Bacteria Associated with Intrinsic Antibiotic Resistance

Generally, when people (either the general public or a physician or laboratory personnel) listen/read the term “antibiotic resistance,” they may think a bacterium that was previously sensitive to a particular antibacterial agent has now developed resistance against it (either through the acquisition of gene via horizontal gene transfer or by mutation). Still, in this universe, innumerable species of bacteria are innately resistant to particular drugs.

Intrinsic resistance is a natural resistance that results from a normal genetic, structural or physiologic state of a microorganism. It is consistently inherited via chromosomal gene transfer.

Importance of Intrinsic Resistance

Intrinsic antibiotic resistance is a naturally occurring phenomenon independent of previous antibiotic exposure and is not caused by a horizontal gene transfer. Remember the famous example of intrinsic resistance, penicillin not working against Mycoplasma. Penicillin kills bacteria by interfering with their cell wall synthesis.

According to CLSI, “Intrinsic resistance is so common that susceptibility testing is unnecessary. For example, Citrobacter species are intrinsically resistant to ampicillin”.

Intrinsic resistance profiles are useful markers to aid in the identification of certain bacteria or bacterial groups. Intrinsic resistance profiles are useful for determining which antimicrobial agents should be included in the battery of drugs tested against specific types of bacteria. For example, routine testing of vancomycin against gram-negative bacilli is not needed.

Mechanism of Intrinsic Resistance

Intrinsic antibiotic resistance is mainly mediated by the impermeability of cellular envelopes, the activity of multidrug efflux pumps, or the lack of drug targets. Enzymes (such as transferases) involved in basic bacterial metabolic processes also confer intrinsic resistance in some bacterial species, such as Pseudomonas aeruginosa, and Staphylococcus aureus.

According to the published findings, such natural resistance can be due to:

• lack of affinity of the drug for the bacterial target
• inaccessibility of the drug into the bacterial cell
• extrusion of the drug by chromosomally encoded active exporters
• innate production of enzymes that inactivate the drug (enzymatic degradation or modification of the antimicrobial agent)

Natural Resistance	Mechanism
Anaerobic bacteria resistant to aminoglycosides	Lack of oxidative metabolism to drive uptake of aminoglycosides
Gram-positive bacteria resistant to aztreonam (beta-lactam)	Lack of penicillin-binding protein (PBP) targets that bind this beta-lactam antibiotic
Gram-negative bacteria resistant to vancomycin	Lack of uptake resulting from the inability of vancomycin to penetrate the outer membrane
Pseudomonas aeruginosa resistant to sulfonamides, trimethoprim, tetracycline, or chloramphenicol	Lack of uptake resulting in ineffective intracellular concentrations of these antibiotics
Klebsiella spp resistant to ampicillin (a beta-lactam target)	Production of beta-lactamases enzymes that destroy ampicillin before it reaches its PBP target
Aerobic bacteria resistant to metronidazole	The inability to anaerobically reduce the drug to its active form
Enterococci resistant to aminoglycosides	Lack of sufficient oxidative metabolism to drive uptake of aminoglycosides
Enterococci resistant to cephalosporins	Lack of PBPs that effectively bind and are inhibited by these beta-lactam agents

Intrinsic Antibiotic Resistance in Gram-Negative Bacteria

Vancomycin inhibits cell-wall synthesis in Gram-positive bacteria, but Gram-negative bacteria generally are intrinsically resistant to vancomycin. The large molecular size of vancomycin and its inability to penetrate the outer bacterial membrane (lipid bilayer doesn’t allow vancomycin to enter Gram-negative cells) makes vancomycin ineffective against Gram-negative bacteria.

Bacterial pathogens that are Intrinsically resistant to Ampicillin are:

1. Acinetobacter baumanni complex
2. Citrobacter freundii
3. Citrobacter koseri
4. Klebsiella (formerly Enterobacter) aerogenes
5. Enterobacter cloacae complex
6. Klebsiella pneumoniae
7. Morganella morganii
8. Proteus vulgaris
9. Pseudomonas aeruginosa
10. Serratia marcescens
11. Yersinia enterocolitica

Bacterial pathogens that are Intrinsically Resistant to Amoxicillin-Clavulanate combination

