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Anti-Infective Therapy

Despite dire warnings that we are approaching the end of the antibiotic era, the incidence of antibiotic-resistant bacteria continues to rise. The proportions of penicillin-resistant Streptococcus pneumoniae, hospital-acquired methicillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus strains continue to increase. Community-acquired methicillin-resistant Staphylococcus aureus is now common throughout the world. Multiresistant Acinetobacter and Pseudomonas are everyday realities in many of our hospitals.

The press is now warning the lay public of the existence of “dirty hospitals.” As never before, it is critical that health care providers understand the principles of proper anti-infective therapy and use anti-infective agents judiciously. These agents need to be reserved for treatable infections — not used to calm the patient or the patient’s family. Too often, patients with viral infections that do not warrant anti-infective therapy arrive at the physicians office expecting to be treated with an antibiotic. And health care workers too often prescribe antibiotics to fulfill those expectations.

Physicians unschooled in the principles of microbiology utilize anti-infective agents just as they would more conventional medications, such as anti-inflammatory agents, anti-hypertensive medications, and cardiac drugs. They use one or two broad-spectrum antibiotics to treat all patients with suspected infections. Many excellent broad-spectrum antibiotics can effectively treat most bacterial infections without requiring a specific causative diagnosis. However, overuse of empiric broad-spectrum antibiotics has resulted in the selection of highly resistant pathogens.

A simplistic approach to anti-infective therapy and establishment of a fixed series of simple rules concerning the use of these agents is unwise and has proved harmful to patients. Such an approach ignores the remarkable adaptability of bacteria, fungi, and viruses. It is no coincidence that these more primitive life forms have survived for millions of years, far longer than the human race. The rules for the use of anti-infective therapy are dynamic and must take into account the ability of these pathogens to adapt to the selective pressures exerted by the overuse of antibiotic, antifungal, and antiviral agents. The days of the “shotgun” approach to infectious diseases must end, or more and more patients will become infected with multiresistant organisms that cannot be treated. Only through the judicious use of anti-infective therapy can we hope to slow the arrival of the end of the antibiotic era.

About Anti-Infective Therapy

  1. Too often,antibiotics are prescribed to fulfill the patient’s expectations, rather than to treat a true bacterial infection.
  2. A single antibiotic cannot meet all infectious disease needs.
  3. Physicians ignore the remarkable adaptability of bacteria, fungi, and viruses at their patient’s peril.
  4. Anti-infective therapy is dynamic and requires a basic understanding of microbiology.
  5. The “shotgun” approach to infectious diseases mustend,orwe maytruly experience the end of the antibiotic era.

Antiviral Drugs (Other Than Antiretroviral Agents)

Most antiviral agents target viral nucleic acid synthesis. Because these agents tend to act at a single step in viral replication, resistance may develop during treatment. The development of resistance is favored by a high viral load, a high intrinsic viral mutation rate (more common in RNA than Deoxyribonucleic acid viruses), and a high degree of selective pressure — that is, prolonged antiviral therapy or repeated courses of treatment. A second method for controlling viral infection is to modify the host immune response. Infusions of antibody preparations and treatment with interferon have proved efficacious in several viral infections.

About Antiviral Therapy

  1. Usually target viral nucleic acid synthesis.
  2. Development of resistance is common and is favored by a)  high viral load, b)  high  intrinsic viral   mutation   rate  (RNA viruses more than Deoxyribonucleic acid viruses), and c)  prolonged or intermittent antiviral therapy.

Antivirals that Block Deoxyribonucleic acid Transcription

Acyclovir, Valacyclovir, Famciclovir

Chemical Structure and Mechanisms of Action

Acyclovir and valacyclovir are synthetic analogs of guanine in which a side chain has been substituted for a sugar moiety. Famciclovir is a acyclic guanosine analog derived from penciclovir, and this prodrug is quickly converted to penciclovir following oral absorption.

These antiviral agents are phosphorylated in virus-infected cells by viral thymidine kinase, forming a monophosphate compound. Host cell kinases then add two additional phosphates, allowing the triphosphate to add to replicating Deoxyribonucleic acid. The acyclic side chain of acyclovir prevents the addition of subsequent nucleic acids to Deoxyribonucleic acid causing premature termination. Penciclovir is not a Deoxyribonucleic acid chain terminator; it acts primarily as a viral Deoxyribonucleic acid polymerase inhibitor. Acyclovir also selectively inhibits viral Deoxyribonucleic acid polymerase. Because these agents require viral thymidine kinase for their initial phosphorylation step, the concentrations of the triphosphate compounds are 40 to 100 times higher in infected than uninfected cells. Acyclovir and famciclovir resistance are most commonly caused by a reduction in viral thymidine kinase. The loss or reduction in viral   thymidine   kinase   activity   impairs   acyclovir phosphorylation and also renders the virus resistant to ganciclovir, because that agent also requires activation by viral thymidine kinase.


Toxicity related to these drugs is generally minimal. Rarely patients develop rash, hematuria, headache and nausea. Neurotoxicity may occur in 1-4% receiving intravenous acyclovir and can result in lethargy, obtundation, coma, hallucinations, seizures, and autonomic instability. Most patients who suffer these complications have renal dysfunction resulting in high acyclovir serum levels. Co-administration of zidovudine and acyclovir increases the risk of developing lethargy.

Table. Systemic Antiviral Agents: Half-Life, Dosing, Renal Dosing,and Cost

Antibiotic (trade name) Half life (h) Dose Dose for reduced creatinine clearance (mL/min)
Acyclovir (Zovirax) 2-2.5 200-800 mg PO X 3-5 daily 5-10mg/kglVq8h <10:800mg POq12h, 2.5-6 mg/kg IV q24h 10-50:800 mgPOq8h, 5-12 mg/kg IV q12-24h
Valacydovir (Valtrex) 2.5-3.3 500 mg POq12hto 1000 mg POq8h 10-50:1 g q12-24h <10:500mgq24h
Famciclovir (Famvir) 2.3 125 mg POq12hto 500 mg PO q8h 10-50:q12-24h <10:125-250 mg q48h
Ganciclovir (Cytovene) 2.5-3.6 5mg/kglVq12h induction, 5 mg/kg q24h maintenance 50-80: Half the dose, same intervals 10-50:2.5 mg/kg q24h, or 1.2 mg/kg q24h maintenance <10:1.2 mg/kg X3 weekly,or 0.6 mg/kg X3 weekly maintenance
Valgancidovir (Valcyte) 4 900 mg POq12h X 3 weeks, then 900 mg q24h 10-50: Half the dose <10:450mgq48h X 3 weeks, then twice weekly
Cidofovir (Vistide) 17-65 5 mg/kg IV twice weekly 50-80: Usual dose <50:Contraindicated
Foscarnet (Foscavir) 3 40-60 mg/kg IV q8h induction, 90-120 mg/kg q24h maintenance 50-80:40-50 mg/kg q8h induction, 60-70 mg/kg q24h maintenance 10-50:20-30 mg/kg q8h induction, 50-70 mg/kg q24h maintenance <10:Contraindicated
Ribavirin (Copegus, Rebetol) 0.5-2 <75 kg:400mg am, and 600 mg PO pm >75kg:600mgPOq12h <50:Not recommended
Interferon a 2B   PEG-lntron: 1.5 (xg/kg SC No changes required
(PEG-lntron, Pegasys)   weekly Pegasys: 180 mg SC weekly  
Oseltamavir (Tamiflu) 6-10 Treatment: 75 mg PO q12h 10-50:75 mgq24h
    Prophylaxis: 75 mg PO q24h <10:Not recommended
Zanamivir (Relenza) 3 5 mg inhalation, 2 inhalations ql 2h X5 days 50-80: Usual dose <50:Nodata
Amantadine (Symmetrel, Symadine) 15-20 <65 years: 100 mg q12h >65 years: 100 mg PO q24h 50-80:100-150 q24h 10-50:100 mg X 2-3 weekly <10:100-200 mg weekly
Rimantadine (Flumadine, Rimantid) 24-30 <65 years: 100 mg POq12h >65 years: 100-200 mg PO q24h <10:100mgq24h

