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NOSOCOMIAL GRAM-NEGATIVE
INFECTIONS
Mohamed Ahmed Badheeb, MBBS.

FACTS
Gram-negative bacteria are typically non-pathogenic in the immunocompetent host.
This is especially true of the Enterobacteriaceae and the non-fermentative gram-
negative bacilli. However, in the debilitated host, gram-negative bacteria can become
significant pathogens
Gram-negative pathogens are common in both nosocomial pneumonia and
bloodstream infections, two of the most difficult nosocomial infections to manage.
Enterobacteriaceae are the most common cause of gram-negative nosocomial
infection; however, non-fermentors, such as Pseudomonas aeruginosa and
Acinetobacter species, are predominant pathogens in the critically ill.

Mortality
Mortality rates for gram-negative bacteremia have not changed dramatically since the era before
antibiotic drugs. Patients with nosocomial ventilator-associated pneumonia (VAP) have higher
mortality rates than similar patients without VAP, but the impact is greatest for certain high-risk
pathogens, such as Acinetobacter species, P. aeruginosa, and Stenotrophomonas maltophilia. There
are several independent risk factors for mortality, including
- The presence of hepatic, renal, or cardiac failure.
- Diabetes mellitus.
- Age older than 60 years.
- Corticosteroid use; antineoplastic therapy.
- Neutropenia
- Shock.

Appropriate Versus Inappropriate Therapy
Inappropriate antimicrobial therapy remains a significant problem in treating nosocomial
infection. Inappropriate antibiotic therapy can be defined in several terms, including;
• antimicrobial use when it is not indicated.
• Use of an antibiotic regimen that does not have activity against the causative pathogen.
• Incorrect dosing
• Wrong administration route.
The consequences of inappropriate use can be significant, including increased rates of
morbidity and mortality, and increased resistance.

Appropriate Versus Inappropriate Therapy
 Antimicrobial resistance plays an important role in inappropriate antimicrobial prescribing.
 One report determined that 20% of all ICU cases (nosocomial and community-acquired infection) of
inappropriate antimicrobial therapy were caused by resistant gram-negative bacilli.
 Gram-negative bacteria were responsible for more than 50% of all inadequately treated nosocomial
infections.
 The mortality rate in the patients who received appropriate therapy was 12.2% compared to 52.1% in
patients receiving inadequate treatment.
 Patients who received inadequate therapy were more likely to develop bloodstream infections, sepsis,
severe sepsis, and septic shock, and they were more likely to receive vasopressors and mechanical
ventilation.
 There is an association between inappropriate therapy and hospital length of stay, ICU length of stay,
and duration of mechanical ventilation.

Antibiotics Resistance !!!!
Antibiotic-resistant gram-negative bacilli infection is more commonly associated with
resistance to empiric antibiotic therapy, requiring treatment change. The most
important gram-negative resistance issues affecting nosocomial infections are
 Extended-spectrum b-lactamases (ESBLs) in K. pneumoniae, E. coli, Enterobacter
species, and Proteus mirabilis.
 Cephalosporin and extended spectrum penicillin resistance mediated by
AmpC b-lactamase found in Enterobacter species and Citrobacter freundii; and
multidrug-resistant P. aeruginosa, Acinetobacter species, and S. maltophilia. (AKA;

Factors That Promote Antimicrobial Resistance
 Health Care Setting Factors
Many factors may be responsible for the increasing incidence of gram-
negative infection. Transmission of antibiotic-resistant pathogens in the acute
care setting is common.
• A variety of health care workers participate in managing acutely ill patients.
• Handwashing or other aseptic techniques are not uniformly or effectively
practiced throughout the health care setting.

Factors That Promote Antimicrobial Resistance
 Patient-specific Factors
Many patient-specific factors increase the infection risk with antimicrobial-resistant pathogens.
Acutely ill patients, especially those in the ICU.
• Require invasive monitoring and therapeutic devices.
• Intensive care unit patients commonly have severe underlying clinical conditions, such as
immunosuppression, cancer, malnutrition, organ failure, and prior interaction with the health
care system.
Patients with severe disease have longer hospital and ICU stays. Late-onset nosocomial infections
among patients in the ICU are more likely to be associated with an antimicrobial-resistant
pathogen.

