Bacterial Resistance to Antibiotics

Prepared by :

Microbiology and Immunology Department

Objectives of the Lecture

1.   The Problem of Antibiotic Resistance:

2.   Bacterial Resistance to Antibiotics:

3.   Biochemical Mechanisms of Resistance:

4.   The General Principles of Antibiotic Policies:

1. The Problem of Antibiotic Resistance

q  Antibiotic resistance is the most common cause of treatment failure in bacterial infectious diseases.

q  Infections with antibiotic-resistant bacteria leads to the use of more expensive and often more toxic drugs, increased length of infection and subsequent hospital stay.

q  The problem is not limited to nosocomial bacteria but also community-acquired pathogens have become resistant to key antibiotics.

2. Bacterial resistance to antibiotics

q  Resistant Organism: An organism not killed or inhibited by drug concentration readily attainable in the patient.

-­‐Resistance to antibiotics was first recognized to sulphonamides in 1935. -In 1941, 6 years after penicillin was introduced 1% of Staphylococcus aureus were resistant to penicillin. -Now, over 90% of S. aureus are resistant to penicillin.

Two Main Types of Bacterial Resistance 1-Inherent (Intrinsic or Innate):

-The properties of the bacterium are responsible for preventing the antibiotic action. -Mediated by the chromosome. Example: Intrinsic resistance to gram-negative bacteria is due to the outer cell membrane which prevents certain antibiotics from reaching their intracellular targets, (not present in Gram-positive cells).

2-Aquired Resistance:

-Occurs when a susceptible bacteria becomes resistant after repeated exposure to a certain antibiotic. -Usually occurs as a result of mutations in the chromosome or by acquisition of genes coding for resistance from an external source (plasmid or transposon).

Genetic bases of acquired resistance

1-Chromosomal mutations: Due to changes in the DNA sequence of the gene (point or frame shift) resulting in development of antibiotic resistance. 2-Exra-Chromosomal Resistance (Plasmids) (R Factors): -Small molecules of DNA [1/10 of the bacterial chromosome], exists away from the nucleoid, can carry from 5 to 100 genes. It often control the formation of enzymes capable of destroying the antimicrobial agents e.g. Chloramphenicol acetyl transferase, ……. -They code for a number of properties including antibiotic resistance. -Plasmids have the ability to transfer within and between species (by conjugation, transduction or transformation), which enhances their ability to transfer antibiotic resistance genes. 3-Transposons: -They are jumping genetic elements capable of transferring or transposing independently from one DNA molecule (chromosomes or plasmids) to another. -The central region of the transposon often codes for antibiotic resistance genes.

1-Decreased permeability of the antibiotic due to alterations in cell membrane structure e.g. Tetracycline and polymyxin. 2- Presence of proteins functioning as efflux pumps that actively remove antibiotic molecules from the cytoplasm to the outside causing low-level multiple antibiotic resistance (MAR) to many unrelated antibiotics e.g. Quinolones, Chloramphenicol, Tetracyclines, Rifampicin & penicillins.

3. Biochemical Mechanisms of Resistance

3- Production of enzymes, which inactivate antibiotics, either through destruction or alteration of the antibiotic molecule. e.g., Staphylococcus produces penicilinase converting penicillin to penicilloic acid. 4- Alterations in the target site which reduce the binding of antibiotics, but allow the target to retain its normal function, e.g., Resistance to Aminoglycosides by developing an altered or by missing a protein on the 30S subunit of ribosomes which does not allow the drug to attach.

5- Overproduction of the target site so that higher antibiotic concentrations are required to exert significant antibacterial action e.g., Trimethoprim, Sulphonamide. 6- Development of altered metabolic pathway that bypass the reaction inhibited by the drug as in case of sulfonamide-resistant bacteria, e.g., they do not require PABA for folic acid synthesis.  

Resistance to β -lactam antibiotics

1- Inactivation of the enzyme:

- β-lactamases hydrolyze the cyclic amide bond in the antibiotic

molecule converting penicillin to penicilloic acid.

- Cephalosporins are subjected to the same mechanism.

2- Alteration in the drug target site:

Alterations in the PBPs affect binding of β-lactam antibiotics.

Example: (MRSA) Methicillin-Resistant S. aureus is a major problem in

hospitals.

3- Reduced permeability:

Changes in the outer membrane porins (proteins) of Gram- negative

bacteria reduces the penetration of β -lactams.