About Acyclovir, Valacyclovir,and Famciclovir

  1. All require viral thymidine kinase phosphorylation for activity.
  2. Acyclovir binds to the replicating viral Deoxyribonucleic acid, causing premature chain termination; acyclovir and famciclovir both inhibit viral Deoxyribonucleic acid polymerase.
  3. Resistance is most commonly mediated by a reduction in viral thymidine kinase.
  4. Toxicity is minimal. Intravenous administration of acyclovir can cause lethargy, obtundation, hallucinations, and seizures.
  5. Valacyclovir is rapidly converted to acyclovir; resulting acyclovir levels are higher than those achieved with oral preparations of acyclovir. Famciclovir is rapidly converted to penciclovir.
  6. Excellent activity against herpes simplex 1 and 2. Oral preparations recommended for treatment and prophylaxis of genital herpes and ocular herpes. Intravenous acyclovir recommended for herpes simplex encephalitis.
  7. Moderate activity against varicella (intravenous acyclovir recommended for the immunocom-promised host), and varicella pneumonia or encephalitis in the normal host. High doses of oral valacyclovir and famciclovir can be used to treat less severe disease.
  8. Famciclovir can also be used to treat hepatitis В virus. Intravenous administration can also cause crystalluria and crystalline nephropathy particularly if the patient is dehydrated. Cyclosporin increases the risk of nephrotoxicity.


The oral absorption of acyclovir is limited, only 15% to 20% of the drug being bioavailable. Absorption tends to be even poorer in transplant patients, necessitating higher oral dosing. The prodrug preparation valacyclovir is rapidly and completely converted to acyclovir by hepatic and intestinal valacyclovir hydrolase. Oral valacyclovir achieves acyclovir serum levels that are 3 to 5 times higher than those achieved by oral acyclovir. Similarly famciclovir is well absorbed orally, and in the liver and intestine, its purine is quickly deacetylated and oxidized to form penciclovir. Acyclovir and penciclovir are widely distributed in tissues and fluids.

Therapeutic levels can be achieved in cere-brospinal fluid, saliva, vaginal secretions, and the aqueous humor. Both drugs are excreted unchanged primarily in the urine. Probenecid reduces renal clearance and increases the half life. Antiviral Activity and Therapeutic Indications — Acyclovir and famciclovir have excellent activity against herpes simplex viruses 1 and 2. Topical administration of these drugs is of minimal efficacy against herpes simplex labialis, and topical preparations are rarely used. Oral acyclovir and famciclovir are recommended for treatment of genital herpes and are used to prevent recurrent herpes genitalis.

Acyclovir is also recommended for the treatment and prevention of recurrent ocular herpes simplex. Intravenous acyclovir has reduced the mortality from herpes simplex encephalitis and is the treatment of choice for that disorder. Acyclovir and famciclovir also have significant activity against varicella; however, higher drug concentrations are required to kill that virus. Intravenous acyclovir is recommended for the treatment of varicella and herpes zoster in the immunocompromised host, and for treatment of varicella pneumonia or encephalitis in the previously healthy adult. Acyclovir demonstrates some activity against Epstein-Barr virus, but is generally not recommended for therapy.

This agent also demonstrates modest protection against cytomegalovirus when used for prophylaxis in allogeneic bone marrow, renal, and liver transplant recipients; however, ganciclovir has proved to be more efficacious. Famciclovir can reduce levels of hepatitis В viral Deoxyribonucleic acid and serum transaminase in patients with chronic hepatitis B. Its effects are additive when combined with interferon. Famciclovir has also been used to treat recurrent hepatitis В following liver transplantation.

Ganciclovir and Valganciclovir

Chemical Structure and Mechanisms of Action

Like acyclovir, ganciclovir is a guanine analog. Ganciclovir has an additional hydroxymethyl group on the acyclic side chain. Viral thymidine kinase converts this analog to the monophosphate form, after which host cell kinase phosphorylation produces the active triphosphate form. Ganciclovir triphosphate competitively inhibits viral Deoxyribonucleic acid polymerase incorporation of guanosine triphosphate into elongating Deoxyribonucleic acid, but does not act as a chain terminator. In infected cells, intracellular concentrations of ganciclovir triphosphate reach levels that are 10 times that of acyclovir triphosphate, and once in the cell, ganciclovir triphosphate persists, having a intracellular half life of 16 to 24 hours.

The resulting higher intracellular concentrations may account for the greater activity of ganciclovir against cytomegalovirus. Ganciclovir is also active against herpes simplex, varicella, and Epstein-Barr virus. Because ganciclovir requires viral thymidine kinase activity for conversion to the active triphosphate form, acyclovir-resistant viral strains with reduced thymidine kinase activity are also less sensitive to ganciclovir. Mutations that alter the structure of the viral Deoxyribonucleic acid polymerase also confer ganciclovir resistance, and these mutants often demonstrate reduced sensitivity to foscarnet and cidofovir.


Significant concentrations of ganciclovir triphosphate accumulate in uninfected cells. Bone marrow progenitor cells are particularly sensitive to this agent. The triphosphate form can incorporate into cellular Deoxyribonucleic acid and block host cell Deoxyribonucleic acid replication. Neutropenia and thrombocytopenia are commonly observed in patients with AIDS who are receiving ganciclovir, and these patients require close monitoring for white blood cell and platelet counts during therapy. The risk is lower, but significant, in transplant patients. Co-administration of zidovudine increases the risk of bone marrow suppression. Discontinuation of treatment is recommended if the absolute neutrophil count drops below 500 cells/mm3. Central nervous system side effects (including headache, confusion, psychosis, coma, and seizures) are also common.

