Evaluation and Treatment for Sepsis
-Dr M A Aleem
Treatment
Approach and Considerations
Early aggressive medical therapy is indicated in patients with suspected sepsis, based on the organ source of sepsisHowever, it is crucial to consider pseudosepsis as a cause of the presenting syndrome complex because most causes of pseudosepsis are readily treatable and reversible if recognized and treated early. Patients with pseudosepsis require supportive therapy rather than antimicrobial treatment.
Patients with sepsis are generally ill and require bed rest or admission to the intensive care unit (ICU) for monitoring and treatment. Admission to an ICU or surgical ICU depends on the severity of the septic process and the degree of organ dysfunction, as well as the need for surgical intervention. Transfer to a facility able to perform diagnostic imaging tests or required surgical procedures if they are not available at the admitting hospital may be necessary.
Determine the likely source of the infection, and administer intravenous (IV) empiric antimicrobial agents until culture results become available, at which point more narrow-spectrum agents can be used (see below). In addition, offer supportive therapy aimed at maintaining organ perfusion, and provide respiratory support when necessary.
In a prospective study of 5787 adults with severe sepsis or septic shock, reported at the 2013 Scientific Assembly of the American College of Emergency Physicians, patients triaged and managed according to 4 clinical goals (blood cultures before antibiotics, lactate before 90 minutes, IV antibiotics before 180 minutes, and 30 mL/kg of IV fluids before 180 minutes) were significantly less likely to die in the hospital than were those for whom all 4 of these goals were not met (22.6% vs 26.5%, respectively).
In a multivariate regression analysis adjusted for age, admission to the intensive care unit (ICU), vasopressor initiation, central venous catheter insertion, and monitoring of central venous pressure and central venous oxygen saturation, complete compliance with the clinical goals was associated with a survival odds ratio of 1.194 (1.04-1.37).
Surgical Intervention
Early evaluation by a surgeon for patients with presumed intra-abdominal or pelvic sepsis is essential, because surgical intervention may be required for cure or resolution of the infection. For example, peritonitis may result in abscesses, which may subsequently need to be drained. Inadequate correction of intra-abdominal perforation or drainage procedures may result in a continuance or relapse of the patient’s septic condition.
The procedures used are dependent on the source of the infection, the severity of the sepsis, the patient’s clinical status, among other factors in individual scenarios.
Coordinate surgical follow-up with the surgeon.
Consultations
Obtain a consultation with a surgeon for patients with presumed intra-abdominal or pelvic sepsis. Early surgical consultation and involvement by the surgical team is essential, because many causes of sepsis involve a perforated viscus, abscess, or obstructing process that requires surgical intervention for cure or resolution of the infection.
Also obtain a consultation with an infectious disease specialist for all patients with sepsis included in the differential diagnosis.
Antimicrobial Therapy
Appropriate antimicrobial therapy depends on adequate coverage of the resident flora of the organ system presumed to be the source of the septic process.Agents suitable for empiric monotherapy regimens (depending on the source and underlying microbiology of the sepsis because the agent must be able to cover all of the likely pathogens) may include the following:
Imipenem
Meropenem
Tigecycline
Piperacillin-tazobactam
Ampicillin-sulbactam
Moxifloxacin
Combination therapeutic regimens include metronidazole plus either levofloxacin, aztreonam, or an aminoglycoside. Many advocate using antistaphylococcal coverage (eg, vancomycin) with an extended cephalosporin, beta-lactam/beta-lactamase inhibitor antibiotic, or a carbapenem.
Although no drug regimen may be superior to another, time to first dose administration is very important. Mortality data suggest that early administration of appropriate antibiotics is correlated with better survival. Alternative agents may be used alone or in combination, with a good adverse-effect profile.
Antibiotics are normally continued until the septic process and surgical interventions have controlled the source of infection. Ordinarily, patients are treated for approximately 2 weeks. As soon as patients are able to tolerate medications orally, they may be switched to an equivalent oral antibiotic regimen in an IV-to-oral conversion program.
Empiric therapy for IV line infections
Because IV line infections are most often due to Staphylococcus aureus [MRSA]) and less commonly due to aerobic gram-negative bacilli, the preferred empiric therapy for these infections is meropenem or cefepime plus additional coverage for staphylococci. If MRSA is prevalent in the institution, add linezolid, vancomycin, or daptomycin.
If coagulase-negative, methicillin-sensitive staphylococci are recovered from the blood (high-level bacteremia; that is, 3 or 4 positive blood cultures out of 4), avoid vancomycin for empiric therapy if possible; these are low-virulence organisms.
Treatment of staphylococcal central line infection may require removal of the line. 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 ofEnterococcus faecium, a vancomycin-resistant enterococci (VRE).