1. Citrobacter freundii
2. Klebsiella (formerly Enterobacter) aerogenes
3. Enterobacter cloacae complex
4. Morganella morganii
5. Pseudomonas aeruginosa
6. Serratia marcescens
7. Yersinia enterocolitica
8. Burkholderia cepacia complex
9. Stenotrophomonas maltophilia

Bacterial pathogens that are Intrinsically Resistant to Ampicillin-sulbactam combination

1. Citrobacter freundii
2. Citrobacter koseri
3. Klebsiella (formerly Enterobacter) aerogenes
4. Enterobacter cloacae complex
5. Proteus vulgaris
6. Pseudomonas aeruginosa
7. Serratia marcescens

Citrobacter koseri is intrinsically resistant to piperacillin, whereas Proteus spp is intrinsically resistant to tetracycline/tigecycline, nitrofurantoin and polymyxin B, and colistin.

Serratia marcescens

AmpC-type β-lactamases are present in the chromosomes of many members of Enterobacteriaceae including Serratia marcescens. These clinically important cephalosporinases encoded on the chromosomes of many Serratia mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and beta-lactamase inhibitor-beta-lactam combinations (ampicillin-sulbactam, amoxicillin-clavulanate).

Serratia marcescens is resistant to the following drugs;

1. Ampicillin
2. Amoxicillin-clavulanate
3. Ampicillin-sulbactam
4. Cephalosporins I: Cefazolin, Cephalothin
5. Cephamycins: Cefoxitin, Cefotetan
6. Cephalosporin II: Cefuroxime
7. Nitrofurantoin
8. Polymyxin B, Colistin

Yersinia enterocolitica

Yersinia enterocolita is resistant to the following drugs;

1. Ampicillin, Amoxicillin
2. Amoxicillin-Clavulanate
3. Ticarcillin
4. Cephalosporins I: Cefazolin, Cephalothin

Acinetobacter baumanni complex is a notorious pathogen that is resistant to most of the available antibiotics. It is intrinsically resistant to

1. Ampicillin, Amoxicillin
2. Amoxicillin-Clavulanate
3. Aztreonam
4. Ertapenem
5. Trimethoprim
6. Chloramphenicol
7. Fosfomycin

Similarly, Pseudomonas aeruginosa is intrinsically resistant to

1. Ampicillin, Amoxicillin
2. Ampicillin-sulbactam
3. Amoxicillin-Clavulanate
4. Cefotaxime
5. Ceftriaxone
6. Ertapenem
7. Tetracyclines/Tigecyclines
8. Trimethoprim
9. Trimethoprim-sulfamethoxazole
10. Chloramphenicol

Both Acinetobacter and Pseudomonas are also intrinsically resistant to penicillin (ie, benzylpenicillin), cephalosporin I (cephalothin, cefazolin), cephalosporin II (cefuroxime), cephamycins (cefoxitin, cefotetan), clindamycin, daptomycin, fusidic acid, glycopeptides(vancomycin, teicoplanin), linezolid, macrolides (erythromycin, azithromycin, clarithromycin), quinupristin-dalfopristin, and rifampin.

Bacteroides spp. which is one of the most frequently isolated anaerobic Gram-negative bacilli is intrinsically resistant to

• Aminoglycosides
• Penicillin and
• Ampicillin

Intrinsic Antibiotic Resistance in Gram-positive Bacteria

Among Gram-positive bacteria, S. saprophyticus is intrinsically resistant to novobiocin, which is the basis for novobiocin sensitivity test done in urine isolate (if CONS is isolated).

Enterococcus faecalis/faecium are intrinsically resistant to

• Cephalosporin*
• Aminoglycosides*
• Clindamycin*
• Trimethoprim
• Trimethoprim-sulfamethoxazole*
• Fusidic acid
  *may appear active in vitro but are ineffective clinically and should not be reported as susceptible.

Enterococci and staphylococci are also intrinsically resistant to aztreonam, polymyxin B/colistin, and nalidixic acid.

Anaerobic Gram-positive bacilli, Clostridium spp. is resistant to aminoglycosides.

References and further reading 

1. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev. 2009 Jan;22(1):161-82, Table of Contents. doi: 10.1128/CMR.00036-08. PMID: 19136439; PMCID: PMC2620637.
2. CLSI: M100S: Performance Standards for Antimicrobial Susceptibility Testing