Anti-Infective Therapy


Valganciclovir is a prodrug that is well absorbed orally and quickly converts to ganciclovir. With oral administration, excellent serum levels that are nearly comparable to intravenous ganciclovir can be achieved. Ganciclovir readily penetrates all tissues and fluids including the brain and cerebrospinal fluid. The drug is primarily excreted unmodified in the urine.

Spectrum of Activity and Treatment Indications

Of the guanine analogs, ganciclovir has the highest activity against cytomegalovirus. Ganciclovir is the treatment of choice for cytomegalovirus infections including retinitis, pneumonia, and colitis. Ganciclovir is also used for prophylaxis of cytomegalovirus in transplant patients. In patients with AIDS who have persistently low CD4 lymphocyte counts, ganciclovir maintenance therapy is required to prevent relapse of cytomegalovirus infection after the treatment of active infection has been completed.

About Ganciclovir

  1. Guanine analog that primarily inhibits viral Deoxyribonucleic acid polymerase.
  2. Like acyclovir and penciclovir, requires viral thymidine kinase for activation. Acyclovir-resistant strains are often resistant to ganciclovir.
  3. Bone marrow suppression is a common toxicity, particularly in AIDS patients.The drug should be discontinued if the neutrophil count drops to less than 500 cells/mm3.
  4. Central nervous system complaints — including confusion, psychosis, coma, and seizures — may occur.
  5. Most active guanine analog against cytomegalovirus (cytomegalovirus). Also active against herpes simplex 1 and 2, varicella, and Epstein-Barr virus.
  6. Recommended for cytomegalovirus retinitis, pneumonia, and colitis. Useful for prophylaxis of immunocompromised transplant patients. Following treatment of active infection in AIDS patients with low CD4 counts, oral valganciclovir is given to prevent relapse.


Chemical Structure, Mechanisms of Action, and Pharmacokinetics

Cidofovir  is an analog of deoxycytidine monophosphate that inhibits viral Deoxyribonucleic acid synthesis. This agent does not require viral kinase for activity, being converted by cellular enzymes to its active diphosphate form. It acts as a competitive inhibitor of viral Deoxyribonucleic acid polymerase and also adds to Deoxyribonucleic acid, substituting for deoxycytidine triphosphate (dCTP), causing premature chain termination. Viral thymidine kinase mutantations do not impair cidofovir activity. Resistance is conferred through viral Deoxyribonucleic acid polymerase mutations. Such mutations can result in cross-resistance to ganciclovir and, less commonly, to foscarnet. Cidofovir is cleared by the kidneys.


Cidofovir is highly nephrotoxic, causing proteinuria in half of treated patients, and azotemia and metabolic acidosis in a significant number. Vigorous saline hydration and co-administration of probenecid reduces nephrotoxicity. The drug should be discontinued if 3+ proteinuria or higher develops, or if serum creatinine increases by more than 0.4 mg/dL. Neutropenia is also commonly encountered.

Spectrum of Activity and Treatment Indications

Cidofovir has activity against many Deoxyribonucleic acid viruses: cytomegalovirus; herpes simplex; herpesvirus 6 and 8; varicella; pox viruses, including smallpox; papilloma viruses; polyoma viruses; and adenoviruses. This agent is approved only for the treatment of cytomegalovirus retinitis in patients with AIDS. Given its highly toxic profile, parenteral use of this drug in other viral infections is likely to be limited. Topical therapy may prove efficacious in acyclovir-resistant herpes simplex infections in patients with AIDS, and it is being studied for the treatment of anogenital warts.

About Cidofovir

  1. An analog of deoxycytidine monophosphate, it causes premature chain termination of viral Deoxyribonucleic acid and also inhibits viral Deoxyribonucleic acid polymerase.
  2. Does not require viral thymidine kinase for conversion to its active form. Acyclovir-resistant strains are usually not resistant to cidofovir.
  3. Highlynephrotoxic;causesproteinuria,azotemia, and metabolic acidosis in nearly half of patients. Saline hydration and probenecid reduce nephrotoxicity. Neutropenia also is common.
  4. Broad spectrum of antiviral activity including cytomegalovirus, herpes simplex, herpesvirus 6 and 8, varicella, pox viruses, papilloma virus, polyoma viruses, and adenoviruses.
  5. Approved for cytomegalovirus retinitis in patients with AIDS. Other indications are currently being explored. However,the usefulness of cidofovir is likely to be limited because of renal and bone marrow toxicity.

About Foscarnet

  1. Blocks binding of deoxynucleotidyl triphos-phatesto viral Deoxyribonucleic acid polymerase.
  2. Nephrotoxicity is common, usually developing during the second week of therapy. Can be reduced by saline hydration. Usually reversible.
  3. Also causes abnormalities in serum calcium, magnesium,and phosphate.
  4. Active against cytomegalovirus, herpes simplex, varicella, Epstein-Barr virus, and herpesvirus 8.
  5. Approved for the treatment of cytomegalovirus retinitis and acyclovir-resistant mucocutaneous herpes simplex.


Chemical Structure and Mechanism of Action

Foscarnet is an inorganic pyrophosphate analog, trisodium phosphonoformate, which reversibly blocks the pyrophosphate binding site of viral Deoxyribonucleic acid polymerase. Foscarnet binding inhibits the polymerase from binding deoxynucleotidyl triphosphates. Mutations to the viral Deoxyribonucleic acid polymerase are primarily responsible for viral resistance; however, resistance among clinical isolates is rare.


Nephrotoxicity is the most common serious side effect of foscarnet, resulting in azotemia, proteinuria, and occasionally acute tubular necrosis. Renal dysfunction usually develops during the second week of therapy and in most cases reverses when the drug is discontinued. Dehydration increases the incidence of nephrotoxicity, and saline loading is of benefit in reducing this complication. Metabolic abnormalities are frequent. Hypocalcemia is the most common, being the result of chelation by foscarnet. Reductions in ionized calcium can cause Central nervous system disturbances, tetany, paresthesias, and seizures. Other metabolic abnormalities include hypophosphatemia, hypomagnesemia, hypokalemia, hypercalcemia, and hyperphosphatemia. To minimize these metabolic derangements, intravenous infusion should not exceed 1 mg/kg per minute. Electrolytes, magnesium, phosphate, and calcium should be closely monitored. Other common side effects include fever,headache, nausea, vomiting, and abnormal liver function tests.


Foscarnet is poorly absorbed orally and is administered intravenously. This drug penetrates all tissues and fluids, achieving excellent levels in the cerebrospinal fluid and vitreous humor. Foscarnet is excreted unmodified, primarily by the kidneys.

Spectrum of Activity and Treatment Indications.

Foscarnet is active against cytomegalovirus, herpes simplex, varicella, Epstein-Barr virus, and herpesvirus 8. It is approved for the treatment of cytomegalovirus retinitis and for acyclovir-resistant mucocutaneous herpes simplex.

