Quick Medical Diagnosis & Treatment 2021

Bacteremia & Sepsis, Gram-Negative

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For further information, see CMDT Part 33-16: Gram-Negative Bacteremia & Sepsis

Key Features

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Most common sites for gram-negative bacteremia
- Genitourinary system
- Hepatobiliary tract
- Gastrointestinal tract
- Lungs
Less common sources include
- Intravenous lines
- Infusion fluids
- Surgical wounds
- Drains
- Pressure injuries

Clinical Findings

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Fevers and chills, often with abrupt onset
However, some patients are hypothermic (temperature ≤ 36.4 °C) at presentation
Hyperventilation with respiratory alkalosis and changes in mental status are important early manifestations
Hypotension and shock are unfavorable prognostic signs

Diagnosis

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Neutropenia or neutrophilia, often with increased numbers of immature forms of polymorphonuclear leukocytes
If possible, three sets of blood cultures from separate sites should be obtained in rapid succession before starting antimicrobial therapy

Treatment

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See Table 30–4
Antibiotics should be given as soon as the diagnosis is suspected, since delays in therapy have been associated with increased mortality rates, particularly once hypotension develops
In general, bactericidal antibiotics should be used and given intravenously to ensure therapeutic serum levels
Penetration of antibiotics into the site of primary infection is critical for successful therapy—ie, if the infection originates in the CNS, antibiotics that penetrate the blood-brain barrier should be used—eg, third- or fourth-generation cephalosporin—but not first-generation cephalosporins or aminoglycosides, which penetrate poorly
Initial therapy for sepsis should include antibiotics active against both gram-positive and gram-negative organisms
Combination therapy has not been shown to be superior to a single-drug regimen with any of several broad-spectrum antibiotics (eg, a third-generation cephalosporin, piperacillin-tazobactam, carbapenem)
If multiple drugs are used initially, the regimen should be modified and coverage narrowed based on the results of culture and sensitivity testing
Remove predisposing factors
- Decrease or stop immunosuppressive medications
- Give granulocyte colony-stimulating factor (filgrastim; G-CSF) to the neutropenic patient with positive blood cultures
Identify source of bacteremia and remove it (central venous catheter) or drain it (abscess)
Supportive measures include maintaining blood pressure with vasopressor medications and managing disseminated intravascular coagulation with antimicrobials for underlying infection and blood products for significant bleeding (Table 14–6)
Corticosteroids are not helpful

Table 30–4.Medication of choice for suspected or documented microbial pathogens (listed in alphabetical order, within classes).

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Table 30–4. Medication of choice for suspected or documented microbial pathogens (listed in alphabetical order, within classes).

Suspected or Proved Etiologic Agent

Medication(s) of First Choice

Alternative Medication(s)

Gram-negative Cocci

Moraxella catarrhalis

Cefuroxime, amoxicillin-clavulanic acid

Ceftriaxone, cefuroxime axetil, a fluoroquinolone,¹ a macrolide,² a tetracycline,³ TMP-SMZ⁴

Neisseria gonorrhoeae (gonococcus)

Ceftriaxone + azithromycin or doxycycline

Cefixime + azithromycin or doxycycline⁵

Neisseria meningitidis (meningococcus)

Penicillin⁶

Ceftriaxone, ampicillin

Gram-positive Cocci

Enterococcus faecalis

Ampicillin ± gentamicin⁷

Vancomycin ± gentamicin

Enterococcus faecium

Vancomycin ± gentamicin⁷

Linezolid,⁸ quinupristin-dalfopristin,⁸ daptomycin,⁸ tigecycline,⁸ tedizolid,⁸ oritavancin⁸

Streptococcus, hemolytic, groups A, B, C, G

Penicillin⁶

Macrolide,² a cephalosporin,⁹ vancomycin, clindamycin

Staphylococcus, methicillin-resistant

Vancomycin

TMP-SMZ,⁴ doxycycline, minocycline, linezolid,⁸ tedizolid,⁸ daptomycin,⁸ televancin,⁸ dalbavancin,⁸ oritavancin,⁸ ceftaroline, delafloxacin

