Updated: Oct 19, 2009
Sepsis is a clinical term used to describe symptomatic bacteremia, with or without organ dysfunction. Sustained bacteremia, in contrast to transient bacteremia, may result in a sustained febrile response that may be associated with organ dysfunction. Septicemia refers to the active multiplication of bacteria in the bloodstream that results in an overwhelming infection.
The pathophysiology of sepsis is complex and results from the effects of circulating bacterial products, mediated by cytokine release, caused by sustained bacteremia. Cytokines, previously termed endotoxins, are responsible for the clinically observable effects of the bacteremia in the host. Impaired pulmonary, hepatic, or renal function may result from excessive cytokine release during the septic process.
Sepsis is an overused term often misapplied to patients with fever, leukocytosis, and hypotension due to other causes, including pseudosepsis. True sepsis is a common cause of hospitalization in the United States. Frequent sources of infection are listed in History.
Sepsis is a common cause of mortality and morbidity worldwide.
The prognosis of sepsis depends on the underlying status and host defenses, prompt and adequate surgical drainage of abscesses, relief of any obstruction of the intestinal or urinary tract, and appropriate and early empiric antimicrobial therapy with the drug spectrum appropriate to the presumed septic source.
Sepsis does not appear to have a racial predisposition.
Sepsis does not appear to have a sexual predisposition.
Elderly men are more likely to develop urosepsis due to benign urinary tract obstruction caused by prostatic hypertrophy.
Table 1. Clinical Conditions Associated With Sepsis and Its Mimics
| Associated With Sepsis (Fevers ³ 102ºF) | Associated With Sepsis (Fevers £ 102ºF) |
|---|---|
Gastrointestinal tract source
| Gastrointestinal tract source
|
| Genitourinary tract source Pyelonephritis | Genitourinary tract source
|
Pelvic source
| Upper respiratory tract source
|
| Lower respiratory tract source Community-acquired pneumonia (with asplenia) | Lower respiratory tract source Community-acquired pneumonia (in an otherwise healthy host) |
| Intravascular source Intravenous-line sepsis | Skin/soft-tissue source Osteomyelitis |
Cardiovascular source
| Cardiovascular source
|
Central nervous system source
|
Adapted from: Cunha BA, Shea KW. Fever in the intensive care unit. Infect Dis Clin North Am. Mar 1996;10(1):185-209.1
Pseudosepsis
It is important to consider other causes or conditions that mimic the clinical and hemodynamic parameters of sepsis. The causes of pseudosepsis need identification because they require supportive, rather than antimicrobial, therapy. Pseudosepsis is a common cause of misdiagnosis in hospitalized patients, particularly in the emergency department and in medical and surgical intensive care units. The most common causes of pseudosepsis include the following:
| Clinical Presentations That Mimic Sepsis | Hemodynamic Parameters That Mimic Sepsis |
|---|---|
| Hemorrhage | Acute pancreatitis |
| Pulmonary embolism | Anaphylaxis |
| MI | Spinal cord injury |
| Pancreatitis | Adrenal insufficiency |
| Diabetic (abdominal crisis) ketoacidosis | |
| SLE flare with abdominal crisis | |
| Ventricular pseudoaneurysm | |
| Massive aspiration/atelectasis | |
| Systemic vasculitis | |
| Diuretic-induced hypovolemia |
| Sepsis Syndrome: No Infection | Sepsis: Bacteremia From GI, GU, Pelvic, Intravenous Source | |
|---|---|---|
| Parameters |
| Proper ID/Process/Source Plus ³ 1 Microbiologic Abnormalities |
| Microbiologic | Positive buffy coat smear result or 2/3 or 3/3 positive blood cultures | |
| Hemodynamic |
| |
| LV|| dilatation | |
| Laboratory |
| ß WBC |
| ß PLTs¶ | |
| ||
| Negative blood cultures excluding contaminants |
| |
| Clinical |
|
|
Sepsis does not cause diagnostic findings in various organs.
Appropriate antimicrobial therapy depends on adequate coverage of the resident flora of the organ system presumed to be the source of the septic process. Empiric monotherapy regimens include imipenem, meropenem, cefoperazone, piperacillin/tazobactam, or sulbactam/ampicillin. Combination therapeutic agents include clindamycin or metronidazole plus levofloxacin, aztreonam, trimethoprim/sulfamethoxazole (TMP-SMZ), or an aminoglycoside.