Other Antiviral Agents


Chemical Structure and Mechanism of Action

Ribavirin is a guanosine analog that contains the d-ribose side chain. It inhibits Deoxyribonucleic acid and RNA viruses alike. The mechanisms of inhibition are complex and not completely understood. Ribavirin is phosphorylated to the triphosphate form by host cell enzymes, and the triphosphate form interferes with viral messenger RNA formation. The monophosphate form interferes with guanosine triphosphate synthesis, lowering nucleic acid pools in the cell.


Systemic ribavirin results in dose-related red blood cell hemolysis; at high doses, it suppresses the bone marrow. The resulting anemia reverses when the drug is discontinued. Intravenous administration is not approved in the United States, but is available for patients with Lhasa fever and some other forms of hemorrhagic fever. Aerosolized ribavirin is associated with conjunctivitis and with bronchospasm that can result in deterioration of pulmonary function. A major concern for health care workers exposed to aerosolized ribavirin are teratogenic and embryotoxic effects noted in some animal studies. Pregnant health care workers should not administer this drug.


Approximately one third of orally administered ribavirin is absorbed. The drug penetrates all tissues and body fluids. Ribavirin triphosphate becomes highly concentrated in erythrocytes (40 times plasma levels) and persists for prolonged periods with red blood cells. The drug is cleared both by the kidneys and by the liver. Aerosolized ribavirin produces high drug levels that have a half life of up to 2.5 h in respiratory secretions. A special aerosol generator is required for proper administration.

Spectrum of Activity and Treatment Recommendations

Ribavirin is active against a broad spectrum of Deoxyribonucleic acid and RNA viruses including respiratory syncytial virus, influenza and parainfluenza virus, herpes, adenovirus, pox viruses, Bunyavirus, and arenaviruses. It is approved in the United States for the aerosol treatment of respiratory syncytial virus bronchiolitis and pneumonia in hospitalized patients. Oral ribavirin in combination with interferon is approved for the treatment of chronic hepatitis C.

About Ribavirin

  1. Guanosine analog that interferes with viral messenger RNA formation and reduces guanosine triphosphate synthesis, lowering nucleic acid pools in the cell.
  2. Systemic drug causes red blood cell hemolysis. Intravenous administration not approved in the United States. Aerosolized form causes conjunctivitis and bronchospasm.
  3. Teratogenic and embryotoxic. Pregnant health care workers should not administer.
  4. Active against Deoxyribonucleic acid and RNA viruses including respiratory syncytial virus (respiratory syncytial virus), influenza and parainfluenza virus, herpes viruses, adenovirus, pox viruses, Bunyavirus, and arenaviruses.
  5. Approved for aerosolized treatment of respiratory syncytial virus bronchiolitis and pneumonia.
  6. Approved for oral administration in combination with interferon for chronic hepatitis С


Chemical Structure and Mechanism of Action

The interferons are proteins of 16 to 27,000 Da molecular weight, synthesized by eukaryotic cells in response to viral infections. These cytokines in turn stimulate host antiviral responses. Interferon receptors regulate approximately 100 genes, and in response to interferon binding, cells rapidly produce dozens of proteins. A wide variety of RNA viruses are susceptible to the antiviral actions of interferons; most Deoxyribonucleic acid viruses are only minimally affected.


Side effects tend to mild when doses of less than 5 million units are administered. Doses of 1 to 2 million units given subcutaneously or intramuscularly are associated with an influenza-like syndrome that is particularly severe during the first week of therapy. This febrile response can be reduced by pre-medication with antipyretics such as aspirin, ibuprofen, and acetaminophen. Local irritation at injection sites is also frequently reported. Higher doses of interferon result in bone marrow suppression, causing granulocytopenia and thrombocytopenia. Neurotoxicity resulting in confusion, somnolence, and behavior disturbances is also  common  when  high   doses  are  administered.

About Interferon for Treatment of Viral Infections

  1. Binds to host cell interferon receptors, upregu-lating many genes responsible for the production of proteins with antiviral activity.
  2. RNA viruses are more susceptible to the antiviral actions of interferons.
  3. The most common side effect is an influenzalike syndrome. At doses above 5 million units, bone marrow suppression and neurotoxicity may develop. Hepatoxicity and retinopathy are commonly associated with high doses.
  4. Approved for chronic hepatitis C, chronic hepatitis B, and Kaposi sarcoma. Intralesional injection approved for condyloma acuminatum. Hepatoxicity and retinopathy are other common side effects with high dose therapy.


Intramuscularly and subcuta-neously interferon-a is well absorbed; other interferons have more variable absorption. Assays for biologic effect demonstrate activity that persists for 4 days after a single dose. Pegylated forms result in slower release and more prolonged biologic activity, allowing for once-weekly administration; these forms are preferred in most instances.

Spectrum of Activity and Treatment Recommendations

The effectiveness of interferons has been limited by the frequent side effects associated with effective doses. Treatment approvals have been issued for interferons in chronic hepatitis C, chronic hepatitis B, Kaposi sarcoma and other malignancies, and condyloma acuminatum.

Anti-influenza Viral Agents

Amantadine and Rimantadine

Mechanism of Action

Amantadine and rimantadine are effective only against influenza A. They bind to and inhibit the M2 protein. This viral protein is expressed on the surface of infected cells, and it is thought to play an important role in viral particle assembly.


Amantadine causes moderate Central nervous system side effects, especially in the elderly. Insomnia, inability to concentrate, and dizziness are most commonly reported. Amantadine also increases the risk of seizures in patients with a past history of epilepsy. Rimantadine causes Central nervous system side effects less frequently, and this agent is now preferred over amantadine.

Treatment Recommendations

To be effective, treatment must be instituted within 48 hours of the onset of symptoms. Efficacy has been proven in healthy adults, but trials have not been performed in high-risk patients.

Neuramidase Inhibitors

Mechanism of Action

The neuramidase inhibitors have activity against both influenza A and B.


Zanamivir is given by inhaler and commonly causes bronchospasm, limiting its usefulness.


To be effective, neuramidase inhibitors must be given within 48 hours of the onset of symptoms. Amantadine, rimantadine, or oseltamavir can be given for a longer duration as prophylaxis in patients at risk of serious complications from influenza during an epidemic. Influenza vaccine is preferred for prophylaxis.

Sepsis Syndrome


Sepsis severe infection leading to organ dysfunction —  is a problem of increasing magnitude in the United States. Estimates of the occurrence of this syndrome range from 300,000 to 500,000 cases per year. Mortality associated with the syndrome has been reported to be between 15% and 60%, governed by factors such as underlying diseases, age, infecting organism, and the appropriateness of empiric anti-infective therapy. Most cases of sepsis syndrome are the result of bacterial infection, but it should be appreciated that the syndrome is also seen in viral infections (for example, dengue fever), fungal infections for example, candidemia), and certain noninfectious diseases (for example, pancreatitis). For the purposes of this chapter, sepsis is presumed to be a result of bacterial agents and their products.