Staphylococcus, methicillin-susceptible

Penicillinase-resistant penicillin¹⁰

Vancomycin, a cephalosporin,⁹ clindamycin, amoxicillin-clavulanic acid, ampicillin-sulbactam

Streptococcus pneumoniae¹¹ (pneumococcus)

Penicillin⁶

A cephalosporin,⁹ vancomycin, clindamycin, a tetracycline,³ respiratory fluoroquinolones¹

Viridans streptococci

Penicillin⁶

Cephalosporin,⁹ vancomycin

Gram-negative Rods

Acinetobacter

Imipenem, meropenem

Tigecycline, minocycline, doxycycline, aminoglycosides,¹² colistin, cefiderocol

Bacteroides, gastrointestinal strains

Metronidazole

Ampicillin-sulbactam, piperacillin-tazobactam, ertapenem

Brucella

Doxycycline + rifampin³

TMP-SMZ⁴ ± gentamicin; ciprofloxacin + rifampin

Burkholderia mallei (glanders)

Streptomycin + tetracycline³

Chloramphenicol + streptomycin

Burkholderia pseudomallei (melioidosis)

Ceftazidime

Tetracycline,³ TMP-SMZ,⁴ amoxicillin-clavulanic acid, imipenem or meropenem

Campylobacter jejuni

Azithromycin

A fluoroquinolone¹

Enterobacter

Ertapenem, imipenem, meropenem, cefepime

Aminoglycoside, a fluoroquinolone,¹ TMP-SMZ⁴

Escherichia coli (uncomplicated outpatient urinary infection)

Nitrofurantoin, fosfomycin

Fluoroquinolones,¹ TMP-SMZ,⁴ oral cephalosporin

Escherichia coli (sepsis)¹³

Cefotaxime, ceftriaxone

Ertapenem,¹³ imipenem¹³ or meropenem,¹³ aminoglycosides,¹² aztreonam, ticarcillin-clavulanate, piperacillin-tazobactam, ceftazidime-avibactam,^13,15 ceftolozane-tazobactam,^13,14 meropenem/vaborbactam,¹⁵ imipenem/cilastatin-relebactam^13,14,15

Haemophilus (respiratory infections, otitis)

Ampicillin-clavulanate

Doxycycline, azithromycin, ceftriaxone, cefuroxime, cefuroxime axetil, TMP-SMZ⁴

Haemophilus (serious infection)

Ceftriaxone

Aztreonam

Helicobacter pylori

Proton pump inhibitor (PPI), clarithromycin, amoxicillin, and metronidazole

PPI, clarithromycin, and amoxicillin or metronidazole

Klebsiella¹³

Ceftriaxone

TMP-SMZ,⁴ aminoglycoside,¹² ertapenem,¹³ imipenem¹³ or meropenem,¹³ a fluoroquinolone,¹ aztreonam, ticarcillin-clavulanate, piperacillin-tazobactam, ceftazidime-avibactam,¹³ ceftolozane-tazobactam,^13,14 meropenem/vaborbactam,¹⁵ imipenem/cilastatin-relebactam^13,14,15

Legionella species (pneumonia)

Azithromycin, or fluoroquinolones¹ ± rifampin

Doxycycline ± rifampin

Prevotella, oropharyngeal strains

Clindamycin

Metronidazole

Proteus mirabilis

Ampicillin

TMP-SMZ,⁴ a fluoroquinolone,¹ a cephalosporin⁹

Proteus vulgaris and other species (Morganella, Providencia)

Ceftriaxone

Ertapenem, imipenem or meropenem, TMP-SMZ,⁴ a fluoroquinolone¹

Pseudomonas aeruginosa

Piperacillin-tazobactam or ceftazidime or cefepime, or imipenem or meropenem or doripenem or aztreonam ± aminoglycoside¹²

