Introduction to bacterial resistance to antibiotics, types of resistance, brief explaining & examples The lecture was presented at Al-Mahmoudiya General Hospital at Wed, 17th Nov. 2021 Represented & updated as part of the training course for fresh appointed pharmacist at 16/5/2023

1. Antibiotics Resistance
Alaa Fadhel Hassan (MSc. Pharmacology)
Drug Information Centre
Al-Mahmoudiya General Hospital

2. Historical quote

3. Antibiotic resistance
• Bacterial-antibiotic resistance is a major global problem, up to the
US CDC report, there is 2.8 million people suffer from bacterial
infections resist antibiotic yearly, resulting in 35 000 deaths/ year.
• The major cause of bacterial resistance is the uncontrolled &
inappropriate consumption of antibiotics world wide.
• Resistance is defined as the micro-organism capacity to disaffect
antibiotic(antimicrobial)-cidal/static action by the usually
achievable antibiotic concentration.

4. Timeline of antibiotic resistance

5. Antibiotic resistance- sequels
Antibiotic selection pressure
Cost of newer antibiotic discovery
Lost of productivity
Healthcare cost
Increased mortality
Bacterial resistant strains spreading
Follow up and visits cost
Increased hospitalization
Failure of therapy

6. Types of antibiotic resistance
Natural
intrinsic
Acquired
Cross-
resistance
Multidrug (pan)
resistance

7. Intrinsic resistance
• It occurs naturally in all bacteria of specific genus/species
due to physiological characteristics of that genus or structural
genes, it is not related to the consumption of antibiotics that’s
why it referred to as insensitive bacteria.
• Results in: lack of target, Innate efflux pumps (↓ affinity) &
antibiotic inactivation.

8. Intrinsic resistance, Examples
• Glycopeptides, macrolides, lincosamides & streptogramins, cannot
pass outer membrane of gm –ve bacteria (Escherichia coli).
• Beta lactam Ab., cannot destroy the L-form shape of bacteria which are
wall-less (Mycoplasma & Ureaplasma).
• Bacteria with low permeability of the outer-membrane because of the
presence endogenous multidrug efflux systems (such as MexAB-OprM
and MexXY-OprM) and a chromosomally encoded b-lactamase (AmpC)
(Pseudomonas aeruginosa).
• Beta-lactams and cyclines, have reduced permeability of the bacterial
cell wall, presence of modifying enzymes, and low affinity for the target
(such as PBP and DNA gyrase) (Mycobacteria).

9. Intrinsic resistance,
Examples from our antibiogram
• ....Mahmoudia General HospitalAntibiotic stwardship ‫الية‬
‫الحياتية‬ ‫المضادات‬
antibiogram2020.xlsx

10. Acquired resistance
• Occur in some bacterial strains of same genus/species due to the
bacterial genetic characteristics (the structures of chromosome or
extrachromosomal like plasmid, transposon, etc.).
• Render bacterial resistance to the antibiotics they were sensitive
to previously.
• Occurrence rate is 1/10000000 cells, but sometimes, it can be
highly prevalent ex., penicillinase production in staphylococci that
is present in more than 90% of the strains.

11. Acquired resistance, Chromosomal
• Occur due spontaneous bacterial chromosomal mutation that
resulted from physical (ultraviolet, etc.) and chemical factors.
• Causes bacterial cell structural changes, resulting in reduced
permeability of antibiotic or target alterations.
• Ex, streptomycin, aminoglycosides, erythromycin &
lincomycin cannot affect bacteria with these Spontaneous
chromosomal mutations, that are 10-7-10-12.

12. Acquired resistance, Extrachromosomal
• Related to mutations that occur in eextrachromosomal genetic
elements that are transferred in various ways like plasmids,
transposons & integrons.
• Extrachromosomal resistance is hereditary, transfer the genetic
material from a bacterium via three ways: transduction by
bacteriophage resistance genes , transformation by DNA binding
protein (competence factor), conjugation via sex pilus between
two living bacteria through transfer of resistance genes, and
transposition.

13. Acquired resistance, Extrachromosomal
• Plasmids are replicable extrachromosomal DNA fragments
within the cytoplasm, which are usually responsible for the
transformation of resistant genes (r-gene) that produce
enzymes which inactivate antibiotics.
• Transposons are freely movable
DNA sequences within the genome
of single cell, replicate during
cointegration & are carried by the
plasmids that transform r-gene.