Empiric therapy for biliary tract infections
The main biliary tract pathogens includeEscherichia coli, Klebsiella species, andEnterococcus faecalis. Coverage for staphylococci is not needed in the biliary tract. Anaerobes are important only in patients with diabetes who haveClostridium perfringens emphysematous cholecystitis.
Preferred monotherapy regimens for biliary tract infections include imipenem, meropenem, ampicillin-sulbactam, or piperacillin-tazobactam.
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 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 regimens for intra-abdominal and pelvic infections include imipenem, meropenem, piperacillin-tazobactam, ampicillin-sulbactam, or tigecycline. Alternate combination therapy for intra-abdominal and pelvic infections consists of clindamycin or metronidazole plus aztreonam, levofloxacin, or an aminoglycoside. Some authors raise concerns about use of tigecycline.
Empiric therapy for urosepsis
The primary uropathogens include gram-negative aerobic bacilli, such as coliforms or enterococci (E faecalisPseudomonas aeruginosa, Enterobacterspecies, and Serratia species are rare uropathogens and are associated with urologic instrumentation.
Preferred monotherapy for urosepsis due to aerobic gram-negative bacilli employs aztreonam, levofloxacin, a third- or fourth-generation cephalosporin, or an aminoglycoside. However, preferred monotherapy for urosepsis due to enterococci (E faecalis) involves the use of ampicillin or vancomycin (penicillin-allergic). For VRE urosepsis, linezolid or daptomycin may be used.
Empiric therapy for community-acquired urosepsis consists of levofloxacin, aztreonam, or an aminoglycoside plus ampicillin. For nosocomial urosepsis, piperacillin-tazobactam, imipenem, or meropenem monotherapy is preferred.
Empiric therapy for staphylococcal, pneumococcal, and meningococcal sepsis
S aureus sepsis is usually associated with infection caused by devices or acute bacterial endocarditis. Empiric therapy may be with nafcillin, an antistaphylococcal agent, a cephalosporin, a carbapenem, daptomycin, or linezolid.
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 (CSF) and should be given in meningeal doses. Consider the regional prevalence of drug-resistant pneumococci when selecting an antibiotic.
Empiric therapy for sepsis of unknown origin
The usual sources of sepsis are the distal gastrointestinal (GI) tract, the pelvis, and the genitourinary (GU) tract. Organisms that should be covered from these areas 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 tigecycline.
Empiric combination therapy includes metronidazole plus either levofloxacin, aztreonam, cefepime, or ceftriaxone.
Outpatient management
If orally administered antibiotics are continued at home, advise the patient about possible adverse effects. If additional antimicrobial therapy is needed outside the hospital setting, it should be given orally, not intravenously. Do not allow the total course of antibiotics to exceed 3 weeks, except for the treatment of liver abscesses, which may require prolonged courses of oral antibiotics for cure or complete clinical resolution.
Medication
Medication Summary
The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.
Antibiotics, Other
Class Summary
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Imipenem/cilastatin
Imipenem-cilastatin is a carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. It is used for treatment of multiple-organism infections in which other agents do not have wide-spectrum coverage or are contraindicated owing to their potential for toxicity.
Meropenem
Meropenem is a carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem. It is less likely to cause seizures and has superior penetration of the blood-brain barrier compared with imipenem.
Piperacillin and tazobactam
Piperacillin-tazobactam inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication. It has antipseudomonal activity.
Ampicillin and sulbactam
Ampicillin and sulbactam is a drug combination of a beta-lactamase inhibitor with ampicillin. It interferes with bacterial cell wall synthesis during active replication, causing bactericidal activity against susceptible organisms. It is an alternative to amoxicillin if the patient is unable to take medications orally. It covers skin, enteric flora, and anaerobes and is not ideal for nosocomial pathogens.
Clindamycin
Clindamycin is primarily used for its activity against anaerobes. It has some activity against Streptococcus species and methicillin-sensitive S aureus (MSSA).
Metronidazole
Metronidazole is an imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. It is usually combined with other antimicrobial agents, except when used for Clostridium difficile enterocolitis, in which monotherapy is appropriate.
Cefepime
Cefepime is a fourth-generation cephalosporin. It has gram-negative coverage comparable to ceftazidime but has better gram-positive coverage (comparable to ceftriaxone). Cefepime is active against Pseudomonas species. It has increased effectiveness against extended-spectrum beta-lactamase (ESBL)–producing organisms. Its poor capacity to cross blood-brain barrier precludes its use for treatment of meningitis.
Levofloxacin
Levofloxacin is a fluoroquinolone with excellent gram-positive and gram-negative coverage. It is an excellent agent for pneumonia and has excellent abdominal coverage as well. High urine concentration necessitates reduced dosing in urinary tract infection.