No single drug/regimen is superior to another. Alternative agents may be used alone or in combination provided they have a low reactive potential and a good adverse-effect profile.
These agents are used to treat various types of infection.
Empiric therapy for intravenous-line infections
Since intravenous-line infections are most often due to Staphylococcus aureus (MSSA or MRSA) and less commonly due to aerobic gram-negative bacilli, the preferred empiric therapy for intravenous-line infections is meropenem, cefoperazone, or cefepime plus additional coverage for staphylococci. If MRSA is prevalent in the institution, add linezolid, vancomycin, or daptomycin.
If coagulase-negative staphylococci are recovered from the blood (high-level bacteremia, ie, 3/4 or 4/4 blood cultures positive), avoid vancomycin for empiric therapy if possible, since this is a low-virulence organism.
Treatment of coagulase-negative staphylococcal central-line infection requires removal of the line. Vancomycin may be given, but central line removal is essential. If the central line cannot be removed for clinical reasons in a patient with MRSA or coagulase-negative staphylococcal infection, empiric suppressive vancomycin therapy is acceptable.
Minimize the use of vancomycin in order to prevent the emergence of Enterococcus faecium, a vancomycin-resistant species.
Empiric therapy for biliary tract infections (cholecystitis/cholangitis)
The main biliary-tract pathogens include Escherichia coli, Klebsiella species, and Enterococcus faecalis. Coverage for staphylococci and anaerobes is not needed in the biliary tract. Anaerobes are important only in patients with diabetes who have Clostridium perfringens emphysematous cholecystitis. Preferred monotherapy for biliary-tract infections is with imipenem, meropenem, piperacillin, or cefoperazone.
Empiric therapy for intra-abdominal and pelvic infections
The main pathogens in the lower abdomen and pelvis include aerobic coliform gram-negative bacilli and B fragilis. Enterococci are permissive/opportunistic pathogens and do not require special coverage. Potent anti– B fragilis and aerobic gram-negative bacillary coverage are essential, in addition to surgical intervention when drainage or repair of intra-abdominal viscera is required.
Preferred monotherapy for intra-abdominal and pelvic infections is imipenem, meropenem, piperacillin/tazobactam, or ampicillin/sulbactam.
Preferred combination therapy for intra-abdominal and pelvic infections is clindamycin or metronidazole plus aztreonam, levofloxacin, or an aminoglycoside.
Empiric therapy for urosepsis
The primary uropathogens include gram-negative aerobic bacilli, eg, coliforms or enterococci (E faecalis, not E faecium vancomycin-resistant enterococci).
Pseudomonas aeruginosa, Enterobacter species, and Serratia species are rare uropathogens and are associated with urological instrumentation.
Preferred monotherapy for urosepsis due to aerobic gram-negative bacilli is with aztreonam, levofloxacin, third- or fourth-generation cephalosporins, or an aminoglycoside.
Preferred monotherapy for urosepsis due to enterococci (E faecalis) is with ampicillin or vancomycin (penicillin-allergic).
Empiric therapy for community-acquired urosepsis is levofloxacin, aztreonam, or an aminoglycoside plus ampicillin. For nosocomial urosepsis, piperacillin, imipenem, or meropenem monotherapy is preferred.
Empiric therapy for other causes of sepsis
S aureus sepsis is usually associated with infection caused by devices or acute bacterial endocarditis. Empiric therapy may be with nafcillin, an anti-staphylococcal, cephalosporin, a carbapenem, linezolid, or clindamycin with or without rifampin.
Pneumococcal or meningococcal sepsis may be treated with penicillin G or a beta-lactam. In patients with associated meningococcal meningitis, the antibiotic selected should penetrate the cerebrospinal fluid and should be given in meningeal doses.
Empiric therapy for sepsis of unknown origin
The usual sources of sepsis are from the distal GI tract, pelvis, or GU tract. For intravenous-line infections, see above.
Organisms that should be covered from the GI/GU tract and pelvis include aerobic gram-negative bacilli (coliforms) and B fragilis. Enterococci are important pathogens in biliary - tract sepsis and urosepsis.
