IDFN On Call: GNR Bacteremia

By: Jonathan Ryder

This morning is an early wake-up, as your pager rings its all-too-well-known tone right before your 5:30 AM alarm. ICU calling. A patient with cirrhosis de-compensated overnight. Blood cultures are growing gram-negative rods. The rapid identification molecular panel identifies this as an Escherichia coli with a KPC gene. The patient was empirically started on meropenem. The ICU wants to know what is the best therapy and next steps.

Gram negative bacteremia is responsible for significant morbidity and mortality, with 90-day mortality rates exceeding 35%. The epidemiology of gram-negative bacteremia differs signifinicantly based on initial source of infection, local antibiograms, and mechanism of acquisition (i.e. hospital-acquired vs community-acquired). Gram negative rods (GNRs) are often associated with urinary tract and gastrointestinal sources of infection. However, in the hospital environment, GNR bacteremia can be associated with central venous catheter infections and pneumonia.

The most common cause of GNR bacteremia is Escherichia coli, specifically when the infection is community-onset. Other common GNRs recovered in blood cultures include Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterobacter cloacae, Proteus mirabilis, and Acinetobacter baumanii. Just as important as understanding the causative pathogen is understanding common mechanisms of GNR resistance. GNRs frequently harbor multiple drug-resistance mechanisms, particularly those infections acquired in the hospital. These might include extended spectrum beta-lactamases (ESBLs), inducible AmpC, and carbapenemases. Many hospitals now have rapid molecular identification panels for identifying both organism and the presence of resistance genes. Below is a list of detectable genes (primarily in Enterobacterales species) to aid in interpretation and selection of antimicrobials:

CTX-M: “Cefotaxime-Munich,” most common ESBL gene, first identified in Munich, Germany, confers resistance to 3rd-generation cephalosporins (e.g., ceftriaxone, cefotaxime)

Empiric drug of choice: carbapenem (e.g., meropenem, imipenem, ertapenem)

KPC: “Klebsiella Pneumonia Carbapenemase,” carbapenemase (confers resistance to carbapenems), serine beta-lactamase (Ambler Class A), first discovered in North Carolina, USA in 1996, most common carbapenemase worldwide, endemic in USA, Columbia, Argentina, Greece and Italy

Empiric drug of choice: novel beta-lactam/beta-lactamase inhibitor (e.g., ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam)

NDM: “New Delhi Metallo-beta-lactamase,” metallo-beta-lactamase (MBL; Ambler Class B), MBLs are among the most drug-resistant carbapenemases (resistant to novel beta-lactam/beta-lactamase inhibitors), first discovered in Sweden in a patient from New Delhi, India in 2009, endemic in India, Pakistan, and Sri Lanka

Empiric drug of choice: aztreonam-avibactam, cefiderocol (seek expert consultation)

IMP: “Imipenem-Resistant Pseudomonas-type,” another metallo-beta-lactamase (Ambler Class B), first discovered in Japan in 1990, endemic in Japan and Taiwan

Empiric drug of choice: aztreonam-avibactam, cefiderocol (seek expert consultation)

VIM: “Verona Integrin-Encoded Metallo-beta-lactamase,” another metallo-beta-lactamase (Ambler Class B), first discovered in Verona, Italy in a Pseudomonas species in 1997, endemic in Greece

Empiric drug of choice: aztreonam-avibactam, cefiderocol (seek expert consultation)

OXA: “Oxacillinase,” serine beta-lactamase (Ambler Class D), OXA-48 is the most common, first discovered in Turkey in 2001, endemic in Turkey, Malta, Middle-East, and North Africa

Empiric drug of choice: ceftazidime-avibactam (if OXA-48)

mcr-1: “Mobilized Colistin Resistance,” confers resistance to colistin, first identified in China

Empiric drug of choice: avoid colistin

Below is a table adapted from an excellent review article from Yohei Doi that demonstrates which novel antibiotics are most effective against specific carbapenemases and other multidrug resistance organisms (Green: has activity; Red: no activity; Yellow: activity in certain circumstances). This table is especially useful for a quick reference while on call to start appropriate empiric therapy.

Treatment Decisions

Generally, treatment will be empiric either based on the gram stain of gram-negative rods or based on a rapid molecular identification. The choice of therapy is dependent on organism, infection source, area of acquisition (community vs hospital), and your hospital antibiogram. Options for empiric therapy include ceftriaxone (especially for community-acquired Enterobacterales), cefepime or piperacillin-tazobactam (for Pseudomonas coverage), and meropenem (for ESBL coverage).

Additional Considerations

Identifying the source is key to management of gram-negative bacteremia, much like other infections. Sometimes, no source is identified, as gram-negatives frequently translocate across the gut wall. However, it is important to target patient symptoms (dysuria, abdominal pain) with appropriate lab testing (urinalysis and culture) and/or imaging (abdominal CT). If there is evidence of pneumonia, then sputum cultures are helpful. And if there is concern for a line infection, then removing the line is important if the patient is unstable or the infection is multidrug resistant. Generally, repeat blood cultures are unnecessary in gram-negative bacteremias unless an endovascular source is suspected.

For more on drug-resistance mechanisms, here are some texts we referenced:

https://pubmed.ncbi.nlm.nih.gov/31724045/