Ciprofloxacin (or levofloxacin) ± piperacillin-tazobactam; ciprofloxacin (or levofloxacin) ± ceftazidime; ciprofloxacin (or levofloxacin) ± cefepime; ceftazidime-avibactam¹³; ceftolozane-tazobactam,¹³ cefiderocol, imipenem/cilastatin-relebactam

Salmonella (bacteremia)

Ceftriaxone

A fluoroquinolone¹

Serratia

Carbapenem

TMP-SMZ,⁴ a fluoroquinolone,¹ ceftriaxone

Shigella

Azithromycin, ciprofloxacin, or ceftriaxone

TMP-SMZ⁴

Vibrio (cholera, sepsis)

A tetracycline³

TMP-SMZ,⁴ a fluoroquinolone¹

Yersinia pestis (plague)

Streptomycin ± a tetracycline³

Chloramphenicol, TMP-SMZ⁵

Gram-positive Rods

Actinomyces

Penicillin⁶

Tetracycline,³ clindamycin

Bacillus (including anthrax)

Penicillin⁶

A macrolide,² a fluoroquinolone¹

Clostridium (eg, gas gangrene, tetanus)

Penicillin⁶

Metronidazole, clindamycin, imipenem, or meropenem

Corynebacterium diphtheria

Macrolide²

Penicillin⁶

Corynebacterium jeikeium

Vancomycin

Linezolid

Listeria

Ampicillin ± aminoglycoside¹²

TMP-SMZ⁴

Acid-fast Rods

Mycobacterium avium complex

Clarithromycin or azithromycin + ethambutol, ± rifabutin

Amikacin, ciprofloxacin

Mycobacterium fortuitum-chelonei

Cefoxitin + clarithromycin

Amikacin, rifampin, sulfonamide, doxycycline, linezolid

Mycobacterium kansasii

INH + rifampin ± ethambutol

Clarithromycin, azithromycin, ethionamide, cycloserine

Mycobacterium leprae

Dapsone + rifampin ± clofazimine

Minocycline, ofloxacin, clarithromycin

Mycobacterium tuberculosis¹⁶

Isoniazid (INH) + rifampin + pyrazinamide ± ethambutol

Other antituberculous drugs (see Tables 9–14 and 9–15)

Nocardia

TMP-SMZ⁴

Minocycline, imipenem or meropenem, linezolid

Spirochetes

Borrelia burgdorferi (Lyme disease)

Doxycycline, amoxicillin, cefuroxime axetil

Ceftriaxone, penicillin, azithromycin

Borrelia recurrentis (relapsing fever)

Doxycycline³

Penicillin⁶

Leptospira

Penicillin⁶

Doxycycline,³ ceftriaxone

Treponema pallidum (syphilis)

Penicillin⁶

Doxycycline, ceftriaxone

Treponema pertenue (yaws)

Penicillin⁶

Doxycycline

Mycoplasmas

Azithromycin or doxycycline

A fluoroquinolone¹

Chlamydiae

C pneumoniae

Doxycycline³

Azithromycin, a fluoroquinolone^1,17

C psittaci

Doxycycline

Chloramphenicol

C trachomatis (urethritis or pelvic inflammatory disease)

Doxycycline or azithromycin

Levofloxacin, ofloxacin

Rickettsiae

Doxycycline³

Chloramphenicol, a fluoroquinolone¹

¹Fluoroquinolones include ciprofloxacin, levofloxacin, moxifloxacin, and others. Gemifloxacin, levofloxacin, and moxifloxacin, the so-called respiratory fluoroquinolones, demonstrate the most reliable activity against penicillin-resistant S pneumoniae and other respiratory infection pathogens. Delafloxacin is predictably active against methicillin-resistant S aureus (MRSA).

²Azithromycin is the preferred macrolide due to increased safety profile and minimal drug interaction potential.