14. Acquired resistance, Extrachromosomal
• Integrons are the antibiotic r-genes
packed on the chromosome or plasmid
which are interconnected with each
other & located near the start of specific
units of integration, however; they can
not afford self transfer.
• Integrons are responsible for multi-
bacterial functions as virulence &
resistance.

15. Cross-resistance
• Generally “It’s a phenomena of shared resistance
between different clinical antibiotic classes, between
antibiotics and disinfectants, biocides or solvents and
between antibiotics and heavy metals”.

16. Cross-resistance
• Refer to bacterial species that resist all antibiotics belonging to
the same/different classes, when these antibiotics share the
mechanisms of action and hence -of resistance, Like the route of
access to the cytoplasm, binding the same target, &/are involved
in the same pathway leading to the inhibition of growth or cell.
• It may occur due to horizontal gene transfer of genetic elements
coding for resistance to multiple antibiotics.

17. Cross-resistance, Examples
• The resistance among erythromycin, neomycin-kanamycin/
cephalosporins and penicillins &/ erythromycin- lincomycin.
• Among quinolones, ciprofloxacin is much more active than
nalidixic acid. therefor, gram-negative bacteria that have suffered
a mutational event in the target of quinolones, the type II
topoisomerases (DNA gyrase and topoisomerase IV) become
much more resistant to nalidixic acid than to ciprofloxacin.

18. Cross-resistance, Examples
Cherny et al. in their additive Bayesian network modelling study
found relationships between variables in a dataset of bacterial
cultures derived from hospitalized patients tested for resistance to
multiple antibiotics.
 [Gentamicin and sulfamethoxazole-trimethoprim in the E. coli & P.
mirabilis]
 [Gentamicin & several b-lactam antibiotics (ceftazidime &
imipenem in the P. aeruginosa &Cefuroxime in the P. mirabilis]
 [Gentamicin & ciprofloxacin in the E. coli, K. pneumoniae and P.
mirabilis]
 [sulfamethoxazole/trimethoprim & ciprofloxacin]

19. Cross-resistance, Examples

20. What about co-resistance & extended
cross-resistance?
• In co-resistance, bacterial strain with cross resistance to specific
class of antibiotics is associated with various mechanisms
(stabilized by genome integration- integrons are the most efficient
way) resulting in multidrug resistance.
• “the consequence of co-resistance is co-selection. Use of a
member of a drug class can co-select resistance to another class
of antibiotics with a totally distinct mode of action, ex.
Streptococcus pneumonia”.

21. Co-resistance & extended cross-resistance
• Extended cross-resistance refer to bacterial strain with cross
resistance to specific class of antibiotics is associated with
single mechanism that can confer resistance to other
antibiotic classes.
• a class of antibiotics can select for resistance to other drug
classes.

22. Extended cross-resistance, Examples
• The methylation of a specific adenine residue in 50S rRNA 
high-level resistance to macrolides, lincosamides, and
streptogramins B (classes have different chemical structure)
• The overexpression of efflux pumps with various substrate
ranges, that are grouped in superfamilies. Like the RND pump in
gram-negative bacteria  export various antibiotic molecules with
very different structures, as well as biocides like triclosan.

23. Multidrug (pan) resistance
• Refer usually to bacterial resistance to the previously used
antibiotics in their treatment, it occur due to inconvenient
prescription/consumption of antibiotics, so that “a particular drug
is no longer able to kill or control the bacteria”.
• It results from either bacterial accumulation of several genes that
each one of them codes for single antibiotic resistance (on
resistant plasmids), or due to increased bacterial expression of
genes responsible for multidrug efflux pumps, antibiotic
inactivation & changing structural targets.

24. Multidrug (pan) resistance
• Bacterial strains
 resist 3 or more antibiotic classes multidrug resistant
 resist all but 1 or 2 antibiotic classes extensively-drug-
resistant
 resist all available antibiotic pan-drug-resistant

25. Multidrug (pan) resistance, Examples
• Multidrug resistance (MDR) Acinetobacter spp. the isolate resist least
of three classes antibiotics (all penicillins and cephalosporins -including
inhibitor combinations, fluroquinolones, and aminoglycosides).
• Extensive drug resistant (XDR) Acinetobacter spp. the isolate that
resist 3 classes of antibiotics described above (MDR) and as well as
carbapenems.
• Pan-resistant (PDR) Acinetobacter spp.  the XDR isolates that also
resist polymyxins (colistin) and tigecycline.

26. “Take home message”, what to do