bacterial resistance and antimicrobial stewardship

antibiotic resistance

when germs (bacteria, fungi) develop the ability to defeat the antibiotics designed to kill them

susceptible (S)

the organism will most likely be eradicated using the standard recommended dose of the antimicrobial

intermediate (I)

the organism may be eradicated if the antimicrobial used obtains high concentrations at the site of infection or higher doses of the drug are utilized

resistant (R) 

the organism is NOT inhibited by the standard dose of the antimicrobial agent or mechanisms of resistance are likely present

how do bacteria become resistant to antibiotics?

1. Lots of germs and very few are resistant. Bacteria may possess genes coding for resistance in their DNA

2. antibiotics kill bacteria causing the illness as well as good bacteria protecting the body from infection

3. the drug-resistant bacteria are now allowed to grow and take over

4. some bacteria give their drug-resistance to other bacteria, causing more problems

mechanisms of bacterial resistance 

• drug inactivation 

  • enzymatic inactivation

  • beta-lactamase enzymes

  • aminoglycoside modifying enzymes

• target site modification

  • genetic mutations alter the site to which drugs bind reducing affinity

  • penicillin binding proteins (PBPs)

  • alterations to DNA gyrase or topoisomerase IV

  • erythromycin ribosome methylase (ERM) gene expression

• decreased permeability

  • efflux pumps

  • porin channel deletion 

  • antibiotic characteristics 

contributing factors for resistant organisms and infections 

• antibiotic use/pressure

• history of infection or colonization with resistant organisms 

• recurrent hospitalizations 

• extended care facility resistance 

• exposure to wound care or hemodialysis 

• patient populations: increased age, increased severity of illness, immunocompromised patients 

the impact of bacterial resistance

• poorer patient outcomes

• decreased treatment options

• increased time to effective therapy

• necessity to utilize older, more toxic agents or newer agents with less data

urgent threats of bacterial resistance

• Candida auris

• Clostridoides difficile

• carbapenemase- resistant Acinetobacter spp

• drug-resistant Neisseria gonorrhoeae

serious threats to antibiotic resistance 

• drug-resistant Candida spp

• extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae

• vancomycin-resistant Enterococcus spp (VRE)

• multi-drug resistant Pseudomonas aeruginosa

• methicillin-resistant S. aureus (MRSA) 

• drug- resistant S. pneumoniae 

• drug-resistant tuberculosis 

concerning threats to antibiotic resistance

• Erythromycin-resistant Group A Streptococcus

• Clindamycin-resistant Group B Streptococcus

Staphylococcus aureus resistance

• Penicillin Resistance

  • ~90%

  • Plasmid Mediated and inducible

  • mechanism = beta-resistance enzyme

• methicillin/oxacillin resistance (MRSA)

  • 13-74% of S.aureus isolates worldwide

  • chromosomally mediated by the mecA gene and constitutive

  • mechanism = target site modification via mutation of PBP2 to PBP2a leading to decreased binding affinity for MOST beta-lactam agents

hospital-acquired MRSA 

• recent hospitalization 

• recent/frequent antibiotic exposure 

• indwelling catheters/devices 

• extended care facility residents 

• chronic wound care/hemodialysis 

community-acquired MRSA

• no recent hospitalization

• no recent antibiotic exposure

• lack of significant PMH

• most commonly associated with skin and soft tissue infections

• infections often associated with necrosis and/or fluid collections

treatment options for hospital-acquired MRSA infection

• vancomycin

• linezolid, tedizolid

• daptomycin

• quinupristin/ dalfopristin

treatment options for community-acquired MRSA 

• HA-MRSA options plus 

• Sulfamethoxazole/ Trimethoprim 

• doxycycline, Minocycline 

• maybe Clindamycin 

vancomycin intermediate S. aureus (VISA)

• MIC: 4-8mcg/ml

• mechanism = cell wall thickening reduces access to the binding site

Vancomycin Resistant S. aureus (VRSA)

• MIC > or = 16mcg/ml

• plasmid mediated genetic information obtained from Enterococcus faecalis

• mechanism = modification of the target site

Streptococcus pneumoniae resistance

• Penicillin resistant S. pneumoniae (PRSP) or penicillin non-susceptible S. pneumoniae (PNSP)

  • nearly 40% of S.pneumoniae isolates are resistant to penicillin

  • susceptibility breakpoints are adjusted and depend on potential for meningitis

  • primary mechanism = target site modification of PBPs(2X, 2B, 1A)

mechanism of S. pneumoniae against Macrolides and fluroquinolones

• target site modifications 

• efflux pumps 

mechanism of S.pneumoniae resistance to Tetracyclines and sulfamethoxazole/trimethoprim

target site modification

vancomycin resistant enterococcus spp(VRE) 

• enterococcus faecalis and enterococcus faecium are most common species 

• vanc resistance to E. faecalis and E. faecium occurs via the acquisition of genes encoded on the van operons via conjugation 

  • VanA gene is transmitted via conjugation by means of mobile genetic elements

  • vanB genes are transmitted via conjugation by means of genetic elements or may be located on chromosomes

  • mechanism = target site modifications of the terminal binding sites and inducible

VRE treatment options 

• daptomycin 

• linezolid, Tedizolid 

• tigecycline 

• minocycline, doxycycline 

• ervacycline, omadacycline 

• fosfomycin

significant drug resistant Gram-Negative organisms

• AmpC beta-lactamase

• Extended-spectrum beta-lactamase (ESBLs)

• carbapenem resistant Enterobacterales (CRE)

• carbapenem resistant Acinetobacter baumannii (CRAB)

• carbapenem resistant Pseudomonas aeruginosa (CRPA)

• multi-drug resistant and difficult to treat Pseudomonas aeruginosa (DTR-P)