Bacterial resistance to antibiotics could be overcomed by 1- Designing new drugs that are unsusceptible to the enzyme attack (β-lactamase resistant penicillin e.g. cloxacillin). 2- Administration of a combination of 2 or more drugs. e.g. - the combination of a β -lactam with a β-lactamase inhibitor (Augmentin®: amoxicillin/clavulanic acid), - the combination of ethambutol and isoniazid in the treatment of tuberculosis. 3- Development of new drugs that can penetrate the outer membrane of gram-negative bacteria (natural peptides with antibacterial activity). 4- Avoiding repeated exposure of microorganisms to a particularly valuable drug by restricting its use specially in hospitals. 5- Maintain sufficiently high levels of the drug in the tissue to inhibit both the original population and first step mutants.

1. Indiscriminate use of antibiotics leads to the development of

drug resistant strains of bacteria.

2. The indiscriminate use of antibiotics before a definite

diagnosis may mask symptoms and produce atypical infections

which may lead later to serious complications.

3. On prolonged or uncontrolled administration, they may be toxic.

4. Some antibiotics may cause allergic reactions in hypersensitive

individuals (more common in penicillin injection).

Complications of Chemotherapy

5. The prolonged use of broad spectrum antibiotics may suppress

normal flora in the mouth and intestine leading to superinfections

such as those caused by Pseudomonas aeruginosa, Staphylococcus aureus,

Proteus or Candida albicans.

6. The early use of antibiotics in some infections as enterics, may

suppress the formation of antibodies, thus depriving the body

from an important natural defense mechanism.

Drug combinations A combination of two antibacterial agents may produce the following

responses. •  Synergism, 1 + 1 > 2 •  Additive effect, 1 + 1 = 2 •  Antagonism (interference), 1 + 1 < 2

The concept of clinical synergism: 1-To obtain a wider spectrum of activity for treatment of mixed infections. 2-To prevent the emergence of resistant organisms as in combined antituberculus therapy. 3-To reduce the dosage of a toxic drug. 4-To protect the effect of an antibiotic as the case with β-lactamase inhibitor and an appropriate β-lactamase-labile penicillin.

1- Unless there is a valid reason for giving an antibiotic, the patient would probably be better off without it: it include the following -Treatment of known or suspected infection based on a clear clinical

and bacteriological diagnosis e.g. in tonsilitis the suspected bacteria is Streptococcus sp. and penicillin treatment is indicated.

-Prevention of bacterial infection: There are a few definite indications for

prophylactic administration of antibacterial drugs e.g. patients who have rheumatic fever need to be protected, especially during childhood, from Streptococcus pyogenes and so penicillin can safely be given in prolonged low dosage for prophylaxis.

- Pre-operative prophylaxis, starting just before operations involving the

intestine, particularly the GIT, and continued for a few days, can reduce the frequency of wound infection.

-Prophylactic administration of penicillin for patients at special risk of

developing gas-gangrene as in major trauma with soil contamination.

The general principles of antibiotic policies

2-In general it is bad treatment to use broad-spectrum antibiotics when an infective condition can be treated with a more specific agent. 3-In cases when immediate drug treatment is necessary, and initial treatment has to be based on guesses, all specimens necessary for the isolation of the causative organism should be collected before treatment is started otherwise isolation is delayed or become difficult. 4-It is essential to use bactericidal and not bacteriostatic therapy when the patient’s immunological defenses are seriously impaired, or when the infection is overwhelming. An important example is bacterial endocarditis. 5- There are situations in which it is essential to use combination of antimicrobial drugs e.g. in treatment of tuberculosis, to reduce the emergence of resistance and to obtain better results. 6- For treatment of superfacial infections it is important to use antibiotics which are rarely or never used systemically e.g. a spray of neomycin, bacitracin and polymyxin.

7-Antibiotic should be given in the proper dose for long enough period then, stop treatment or change to another drug if the patient is not responding well to the initial drug..

(Sometimes prolonged treatment is required e.g. in treatment of tuberculosis). 8-Avoid the use of antibiotics as food supplement for animals and avoid

liberation of antibiotic powders and solutions into the environment to reduce the spread of microbial resistance.

9-To reduce the emergence of antibiotic-resistant strains in hospitals, use

antibiotics in rotation and keep particular antibiotics for use only on special occasions.