³All tetracyclines have similar activity against most microorganisms. Minocycline (the most active tetracycline) and doxycycline are more active than tetracycline against S aureus.

⁴TMP-SMZ is a mixture of 1 part trimethoprim and 5 parts sulfamethoxazole.

⁵Test of cure required if ceftriaxone not used.

⁶Penicillin G is preferred for parenteral injection; penicillin V for oral administration.

⁷Addition of gentamicin indicated only for severe enterococcal infections (eg, endocarditis, meningitis).

⁸Linezolid, tedizolid, daptomycin, televancin, dalbavancin, and oritavancin should be reserved for the treatment of vancomycin-resistant isolates or in patients intolerant of vancomycin.

⁹Most intravenous cephalosporins (with the exception of ceftazidime) are active against streptococci and staphylococci.

¹⁰Parenteral nafcillin or oxacillin; oral dicloxacillin, cloxacillin, or oxacillin.

¹¹Infections caused by isolates with intermediate resistance may respond to high dose penicillin or ceftriaxone or the respiratory fluoroquinolones (gemifloxacin, levofloxacin, and moxifloxacin). Infections caused by highly penicillin-resistant isolates should be treated with vancomycin. Penicillin-resistant pneumococci are often resistant to macrolides, tetracyclines, and TMP-SMZ.

¹²Aminoglycosides—gentamicin, tobramycin, amikacin, netilmicin—should be chosen on the basis of local patterns of susceptibility.

¹³Extended beta-lactamase–producing (ESBL) isolates should be treated with a carbapenem. If a carbapenem cannot be used, ceftazidime-avibactam or possibly ceftolozane-tazobactam can be considered.

¹⁴Ceftolozane-tazobactam, cefiderocol, imipenem/cilastatin-relebactam and occasionally ceftazidime-avibactam may be active against multidrug-resistant P aeruginosa.

¹⁵Consider in cases of infection due to carbapenemase-producing Enterobacteriaceae.

¹⁶Resistance is common and susceptibility testing must be performed.

¹⁷Ciprofloxacin has inferior antichlamydial activity compared with levofloxacin or ofloxacin.

±, alone or combined with.

Table 9–14.Characteristics of antituberculous medications.

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Table 9–14. Characteristics of antituberculous medications.

Medication

Most Common Side Effects

Tests for Side Effects

Drug Interactions

Remarks

Isoniazid

Peripheral neuropathy, hepatitis, rash, mild CNS effects.

AST and ALT; neurologic examination.

Phenytoin (synergistic); disulfiram.

Bactericidal to both extracellular and intracellular organisms. Pyridoxine, 25–50 mg orally daily is given as prophylaxis for neuritis; 50–100 mg orally daily as treatment for it.

Rifampin

Hepatitis, fever, rash, flu-like illness, gastrointestinal upset, bleeding problems, kidney failure.

CBC, platelets, AST and ALT.

Rifampin inhibits the effect of oral contraceptives, quinidine, corticosteroids, warfarin, methadone, digoxin, oral hypoglycemics; aminosalicylic acid may interfere with absorption of rifampin. Significant interactions with protease inhibitors and nonnucleoside reverse transcriptase inhibitors.

Bactericidal to all populations of organisms. Colors urine and other body secretions orange. May discolor contact lenses.

Rifapentine

Bone marrow suppression, hematuria/pyuria, hepatitis, gastrointestinal upset, flu-like illness.

CBC, platelets, AST and ALT.

Strong cytochrome P450 inducer with multiple drug interactions. Use in HIV patients receiving antiretroviral therapy should be limited to experts in antiretroviral therapy.

Bactericidal to both extracellular and intracellular organisms. Colors urine and other body secretions orange. Long half-life, can be administered weekly in LTBI prophylaxis. Not for use in induction phase of therapy.

Pyrazinamide

Hyperuricemia, hepatotoxicity, rash, gastrointestinal upset, joint aches.