Vancomycin
Vancomycin provides gram-positive coverage and good hospital-acquired MRSA coverage. It is now used more frequently because of the high incidence of MRSA. Vancomycin should be given to all septic patients with indwelling catheters or devices. It is advisable for skin and soft-tissue infections.
Trimethoprim/sulfamethoxazole
The broad spectrum and action of trimethoprim and sulfamethoxazole (TMP-SMZ) against organisms found in patients with cystic fibrosis and the convenience of oral administration make this combination useful for treatment of milder infections in an outpatient setting.
Aztreonam
Aztreonam is a monobactam, not a beta-lactam, antibiotic that inhibits cell wall synthesis during bacterial growth. It is active against gram-negative bacilli but has very limited gram-positive activity and is not useful for anaerobes. Aztreonam lacks cross-sensitivity with beta-lactam antibiotics. It may be used in patients who are allergic to penicillins or cephalosporins.
The duration of therapy depends on the severity of infection and is continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. Doses that are smaller than indicated should not be used.
Transient or persistent renal insufficiency may prolong serum levels. After the initial loading dose of 1 or 2 g, reduce the dose by one half for an estimated CrCl of 10-30 mL/min/1.73 m2. When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age) can approximate CrCl (serum creatinine should represent a steady state of renal function):
• Males: CrCl = [(weight in kg)(140 - age)] divided by (72 X serum creatinine in mg/dL)
• Females: 0.85 X above value
In patients with severe renal failure (CrCl < 10 mL/min/1.73 m2), those supported by hemodialysis, a usual dose of 500 mg, 1 g, or 2 g is given initially.
The maintenance dose is one fourth of the usual initial dose given at the usual fixed interval of 6, 8, or 12 hours. For serious or life-threatening infections, supplement maintenance doses with one eighth of the initial dose after each hemodialysis session.
Elderly persons may have diminished renal function. Renal status is a major determinant of dosage in these patients. Serum creatinine may not be an accurate determinant of renal status. Therefore, as with all antibiotics eliminated by the kidneys, obtain estimates of CrCl and make appropriate dosage modifications. Insufficient data are available regarding intramuscular (IM) administration to pediatric patients or dosing in pediatric patients with renal impairment. Aztreonam is administered intravenously only to pediatric patients with normal renal function.
Linezolid
Linezolid is used as an alternative drug in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci. It is also effective against MRSA and penicillin-susceptible S pneumoniae infections.
This agent is an oxazolidinone antibiotic that prevents formation of the functional 70S initiation complex, which is essential for the bacterial translation process. Linezolid is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci.
Ceftriaxone (Rocephin)
Ceftriaxone is a third-generation cephalosporin with broad-spectrum, gram-negative activity. It has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone is used for increasing prevalence of penicillinase-producing microorganisms. It inhibits bacterial cell wall synthesis by binding to 1 or more penicillin-binding proteins. Cell wall autolytic enzymes lyse bacteria, while cell wall assembly is arrested.
Daptomycin
Daptomycin causes membrane depolarization by binding to components of the cell membrane of susceptible organisms. It inhibits DNA, RNA, and protein synthesis intracellularly. It is a bactericidal antibiotic.
Nafcillin
Nafcillin is a broad-spectrum penicillin. It is used for methicillin-sensitive S aureus and is the initial therapy for suspected penicillin G–resistant streptococcal or staphylococcal infections. In severe infections, start with parenteral therapy and change to oral therapy as the condition warrants. Because of thrombophlebitis, particularly in elderly persons, administer parenterally for only 1-2 days; change to oral therapy as indicated clinically.
Rifampin (Rifadin)
Rifampin is for use in combination with at least 1 other antituberculosis drug. It inhibits RNA synthesis in bacteria by binding to the beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription. Cross-resistance may occur.
Daptomycin
This is the first of a new antibiotic class called cyclic lipopeptides. It binds to bacterial membranes and causes rapid membrane potential depolarization, thereby inhibiting protein, DNA, and RNA synthesis, and ultimately causing cell death. It is indicated for complicated skin and skin structure infections caused by S aureus (including methicillin-resistant strains), S pyogenes, S agalactiae, S dysgalactiae, and E faecalis(vancomycin-susceptible strains only).
Tigecycline
Tigecycline is a glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. It inhibits bacterial protein translation by binding to the 30S ribosomal subunit, and it blocks the entry of amino-acyl tRNA molecules in ribosome A site. It is indicated for complicated skin and skin structure infections caused by E coli, E faecalis(vancomycin-susceptible isolates only), S aureus (methicillin-susceptible and -resistant isolates), S agalactiae, S anginosus group (includes S anginosus, S intermedius, and S constellatus), S pyogenes and B fragilis.
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