About the Prevalence and Definitions of Sepsis Syndrome

  1. Prevalence is 300,000-500,000 cases per year in the United States.
  2. Mortality ranges from 15% to 60%.
  3. Sepsis syndrome is systemic inflammatory response syndrome caused by microbial products.
  4. Viruses (dengue fever), fungi (Candida), and noninfectious diseases (pancreatitis, tissue ischemia, severe trauma) can also cause systemic inflammatory response syndrome.
  5. Severe sepsis is defined as systemic inflammatory response syndrome caused by microbial products that is associated with organ dysfunction.
  6. Septic shock is shock associated with sepsis that is unresponsive to volume replacement.
  7. Bacteremia does not always cause sepsis syndrome, and sepsis syndrome is not always caused by bacteremia.


Sepsis represents a continuum that progresses from localized infection to severe sepsis. “Sepsis” is best defined as the systemic inflammatory response syndrome (systemic inflammatory response syndrome) caused by microbial products. This definition acknowledges that systemic inflammatory response syndrome may be produced by entities other than infection and that, in the absence of viable organisms, microbial products are capable of producing this clinical picture. “Severe sepsis” is defined as sepsis with organ dysfunction, and it represents progression of systemic inflammatory response syndrome with more severe pathophysiologic disturbances. “Septic shock” is hypotension due to sepsis that has become unresponsive to initial attempts at volume expansion. “Infection,” often colloquially called “sepsis,” indicates the presence of infection and should not be considered synonymous with sepsis syndrome. Bacteremia is often called sepsis, and although some bacteremias result in sepsis syndrome, not all sepsis syndromes are caused by bacteremia. In fact, in earlier clinical trials of biologic agents in sepsis syndrome, using the best possible definitions and available laboratory studies, fewer than 40% of patients have had proven infection.


Systemic inflammatory response syndrome results from the activation of cellular pathways that lead to a triggering of innate immune responses and coagulation mechanisms. The pathways are linked to ancient mechanisms that defend the host by responding to tissue injury or the presence of microbial products. This innate immune response eventually leads to a classic adaptive immune response characterized by the production of antibodies, activated T cells and memory of antigens. Much is now known about the microbial triggers of this system, with most of the information having been obtained using a portion of the gram-negative cell wall, the lipopolysaccharide molecule or endotoxin. It is clear, however, that gram-positive cell wall material — specifically peptidoglycans and lipoteichoic acid, toxins produced by gram-positive bacteria, and fungal cell walls — is also recognized by a family of molecules on the surfaces of target cells. This recognition leads to the synthesis of molecules that trigger inflammation and coagulation pathways.

Cell Wall Factors

In gram-negative bacteria, the cytoplasmic bilayer is covered with a layer of peptidoglycan. Overlying the peptidoglycan layer is an outer membrane, into which endotoxin is inserted. Endotoxin is the most carefully studied microbial substance implicated in sepsis syndrome and shock. There is compelling evidence that endotoxin plays a key role in the pathogenesis of gram-negative sepsis. Its structural organization is common across all gram-negative bacteria. From the outside going inward, it consists of an “O” side chain that is joined to a core, which is in turn connected to the “business” end of the molecule, the lipid A portion. Lipid A is anchored into the outer membrane.

The triggering of the inflammatory and coagulation systems is believed to begin with the interaction of lipopolysaccharide with cellular receptors on macrophages and mononuclear leukocytes. The structure of lipid A is remarkably well conserved in most common gram-negative bacteria, irrespective of the species from which it is obtained. Indeed, the clinical features of sepsis caused by Escherichia coli are similar to those caused by Klebsiella or Enterobacter species. The infusion of lipopolysaccharide or lipid A into animals results in a sepsis-like picture.

Endotoxin can be found in the blood of patients with gram-negative sepsis. In some cases, such as meningococcemia, there is a good correlation between the plasma level of endotoxin and the outcome; even in more “general” types of gram-negative infection, the presence of endotoxemia correlates with more severe physiologic variables. In addition to lipopolysaccharide, fungal cells walls, gram-positive cell walls and possibly bacterial flagellins are also capable of interacting with macrophages to trigger the sequence of events leading to sepsis and shock. Endotoxin is not present in gram-positive bacteria. Instead, the cell wall contains a thick layer of peptidoglycan on its surface. In capsular strains the peptidoglycan lies directly beneath the capsule. Embedded in the peptidoglycan are molecules of lipoteichoic acid. Several in vitro studies have demonstrated that these structural components of gram-positive cell walls are able to mimic some of the properties of endotoxin — for example, their ability to induce proin-flammatory cytokines from mononuclear cells.

Secreted Factors

In addition to factors that are integral parts of the cell wall, secreted factors from gram-positive bacteria are believed to cause septic shock. The prototypical factor is toxic shock syndrome toxin 1 (TSST-1), produced by some strains of Staphylococcus aureus. Toxic shock syndrome was first described in menstruation-associated staphylococcal infection of young women. Fever and profound shock were often followed by conjunctival and palmar hyperemia and desquama-tion. This condition proved to be associated with the production of an exotoxin, TSST-1. Another secreted factor responsible for shock was discovered in strains of the gram-positive bacteria Streptococcus pyogenes. It is called streptococcal pyrogenic exotoxin A (SPEA). Clinically, the action of SPEA has been identified in necrotizing fasciitis due to Strep, pyogenes associated with shock. Infection is hypothesized to lead to local or systemic release of toxins, massive lymphocyte activation, and release of cytokines, resulting in cellular injury and organ failure. This mechanism bypasses the macrophage, and the cytokine cascade is triggered at the level of the T cells. This bypassing of the macrophage has given rise to the term “superantigen” to describe toxins that, unlike conventional antigens that require processing by macrophages and dendritic cells are able to directly activate lymphocytes.

About the Bacterial Products That Cause Sepsis Syndrome

  1. In gram-negative bacteria, lipopolysaccharide, also called endotoxin, is linked to the outer membrane. a)  Endotoxin alone can produce the syndrome. b)  Endotoxin (lipopolysaccharide) is found in the bloodstream of patients with gram-negative bacteremia. c)  Endotoxin (lipopolysaccharide) blood levels correlate with the clinical severity of sepsis syndrome.
  2. 2.  Gram-positive bacteria produce peptidogly-cans, and lipoteichoic acid can mimic endo-toxins. 3.  Gram-positive bacteria also secrete exotoxins. a)  Staphylococcus aureus can secrete toxic shock syndrome toxin 1 (TSST-1). b)  Streptococcus pyogenes secretes streptococcal pyrogenic exotoxin A (SPEA). c)  Called “superantigens,” these exotoxins bypass macrophages and directly stimulate T cells.

