What are the clinically significant aspects of Gram-negative bacilli (GNB)?

From the Guidelines

Gram-negative bacilli are clinically significant pathogens that require prompt recognition and appropriate management, with a focus on empiric therapy including beta-lactams, carbapenems, and combination therapy for resistant strains, as well as infection control measures to prevent transmission. These rod-shaped bacteria possess an outer membrane containing lipopolysaccharide (LPS), which contributes to their virulence and antibiotic resistance. Common clinically relevant gram-negative bacilli include Escherichia coli, Klebsiella, Pseudomonas aeruginosa, Acinetobacter, and Enterobacter species. They cause various infections including urinary tract infections, pneumonia, bacteremia, and intra-abdominal infections.

When treating these infections, empiric therapy often includes:

• Beta-lactams like ceftriaxone (1-2g IV daily) or piperacillin-tazobactam (4.5g IV q6h)
• Carbapenems like meropenem (1g IV q8h) for more resistant strains
• Combination therapy with an antipseudomonal beta-lactam plus an aminoglycoside or fluoroquinolone for Pseudomonas infections

Antibiotic resistance is a major concern, particularly extended-spectrum beta-lactamase (ESBL) production and carbapenem resistance, as highlighted in the 2023 guidelines for the diagnosis, treatment, prevention, and control of infections caused by carbapenem-resistant gram-negative bacilli 1. Obtaining cultures before starting antibiotics is crucial for targeted therapy, as emphasized in the management of intra-abdominal infections: recommendations by the WSES 2016 consensus conference 1. The LPS component can trigger septic shock through cytokine release, requiring aggressive fluid resuscitation and vasopressors in severe cases.

Healthcare-associated infections with these organisms often show multidrug resistance patterns, necessitating infection control measures including contact precautions and proper hand hygiene to prevent transmission, as recommended by the Italian Society of Infection and Tropical Diseases (SIMIT) and other organizations 1. The choice of empiric antibiotic regimens should be based on local epidemiology, individual patient risk factors for difficult-to-treat pathogens, clinical severity of infection, and infection source, as stated in the WSES 2016 consensus conference 1.

In patients with complicated intra-abdominal infections, a short course of antibiotic therapy (3-5 days) after adequate source control is a reasonable option, as demonstrated by the recent prospective trial by Sawyer et al. 1. However, in critically ill patients with ongoing sepsis, an individualized approach should be always mandatory, and patient's inflammatory response should be monitored regularly, as recommended by the WSES 2016 consensus conference 1.

Overall, the management of gram-negative bacilli infections requires a comprehensive approach, including prompt recognition, appropriate empiric therapy, and infection control measures to prevent transmission and reduce the risk of antibiotic resistance.

From the FDA Drug Label

Resistance There are several mechanisms of resistance to carbapenems:

1. decreased permeability of the outer membrane of gram-negative bacteria (due to diminished production of porins) causing reduced bacterial uptake,
2. reduced affinity of the target PBPs,
3. increased expression of efflux pump components, and
4. production of antibacterial drug-destroying enzymes (carbapenemases, metallo-β-lactamases). Cross-resistance is sometimes observed with isolates resistant to other carbapenems.

The clinically significant aspects of Gram-negative bacilli (GNB) include:

• Mechanisms of resistance: GNB can develop resistance to carbapenems through various mechanisms, such as decreased permeability, reduced affinity of target PBPs, increased expression of efflux pump components, and production of antibacterial drug-destroying enzymes.
• Cross-resistance: Cross-resistance can occur between different carbapenems, making treatment more challenging.
• Production of carbapenemases: GNB can produce enzymes that destroy carbapenems, rendering them ineffective.
• Efflux pumps: GNB can use efflux pumps to remove antibacterial agents from the cell, reducing their effectiveness 2.

From the Research

Clinically Significant Aspects of Gram-Negative Bacilli (GNB)

• Gram-negative bacilli are a significant cause of morbidity and mortality, particularly in hospitalized patients with severe illnesses 3
• The emergence and spread of multi-drug resistant GNB are major concerns, with factors such as poor infection control practices, indiscriminate use of broad-spectrum antimicrobial agents, and increasing severity of illness contributing to the problem 3
• Certain species of GNB, such as Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli, are commonly associated with bacteremia and have high rates of antibiotic resistance 4, 5

Antibiotic Resistance and Treatment

• The prevalence of extended-spectrum β-lactamases (ESBL)-producing GNB is high, particularly in nosocomial infections, and is associated with increased mortality 4, 5
• Novel antimicrobial agents, such as tigecycline, have shown promise in treating resistant GNB infections, but optimizing their use to delay the emergence and spread of resistance is crucial 3, 6
• Predicting antimicrobial resistance in GNB can help balance the need for appropriate empiric antibiotics with the need to minimize the use of broad-spectrum agents 7

Risk Factors for Resistance

• Prior antibiotic use, nursing home residence, and transfer from an outside hospital are associated with resistance to multiple antibiotics, including piperacillin-tazobactam, cefepime, and meropenem 7
• Infection with certain species, such as Pseudomonas or Acinetobacter spp., is linked with resistance to specific antibiotics, such as meropenem 7
• Clinical decision trees can be used to distinguish patients at low, intermediate, or high risk of resistance to various antibiotics, using simple variables such as prior antibiotic use and nursing home residence 7