesions in 14%; 75% with generalized maculopapular rash or petechiae; 11% with purpura. Meningitis was most frequent in the first group, and death in the third group.

21.
Kirsch, E.A., et al. Pathophysiology, treatment and outcome of meningococcemia: A review and recent experience. Pediatr. Infect. Dis. J. 15:967–979, 1996.
A well documented review (131 references) of epidemiology, clinical features, pathophysiology, therapy, and prognosis of meningococcemia. For a more recent review of the pathophysiology of meningococcemia, see Eur. J. Pediatr. 157:869–880, 1998.
Salmonella

22.
Torrey, S., Fleisher, G., and Jaffe, D. Incidence of Salmonella bacteremia in infants with Salmonella gastroenteritis. J. Pediatr. 108:718–721, 1986.
Estimates a 6% incidence.

23.
St. Geme, J., et al. Consensus: Management of Salmonella infection in the first year of life. Pediatr. Infect. Dis. J. 7:615–621, 1988.
A group of experts give their opinions regarding how to manage infants with suspected Salmonella infection who are not “toxic” appearing and are well hydrated.
Septic Shock

24.
Hayden, W. Sepsis terminology in pediatrics. J. Pediatr. 124:657–658, 1994.
The author proposes adoption of the system developed by the Society of Critical Care Medicine and the American College of Chest Physicians in the classification of sepsis in children.

25.
Tapiero, B., and Lebel, M. Bacteremia, sepsis and septic shock. In:Jenson, H., and Baltimore, R. (eds.). Pediatric Infectious Disease. Principles and Practice. Norwalk, Connecticut: Appleton and Lange, 1995.
An excellent and comprehensive discussion of the definition, etiology, predisposing risk factors, clinical features, diagnosis, and treatment of bacteremia, sepsis, and septic shock. For a concise review of the definition, epidemiology, and prognosis of sepsis, see Pediatr. Emerg. Care 13:277–281, 1997. For a current overview of pediatric septic shock, see Pediatr. Rev. 20:303–308, 1999.

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