Host Cell Receptors for Bacterial Products

A detailed discussion of the physiologic host responses to bacteria is beyond the scope of this chapter. Good evidence suggests that, in gram-negative infections, monocyte-macrophage or dendritic cells are the first cells to respond to endotoxin. Endotoxin first binds to lipopolysaccharide-binding protein, an acute-phase protein produced by the liver. The lipopolysaccharide-protein complex acts as the ligand for CD 14 (a cell-surface receptor on mononuclear cells) and to toll-like receptor (TLR) 2 or 4 on these cells. There are a number of TLRs that recognize different substances regardless of microbial origin. For example, TLR2 recognizes peptidoglycans, mannans, lipoteichoic acids, and some lipopolysaccharide molecules; TLR4 recognizes lipopolysaccharide; and TLR5 recognizes bacterial flagellin. TLR receptors and co-receptors bind the foreign stimulant and internalize it. Internalization results in signal transduction and cell activation, leading to cytokine release.

Cytokine and Other Inflammatory Mediator Cascades

The activation of monocytes leads to the production of the proinflammatory cytokines (that is, the cytokines that stimulate inflammation), particularly tumor necrosis factor a and interleukin 1 (IL-1). Infection also activates other host pathways, including the complement and coagulation pathways and the production of reactive oxygen intermediates. Many studies have been conducted in animals in which cytokines have been measured in response to both purified bacterial components and, perhaps more informatively, live bacterial infection. Intravenous injection of live E. coli into mice, rabbits, or baboons results in a consistent picture in which proinflammatory cytokines such as IL-1, IL-6, IL-8, and tumor necrosis factor a, are released in a well-ordered sequence, followed by interferon gamma and then counterregulatory cytokines such as IL-10. This picture is similar to that seen when endotoxin is injected into humans.

How Infection Leads to Septic Shock

It must be realized that these events represent a continuum, and they progress at speeds that have not been characterized. However, the general belief is that the larger the inoculum of the challenge molecule, lipopolysaccharide or gram-positive toxins, the more likely the process is to progress rapidly. Additionally the various cell-wall products are likely to differ in their intrinsic potency to stimulate the innate immune system. For example, clinical observation suggests that endotoxin is a more powerful stimulant than are the cells walls of enterococci or coagulase-negative staphylococci, because humans demonstrate a remarkable tolerance for bacteremia attributable to those organisms.

About the Roles of Host Cells in Sepsis Syndrome

  1. Monocyte-macrophages or dendritic cells are the first cells to respond to endotoxin (lipopolysaccharide).
  2. Endotoxin binds to lipopolysaccharide-protein in serum, and this complex binds to CD14 receptors and to toll-like receptor 4 (TLR4) on mononuclear cells.
  3. TLR2 binds peptidoglycans, lipoteichoic acids found in gram-positive bacteria, and mannans found on fungi. It also binds to some forms of lipopolysaccharide.TLR-5 bind bacterial flagellin.
  4. Receptor binding stimulates monocyte- macro-phagesto release a)  proinflammatory cytokines tumor necrosis factoraand interleukin-1,stimulating inflammation. b)  toxic oxygen byproducts. c)   products that activate the complement and coagulation cascades.

Clinical Manifestations

Case 1

A 66-year-old white woman underwent elective thoracoabdominal aneurysm repair. Three days after surgery, she became confused and developed a new fever. She had no cough, nodysuria, and no abdominal pain. A surgical drain was noted to be leaking increasing amounts of serous fluid. She was receiving vancomycin for operative prophylaxis. On physical exam, her temperature was 39°C, her pulse was 143 per minute, and her blood pressure was 110/70 mm Hg. She was intubated and on a respirator. She appeared toxic and somewhat lethargic. No skin lesions were noted, and her respiratory, cardiac, and abdominal exams were unremarkable. Her extremities were warm to the touch. Chest X-ray revealed no infiltrates. Laboratory workup showed that the patient’s peripheral white blood cell (white blood cell) count had dropped to 1400/mm3 from 22,600/mm3 the day before, with 24% polymorphonuclear leukocytes, 37% bands, and 9% metamyelocytes. Her hematocrit was 30%; blood urea nitrogen, 41 mg/dL; serum creatinine, 1.0 mg/dL; and HCOy 26 mEq/L. Blood cultures and culture of the surgical drain subsequently grew Escherichia coli. Computed tomography scan of the abdomen failed to reveal an abscess. She was initially treated with intravenous cefepime and subsequently switched to ceftriaxone. Except for a brief bout of hypotension requiring intravenous saline and dopamine, she fully recovered and was subsequently discharged from the hospital.


As noted in case 1, fever is usually the first and most common manifestation of sepsis. In general, the higher the temperature, the more likely a patient is to be bacteremic. However, it should be emphasized that hypothermia and normal body temperature are seen in patients who are bacteremic. In fact, there is good reason to believe that hypothermia is a poor prognostic indicator in bacteremic patients, indicating an inability to mount an adequate inflammatory response.

Hemodynamic Changes

Tachycardia is a concomitant finding with fever and is to be expected. Case 1 had marked sinus tachycardia associated with her bacteremia. Bradycardia, on the other hand, is unusual, and has been reported in patients with specific bacterial infections, such as typhoid fever and brucellosis. Of the easily measurable hemodynamic changes, hypotension is the most important in determining outcome. Failure to reverse hypotension in its early stages results in serious end-organ damage that may not be reversed by antibiotics or other therapy. The stage at which hypotension is reversible is called pre-shock. The pre-shock stage is often characterized by warm skin, diminished mentation (often worse in the elderly), and oliguria. Persistent hypotension leads to the well-recognized septic shock findings of cool skin, acute renal failure, and, on occasion, hepatic injury.

About the Clinical Manifestations of Sepsis Syndrome

  1. Fever: a)  Fever is the usual presentation. The higher the fever, the more likely the patient is to be bacteremic. b)  Hypothermia or normal temperature in association with bacteremia is a bad prognostic sign.
  2. Hemodynamic changes: a)  Tachycardia in association with fever is the rule; pulse is slower in typhoid fever and brucellosis. b)  Hypotension is the most important determinant of outcome. Failure to reverse early warm pre-shock leads to irreversible organ damage and death.
  3. Acid-base balance a)  Initially, respiratory alkalosis develops in response to anaerobic metabolism and lactic acid build-up. Recognizing this pre-shock syndrome is critical. b)  Failure to treat leads to metabolic acidosis and an increased likelihood of death.
  4. Respiratory changes a)  Hyperventilation occurs early. b)  Hypoxia and adult respiratory distress syndrome are common. Chest X-ray reveals pulmonary edema.

Acid-Base Disturbances

Reduced tissue perfusion requires a change from aerobic to anaerobic metabolism and causes lactic acid accumulation. Lactic acid and elevated cytokine levels stimulate the respiratory center, resulting in hyperventilation, which initially produces a respiratory alkalosis. This is the first pronounced change that is seen in impending shock. It is diagnostic, and it is usually seen at a time when the hemodynamic changes are reversible with fluid resuscitation. Recognition of this early stage is thus vital to making improvements in the management of a patient with sepsis syndrome. Metabolic acidosis can develop just before or can accompany hypotension, and it signals the beginning of a fatal downward spiral. Case 1 was recognized and treated before the development of acidosis, which explains the patient’s rapid recovery.

