From the Guidelines
Gram-negative blood cultures require prompt antibiotic treatment with broad-spectrum antibiotics, such as piperacillin-tazobactam, cefepime, or meropenem, to prevent serious morbidity and mortality, as gram-negative bacteremias are associated with greater mortality compared to gram-positive bacteremias 1.
Key Considerations
- Initial empiric therapy should include a beta-lactam antibiotic, potentially combined with an aminoglycoside like gentamicin for synergy in severe cases, as recommended by the Infectious Diseases Society of America 2.
- Treatment should be narrowed once the specific organism and its susceptibilities are identified, typically continuing for 7-14 days depending on the source of infection, organism virulence, and patient response.
- Removal of any infected devices or drainage of abscesses is essential if present, and source control investigations should include evaluation for urinary tract infections, intra-abdominal infections, pneumonia, or infected vascular access.
Antibiotic Choices
- Piperacillin-tazobactam (4.5g IV every 6 hours) is a suitable option for initial empiric therapy, as it provides broad-spectrum coverage against gram-negative bacteria, including Pseudomonas aeruginosa 3.
- Cefepime (2g IV every 8 hours) and meropenem (1g IV every 8 hours) are also effective options, with cefepime being considered a reliable first-line agent for empirical antibiotic coverage for fever and neutropenia 3.
Mortality Risk and Timing of Treatment
- Gram-negative bacteremia carries significant mortality risk (15-40%) due to endotoxin release that can trigger inflammatory cascades leading to sepsis, emphasizing the importance of rapid administration of appropriate antibiotics within the first hour of recognition 1.
- Each hour of delay in antibiotic administration is associated with approximately 8% increase in mortality, highlighting the need for prompt treatment.
From the FDA Drug Label
Gram-negative bacteria Citrobacter freundii Enterobacter cloacae Escherichia coli Haemophilus influenzae Klebsiella oxytoca Klebsiella pneumoniae Legionella pneumophila Acinetobacter baumannii* Aeromonas hydrophila Citrobacter koseri Enterobacter aerogenes Haemophilus influenzae (ampicillin-resistant) Haemophilus parainfluenzae Pasteurella multocida Serratia marcescens Stenotrophomonas maltophilia
Tigecycline has been shown to be active against most of the above-mentioned Gram-negative bacteria, both in vitro and in clinical infections. However, the efficacy of tigecycline in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials for some of them 4.
Gram-negative bacteria Acinetobacter calcoaceticus Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus influenzae Haemophilus parainfluenzae Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Neisseria meningitidis Proteus mirabilis Proteus vulgaris Pseudomonas aeruginosa Serratia marcescens
Ceftriaxone is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis and has activity against the above-mentioned Gram-negative bacteria, both in vitro and in clinical infections 5.
- Key points:
- Tigecycline and Ceftriaxone have different mechanisms of action and are effective against different Gram-negative bacteria.
- The efficacy of these drugs in treating clinical infections caused by these bacteria has been established in adequate and well-controlled clinical trials for some of them, but not all.
- Tigecycline is considered bacteriostatic in general, but has demonstrated bactericidal activity against some isolates.
- Ceftriaxone is a bactericidal agent.
- Resistance to these drugs can occur through different mechanisms.
From the Research
Gram-Negative Blood Cultures
- Gram-negative bloodstream infections (GNBSI) are common and carry considerable mortality, with treatment complicated by increasing antimicrobial resistance 6
- New rapid diagnostic tests (RDT) for pathogen identification and antibiotic susceptibility are associated with improved antimicrobial stewardship and reduced length of stay, but no mortality benefit or patient-related outcomes are reported 6
- The use of new beta-lactam beta-lactamase inhibitors (BLBLIs) for treating multidrug-resistant Gram-negative bacteria is supportive, but questions regarding combinations, optimal dosing, mode of administration, and resistance emergence remain to be clarified 6, 7
Predicting Resistance
- Predicting antimicrobial resistance in gram-negative bacteria could balance the need for administering appropriate empiric antibiotics while also minimizing the use of clinically unwarranted broad-spectrum agents 8
- Prior antibiotic use, nursing home residence, and transfer from an outside hospital are associated with resistance to piperacillin-tazobactam, cefepime, and meropenem 8
- Clinical decision trees can be used to distinguish patients at low, intermediate, or high risk of resistance to these antibiotics 8
Treatment Options
- New beta-lactam agents, including ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, and cefiderocol, have been approved for the treatment of resistant gram-negative infections 7
- Imipenem, cefepime, and ceftazidime are preferred beta-lactam regimens for the empirical treatment of gram-negative pulmonary infections in the ICU based on pharmacokinetics/pharmacodynamics 9
- Shortened (≤7 days) duration of therapy and early oral step down for GNBSI are supported by the literature 6
Antimicrobial Management
- Immediate, empiric, broad-spectrum therapy is necessary to reduce mortality in sepsis, but this approach can drive antimicrobial overuse and resistance 10
- Biomarkers such as procalcitonin can provide decision support for antibiotic use and guide duration of antibiotic therapy 10
- Antimicrobial stewardship is crucial to minimize the development of resistance and optimize patient outcomes 6, 10