Uric acid, AST, ALT.

Rare.

Bactericidal to intracellular organisms.

Ethambutol

Optic neuritis (reversible with discontinuance of drug; rare at 15 mg/kg); rash.

Red-green color discrimination and visual acuity.

Rare.

Bacteriostatic to both intracellular and extracellular organisms. Mainly used to inhibit development of resistant mutants. Use with caution in kidney disease or when ophthalmologic testing is not feasible.

Streptomycin

Eighth nerve damage, nephrotoxicity.

Vestibular function (audiograms); BUN and creatinine.

Neuromuscular blocking agents may be potentiated and cause prolonged paralysis.

Bactericidal to extracellular organisms. Use with caution in older patients or those with kidney disease.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CBC, complete blood count; LTBI, latent tuberculosis infection.

Table 9–15.Recommended dosages for the initial treatment of tuberculosis.¹

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Table 9–15. Recommended dosages for the initial treatment of tuberculosis.¹

Medication

Daily²

Cost³/Day

Twice a Week²

Cost³/Wk

Three Times a Week²

Cost³/Wk

Isoniazid

5 mg/kg

Max: 300 mg/dose

$0.31/300 mg

15 mg/kg

Max: 900 mg/dose

$1.86

15 mg/kg

Max: 900 mg/dose

$2.79

Rifampin

10 mg/kg

Max: 600 mg/dose

$2.66/600 mg

10 mg/kg

Max: 600 mg/dose

$5.32

10 mg/kg

Max: 600 mg/dose

$7.98

Pyrazinamide

18.2–26.3 mg/kg

Max: 2 g/dose

$13.95/2 g

Weight-based dosing: see references below¹

—

Weight-based dosing: see references below¹

—

Ethambutol

14.5–21.1 mg/kg

Max: 1.6 g/dose

$3.74/1.6 g

Weight-based dosing: see references below¹

—

Weight-based dosing: see references below¹

—

¹Data from Nahid P et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of drug-susceptible tuberculosis. Clin Infect Dis. 2016 Oct 1;63(7):e147–95.

²All dosing regimens should be used with directly observed therapy.

³Average wholesale price (AWP, for AB-rated generic when available) for quantity listed. Source: IBM Micromedex. Red Book (electronic version). IBM Watson Health, Greenwood Village, CO, USA. Available at https://www.micromedexsolutions.com/ (cited March 25, 2020). AWP may not accurately represent the actual pharmacy cost because wide contractual variations exist among institutions.

Also available at www.cdc.gov/tb/topic/treatment/guidelinehighlights.htm.

Table 14–6.Management of DIC.

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Table 14–6. Management of DIC.

I. Assess for underlying cause of DIC and treat.

II. Establish baseline platelet count, PT, aPTT, D-dimer, fibrinogen.

III. Transfuse blood products only if ongoing bleeding or high risk of bleeding.

Platelets: goal > 20,000/mcL (most patients) or > 50,000/mcL (severe bleeding, eg, intracranial hemorrhage)

Cryoprecipitate: goal fibrinogen level > 80–100 mg/dL

Fresh frozen plasma: goal PT and aPTT < 1.5 × normal

Packed red blood cells: goal hemoglobin > 8 g/dL or improvement in symptomatic anemia

IV. Follow platelets, aPTT, PT, fibrinogen every 4–12 hours as clinically indicated.

V. If persistent bleeding due to severe consumption or consumption that requires excessive blood product use, consider use of heparin¹ (initial infusion, 5 units/kg/h) and titrate to desired clinical goals; do not administer bolus.

VI. Follow laboratory parameters every 4–12 hours as clinically indicated until DIC resolves

¹Contraindicated if platelets cannot be maintained at > 50,000/mcL, in cases of gastrointestinal or central nervous system bleeding, in conditions that may require surgical management, or placental abruption.

aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; PT, prothrombin time.

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Bacteremia & Sepsis, Gram-Negative

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