Anti-Infective Therapy

Respiratory Changes

Tachypnea is a common feature of sepsis, generated by cytokine stimulation of the central nervous system, elevated body temperature, and the accumulation of lactic acid. In addition to hyperventilation, severe depression of oxygenation is often seen. The adult respiratory distress syndrome commonly develops in septic shock and can be experimentally induced by endotoxin. Endotoxin is thought to activate neutrophils that become trapped in the small vessels of the lungs and cause vessel-wall damage and leakage of fluid into the alveoli. Adult respiratory distress syndrome is diagnosed by chest X-ray changes that mimic cardiac pulmonary edema, and it is accompanied  by severe hypoxemia. However, patients with sepsis may also demonstrate pneumonia on chest X-ray, and infection of the lungs can be accompanied by bacteremia and sepsis syndrome.


Diagnosis of sepsis syndrome is perhaps the greatest challenge encountered in designing clinical trials for new therapeutic agents. If fever, tachycardia, and tachypnea with or without leukocytosis are used to define systemic inflammatory response syndrome, then this definition includes other causes in addition to infection. Therefore evidence of actual infection must be sought. The most prevalent sites of infection are the lungs, bloodstream, abdomen, and wounds.

Even with a positive bacterial culture from any of these sites, sepsis in patients fitting the broad definitions of systemic inflammatory response syndrome remains an uncertainty. In fact, most patients with pneumonia would fit this definition of sepsis syndrome, although they rarely require intensive care. The strictest criteria should include the presence of a positive blood culture, preferably two, and should exclude most cases of coagulase-negative staphylococci that are common skin contaminants. Exceptions to a positive blood culture would have to be made in patients presenting clear clinical evidence of an intra-abdominal infection such as peritonitis. Adjunctive information should also include the presence of hypotension that is not a result of hypovolemia or a recent cardiac event.

Critical diagnostic tools that are not currently available include a means to rapidly diagnose the presence of bacteria in the blood and a method to rapidly quantify the inflammatory response. (Infection produces more inflammation than does a noninfectious cause.) Such tests would guide a decision to initiate or not to initiate antibiotics and activated protein С. A method for detecting early organ damage would also be helpful for determining the severity of systemic inflammatory response syndrome. Currently, reliance must be placed on clinical assessment of illness severity and supportive bacteriologic studies that usually do not become available for 24-48 hours. The presence of other abnormalities such as thrombocytopenia, evidence of fibrinogen consumption, and clot lysis are helpful, and when accompanied by hypotension, increased cardiac output and changes in peripheral vascular resistance may serve to define infection as the cause of systemic inflammatory response syndrome.

However, these findings are more likely to be seen in the more severe cases, where the diagnosis of infection is already clinically apparent. Case1 had a marked drop in peripheral white blood cell, with a marked shift to the left and a high percentage of immature granulocyte forms indicating marked consumption of granulocytes. That finding served as a useful warning that sepsis had developed, and it precipitated the administration of broad spectrum antibiotic coverage.

About the Diagnosis of Sepsis Syndrome

  1. Early diagnosis is difficult and is based on clinical findings.
  2. Fever, tachycardia, and hypotension need to be accompanied by documented bacteremia.
  3. Tests to quickly demonstrate bacteremia, to accurately assess the extent of inflammation, and to assess organ ischemia are not currently available.
  4. Thrombocytopenia and evidence of fibrinogen consumption and clot lysis combined with hypotension, increased cardiac output, and reduced peripheral vascular resistance suggest the diagnosis.
  5. These common clinical and laboratory findings are indicative of sepsis:
  • Temperature: <36°C or >38°C
  • Pulse rate: >90/min
  • Respiratory rate: >20 per minute
  • PaC02: <32, with pH >7.45 (early sepsis)
  • white blood cell count: <4000/mm3 or >12,000/mm3 with a band count > 10%
  1. Chills, lethargy, hemorrhagic skin lesions These   laboratory studies   are   recommended   in patients with suspected sepsis syndrome:
  • Two blood cultures, urine culture, and sputum culture if the patient has chest X-ray abnormalities
  • Complete blood count with differential and platelets
  • Coagulation studies to include international normalized ratio, fibrinogen, and D-dimers or fibrin split products
  • Blood gases and metabolic panels


Antibiotic Therapy

The outcome of patients with sepsis, in particular those with bacteremia, is governed by host and microbial factors alike. In some studies, certain organisms, including Pseudomonas aeruginosa and Candida species have been suggested to carry a higher mortality rate.

Table. Empiric Antibiotic Therapy for Sepsis Syndrome

Site of infection Pathogens to be covered Antibiotics
Lung (hospital acquired) Pseudomonas aeruginosa Enterobacter Cefepime, or ticarcillin-clavulanate Piperacillin-tazobactam, plus aminoglycoside
Abdomen or pelvis Gram-negative rods Anaerobes Ticarcillin-clavulanate, or piperacillin-tazobactam, plus aminoglycoside Imipenem or meropenem
Urinary tract Escherichia coli Klebsiella Proteus Ciprofloxacin Ceftriaxone
Skin Staphylococcus aureus Streptococcus pyogenes Mixed aerobic/anaerobic (necrotizing fasciitis) Oxacillin,or vancomycin Ticarcillin-clavulanate Piperacillin-tazobactam Imipenem or meropenem
Bacteremia of unknown source (hospital acquired) Methicillin-resistant Staph. aureus (methicillin-resistant Staphylococcus aureus) Gram negative rods Cefepime, plus vancomycin
Bacteremia of unknown source (community acquired) Staph. aureus Strep, pneumoniae Esch. coli Klebsiella Proteus Vancomycin, plus ceftriaxone or cefepime

Polymicrobial bacteremia also carries an increased mortality risk. Therefore, if the clinical situation is epidemiologically consistent with the isolation of more risky pathogens, consideration must be given to covering these possibilities empirically. The other microbial factor of significance is the susceptibility of the pathogen to empiric therapy. Patients with gram-negative bacteremia treated empirically with antibiotics to which their organism is resistant have significantly higher mortality rates.

Therefore, empiric therapy should be embarked upon with a knowledge of local susceptibility patterns, and in situations in which a bacterium was previously isolated from a suspicious site, empiric therapy should cover its susceptibility pattern. These foregoing considerations aside, other factors may possibly help in choosing empiric therapy for sepsis. In patients presenting with sepsis and a petechial skin rash, consideration must be given to meningococ-cemia, gonococcemia, S. aureus bacteremia or localized S. aureus infection, and streptococcal bacteremia or localized S. pyogenes infection.