Nosocomial Gram negative Infections

- ESBL
- SPICE organisms
Specific Resistance Mechanisms

General Overview
 Beta-lactamases are enzymes that open the beta-lactam ring, inactivating the antibiotic.
 TEM-1 and TEM-2 are the most common plasmid-mediated beta-lactamases in gram-
negative bacteria, including Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus
influenzae, and Neisseria gonorrhoeae, they hydrolyze penicillins and narrow spectrum
cephalosporins, such as cephalothin or cefazolin. However, they are not effective against
higher generation cephalosporins with an oxyimino side chain, such as cefotaxime,
ceftazidime, ceftriaxone, or cefepime.
 There are different varities for ESBL, including:
 SHV beta-lactamases, hydrolyze beta-lactams such as penicillins and narrow spectrum.
 CTX-M beta-lactamases, hydrolyze cefotaxime than other oxyimino-beta-lactam
substrates (eg, ceftazidime, ceftriaxone, or cefepime).
 OXA beta-lactamases, hydrolyze oxacillin and related anti-staphylococcal penicillins.

Extended-spectrum b-Lactamase
 Extended-spectrum b-lactamases are b-lactamases capable of hydrolyzing penicillins, broad- and
extended spectrum cephalosporins that contain the oxyimino side chain, and monobactams, and are
inhibited by clavulanic acid.
 Extended-spectrum b-lactamases have been isolated from a variety of Enterobacteriaceae, as well as P.
aeruginosa. Originally, they were found inK. pneumoniae and E. coli, but are now common in other
gram-negative organisms such as the Enterobacter species.
 Genes that code for ESBL are carried on plasmids and can be transferred easily from one organism to
another. Extended-spectrum b-lactamase-producing organisms remain susceptible to cephamycins
(cefoxitin and cefotetan). The frequency of fluoroquinolone resistance is higher in ESBL-producing
organisms than among non-ESBL-producing K. pneumoniae or E. coli.

TREATMENT OPTIONS FOR ESBL
Preferred agents — The preferred, proven therapeutic options for severe infections caused by extended-spectrum
beta-lactamase (ESBL)-producing organisms are carbapenems (imipenem, meropenem, doripenem, and ertapenem).
The combination cephalosporin-beta-lactamase inhibitor agents (ceftolozane-tazobactam and ceftazidime-
avibactam) and the broad-spectrum tetracycline eravacycline appear promising, although data on their clinical
efficacy are too limited at this time to recommend their routine use, and it is not clear that they provide additional
benefit over carbapenems.
For complicated UTI, plazomicin is another option that can be active against ESBL-producing isolates that are resistant
to other aminoglycosides.
For simple cystitis, oral fosfomycin and nitrofurantoin are other potential options that may retain activity against ESBL-
producing isolates.

AmpC-type b-Lactamase
AmpC beta-lactamases (AmpC) are enzymes which convey resistance to penicillins, second and
third generation cephalosporins and cephamycins. However, they do not convey resistance to
fourth generation cephalosporins.
The genes for these enzymes occur naturally in some bacteria species as so-called chromosomal
AmpC (e.g. in E. coli, but not in Salmonella up to now).
The important thing is the increasing number of AmpC genes localised outside the chromosome
on so-called plasmids, which is why they are often referred to as ”plasmidic AmpC” (pAmpC). They
ensure the constant formation of the enzyme and lie on transmissible gene sections. These can be
exchanged between bacteria of the same type or of different types (horizontal gene transfer)

AmpC-type b-Lactamase and SPICE organisms
Most Enterobacteriaceae carry AmpC cephalosporinases, but these enzymes
are considered clinically problematic in the so-called SPICE organisms
(Serratia, indole-positive Proteus, Citrobacter, and Enterobacter, as well as
Providencia, Morganella, and Hafnia).
AmpC-mediated b-lactamase confers resistance to first-, second-, and third
generation cephalosporins, in addition to monobactams, such as aztreonam,
and to some penicillins.

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Nosocomial Gram negative Infections

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