Preferred empiric monotherapy includes meropenem, imipenem, piperacillin/tazobactam, or cefoperazone.
Empiric combination therapy includes (1) levofloxacin plus either clindamycin or metronidazole, (2) aztreonam, (3) cefepime plus either clindamycin or metronidazole, or (4) ceftriaxone or aminoglycoside plus metronidazole.
For treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated because of potential for toxicity.
1 g IV q6h
<12 years: Not established; 15-25 mg/kg/dose IV q6h suggested
>12 years: Administer as in adults
Coadministration with cyclosporine may increase adverse CNS effects of both agents; coadministration with ganciclovir may result in generalized seizures
Documented hypersensitivity
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Adjust dose in renal insufficiency; avoid use in children <12 y; avoid use in those with CNS disorders/seizures
Semisynthetic carbapenem antibiotic that inhibits bacterial cell wall synthesis.
1 g IV q8h
<10 years: Not established
>10 years: Administer as in adults
Probenecid increases serum levels
Documented hypersensitivity to carbapenem or beta-lactams; first trimester of pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Adjust dose in renal impairment; pseudomembranous colitis and thrombocytopenia may occur, requiring immediate discontinuation of medication
Beta-lactam antibiotic that inhibits bacterial cell wall synthesis. A third-generation cephalosporin with antipseudomonal and antistaphylococcal activity. Only cephalosporin with anti-enterococcal (E faecalis) activity. Active against S aureus (MSSA), aerobic gram-negative bacilli, E faecalis, and B fragilis.
2 g IV q12h
<10 years: Not established
>10 years: Administer as in adults
Alcohol ingestion within 72 h induces disulfiramlike reaction
Documented hypersensitivity
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
May increase in PT or INR; may need prophylactic administration of AquaMEPHYTON 10 mg IM q1wk to all critically ill patients receiving any beta-lactam antibiotic
A quinolone that exerts a bactericidal effect by interfering with DNA gyrase in bacterial cells; highly active against gram-negative and gram-positive organisms.
500 mg IV q24h
<10 years: Not established
>10 years: Administer as in adults
Antacids, iron, and zinc salts may reduce serum levels; administer antacids 1-2 h before or after taking
Documented hypersensitivity; pregnancy; breastfeeding
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Superinfections may occur with prolonged or repeated antibiotic therapy
Semisynthetic extended-spectrum penicillin that inhibits bacterial cell wall synthesis by binding to specific PBPs; most effective of the antipseudomonal penicillins.
Tazobactam increases piperacillin activity against S aureus, Klebsiella, Enterobacter, and Serratia species; (greatest increase in activity against B fragilis) but does not increase antiP aeruginosa activity.
Intra-abdominal and pelvic infections: The main pathogens in the lower abdomen and pelvis are aerobic coliform gram-negative bacilli and B fragilis. Enterococci are permissive and opportunistic pathogens and do not require special coverage.
4.5 g IV q8h (piperacillin 4 g/tazobactam 0.5 g)
<10 years: Not established
>10 years: Administer as in adults
Probenecid increases piperacillin serum levels; synergistic effect with aminoglycosides; heparin increases risk of bleeding; may decrease efficacy of oral contraceptives; tetracycline may decrease effectiveness
Documented hypersensitivity
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Renal impairment; may interfere with platelet function
A combination beta-lactam and beta-lactamase inhibitor that suppresses bacterial cell wall synthesis by binding to specific PBPs. Sulbactam increases effectiveness against beta-lactamase–producing microorganisms. Sulbactam increases the activity of ampicillin against S aureus, Klebsiella, Enterobacter, and Serratia species; greatest increase in activity against B fragilis.
3 g IV q6h (ampicillin 2 g / sulbactam 1 g)
<10 years: Not established
>10 years: Administer as in adults
Probenecid increases serum levels; decreases effectiveness of oral contraceptives
Documented hypersensitivity
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Adjust dose in renal impairment
Binds to ribosomes in bacterial cells. Highly active against most anaerobes, including B fragilis, but not active against aerobic gram-positive or gram-negative organisms.
In intra-abdominal or pelvic infections, it must always be used in combination with another antibiotic active against aerobic gram-negative bacilli, which accompany B fragilis.