The preferred approach is to direct therapy to the most probable site of origin of the infection and to cover the most likely pathogens from that site. It must be recognized that coverage for every possible pathogen is not possible, and certain pathogens in certain locations are unlikely to be responsible for life-threatening sepsis. Such organisms include enterococci at most sites and S. aureus in the respiratory tract. These recommendations are made with the assumption that 90% of organisms are sensitive to the drugs chosen, except for hospital-acquired pathogens.

Certain hospitals may have specific resistance problems with any given pathogen. In these cases, empiric therapy must be adjusted to reflect antibiotic sensitivities of the local bacterial flora. The regimens suggested in Table 2.1 will cover most other pathogens that are isolated at these sites in significant numbers. In 24 — 48 hours after blood culture results are available, the antibiotic regimen must be adjusted, with narrower spectrum antibiotics utilized whenever possible to reduce the likelihood of selecting for highly resistant pathogens.

Patient Management

Management of patients with sepsis syndrome requires prompt administration of antibiotics and volume expansion, initially with normal saline. The duration of hypotension before the administration of effective antibiotics has been found to be extremely important in the survival of hypotensive patients. Each hour of delay up to 6 hours resulted in an increase in mortality of 7.9%. If there is a drainable site of infection in the abdomen or pelvis, or if those locations are the possible sources of infection, immediate surgical consultation must be sought. Similarly the presence of gas in soft tissues or clinical evidence of a necrotizing infection mandates surgical consultation and possibly intervention. Any intravascular catheter in place must be removed and cultured. The following measurements are suggested in patients who are initially stable and kept on a conventional ward:

  1. Hourly measurement of vital signs and urine output
  2. Two-hourly measurement of arterial blood pH, PaCO2, and PaQ2
  3. Blood lactate and coagulation parameters initially, and perhaps every 4-6 hours until a clear sense develops of how the patient is progressing Failure of the patient to respond to fluids and antibiotics — as indicated by a persistent fall in blood pressure, accumulation of lactate, increasing hypoxemia, and laboratory signs suggesting a coagulopathy —  dictate that the patient be moved to an intensive care unit for closer monitoring and more aggressive hemodynamic support. There are no proven superior therapies at this time. Judicious use of vasopressors is generally recommended, beginning with dopamine and progressing to norepinephrine. Aggressive fluid resuscitation should be continued with specific attention to central venous pressures and pulmonary vascular congestion. Further management needs to be deferred to the intensive care specialists.

About the Treatment of Sepsis Syndrome

  1. Empiric antibiotic therapy must take into account a)  the presumed primary anatomic site of the infection leading to bacteremia. b)  local hospital antibiotic sensitivities. c)  sensitivities for bacteria previously grown from possible sites of bacteremia.
  2. Empiric therapy must be readjusted based on blood culture results.
  3. Volume expansion with normal saline must be initiated emergently.
  4. Surgical consultation is required for possible intra-abdominal sepsis and for potential cases of necrotizing fasciitis.
  5. Potentially infected intravascular catheters must be removed.
  6. Monitoring of patients on conventional wards should include a)  hourly vital signs. b)  2-hourly arterial blood gases. c)  4-to б-hourly serum lactate measurements.
  7. Deterioration of these parameters warrants transfer to an intensive care unit.

Adjunctive Therapies

Many different substances have been used to reverse the persistent hypotension and associated end-organ damage associated with sepsis syndrome. Most of these adjunctive measures have failed to improve mortality in large studies. Given current knowledge of the pathogenesis of sepsis, additional trials are likely to be undertaken in the future. These are some of potential therapies that have not proved beneficial to date:

  1. Anti-inflammatory agents such as ibuprofen and even narcotic antagonists have not proven to be of value in large scale studies.
  2. Monoclonal antibody against the core of the endotoxin molecule has not been conclusively shown to be beneficial.
  3. Antibody against tumor necrosis factor a and the tumor necrosis factor a receptor have failed.
  4. Studies utilizing IL-1 receptor antagonists have been inconclusive.
  5. Platelet activating factor antagonists have failed.


The use of corticosteroids in septic shock has been under debate for decades. It is known that some of these patients have or develop adrenal insufficiency. Recent studies have re-examined this question with the startling revelation that, as compared with high doses, low physiologic doses of corticosteroids for 7 days are associated with improved survival. However, debate continues regarding whether only patients with adrenal insufficiency should receive these agents or whether all patients should be so treated. Further studies will be required to clarify the efficacy of low-dose steroids; however, pending these studies, treatment with 200-300 mg of hydrocortisone or its equivalent daily for 7 days should be strongly considered.


Investigations of sepsis have shown that protein С levels are low and that septic patients are unable to activate this substance. Protein С plays a key role in inhibiting coagulation, and it may be an important inhibitor of monocyte activation. Animal studies have shown that infusion of activated protein С reduces mortality in lethal E. coli infections. Clinical trials in humans have subsequently shown a modest reduction of mortality in septic shock when patients are treated with activated protein C. This agent, now called drotrecogin a, has now been approved by the U.S. Food and Drug Administration as an adjunct to standard therapy for the treatment of severe sepsis. Drotrecogin a reduced mortality to 24.7% from 30.8% in placebo-treated patients over 28 days, a statistically significant reduction. Because of the complexity of patient inclusion criteria, very high costs, and potential for bleeding complications, this agent is reserved for use by intensive care and infectious disease specialists. Its major contraindication is recent surgery, the risk of bleeding complications being prohibitively high in the postoperative patient population.

About Adjunctive Therapies for Sepsis Syndrome

  1. Multiple clinical trials have failed to document efficacy for a)  anti-inflammatory agents. b)  monoclonal antibody against endotoxin. c)  anti-tumor necrosis factor a antibodies. d)  interleukin-1 antagonists. e)  platelet activating factor antagonists.
  2. Corticosteroids is low doses may be beneficial.
  3. Activated protein С (drotrecogin a) is of limited efficacy (6% reduction in mortality) and a)  is extremely expensive; b)  should only be given by intensive care or infectious disease specialists; and c)  is contraindicated in postoperative patients because of bleeding complications.


The physician first needs to make an immediate decision about severity of the illness, and with clinical experience, most physicians become skilled at recognizing the sickest patients. Among the severely ill, patients with sepsis syndrome have the highest mortality and morbidity. Early recognition of sepsis and efforts to remove the precipitating cause and to deliver aggressive fluid and vasopressor therapy, optimal supportive care for organ dysfunction, and empiric antimicrobial therapy for the most likely microbial pathogens remain the standard of care. It is important that the physician reassess empiric antibiotic coverage in 48 hours when culture results have returned. The organisms grown on blood culture can help to identify the site of primary infection. They also often allow the spectrum of antibiotic coverage to be narrowed, reducing the likelihood of patient colonization with highly resistant bacterial flora.  Activated protein С is of modest benefit, but not all patients are candidates for this agent. However, agents of this type that will be more effective are likely to be developed in the future, as more is learned about the mechanisms involved in the progression of sepsis.

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