1 g IV q24h
<10 years: Not established
>10 years: Administer as in adults
Phenytoin and phenobarbital decrease serum levels; increases PT with warfarin; increases lithium levels and toxicity; cimetidine may increase serum levels
Documented hypersensitivity
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Disulfiramlike reaction if taken within 72 h of alcohol consumption
Exerts a bacteriostatic effect by interfering with bacterial metabolism at the ribosomal level. It is highly active against all staphylococci except MRSA. Some strains of S epidermidis are resistant. It is excellent against B fragilis but is not active against aerobic gram-negative bacilli. In mixed intra-abdominal or pelvic infections, it must always be used in combination therapy with an antibiotic active against aerobic gram-negative bacilli. No antienterococcal activity.
600 mg IV q8h
<10 years: Not established
>10 years: Administer same as in adults
Increased neuromuscular blockade
Documented hypersensitivity; avoid in patients who have recently had C difficile diarrhea or colitis
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Caution in advanced cirrhosis; avoid in patients with preexisting inflammatory bowel disease; discontinue if diarrhea or colitis occurs during therapy
A monobactam that inhibits cell wall synthesis during bacterial growth. Active against gram-negative bacilli.
2 g IV q8h
90-120 mg/kg/d divided IV/IM q6-8h
Tetracyclines may reduce effects of this medication
Documented hypersensitivity
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Adjust dose in renal insufficiency; not active against B fragilis or enterococci
Inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription.
400 mg PO/IV qd
<18 years: Not recommended
>18 years: Administer as in adults
Antacids and electrolyte supplements reduce absorption; loop diuretics, probenecid, and cimetidine increase serum levels; NSAIDs enhance CNS stimulating effect; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT); ferrous sulfate decreases bioavailability (administer moxifloxacin 4 h prior or 8 h following ferrous sulfate); coadministration with drugs that prolong QTc interval (quinidine, procainamide, amiodarone, sotalol, erythromycin, tricyclic antidepressants) increase risk of life-threatening arrhythmia
Documented hypersensitivity; known QT prolongation; concurrent administration of drugs that cause QT prolongation
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); superinfections may occur with prolonged or repeated antibiotic therapy; fluoroquinolones have induced seizures in CNS disorders and have caused tendinitis or tendon rupture
Bactericidal activity results from inhibition of cell wall synthesis and is mediated through ertapenem binding to PBPs. Stable against hydrolysis by various beta-lactamases, including penicillinases, cephalosporinases, and extended spectrum beta-lactamases. Hydrolyzed by metallo-beta-lactamases.
1 g qd for 14 d if IV and 7 d if IM; infuse over 30 min if IV
CrCl <30 mL/min/1.73 m2: 500 mg IV qd
<3 months: Not established
3 months to 12 years: 15 mg/kg IV q12h; not to exceed 1 g/d
>12 years: Administer as in adults
Probenecid may reduce renal clearance of ertapenem and increase half-life, but benefit is minimum and does not justify coadministration
Documented hypersensitivity to drug or amide type anesthetics
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Pseudomembranous colitis may occur; seizures and CNS adverse reactions may occur; when using with lidocaine to administer intramuscularly, avoid inadvertent injection into blood vessel; decrease dose in renal failure; serious and occasionally fatal hypersensitivity reactions may occur with beta-lactams, caution with previous hypersensitivity reactions to penicillin, cephalosporins, other beta-lactams, or other allergens; do not mix or coinfuse in same IV line as other medications; do not mix with dextrose-containing diluents
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sepsis, bacterial sepsis, urosepsis, septic shock, bacteremia, symptomatic bacteremia, septicemia, leukocytosis, pseudosepsis, bacteruria
Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Pranatharthi Haran Chandrasekar, MD, Director of Infectious Disease Fellowship, Professor, Department of Internal Medicine, Harper Hospital, Wayne State University School of Medicine
Pranatharthi Haran Chandrasekar, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment
Thomas M Kerkering, MD, Chief of Infectious Diseases, Virginia Tech, Carilion School of Medicine, Roanoke, Virginia
Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society
Disclosure: Nothing to disclose.
Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Michael Stuart Bronze, MD, Professor, Stewart G Wolf Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Association of Professors of Medicine, Association of Program Directors in Internal Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.