Antibiotics

Introduction

An antibiotic (pl. antibiotics) is a substance that selectively kills (bactericidal) or inhibits (bacteriostatic) growth of bacteria. Below is a compilation of various antibiotics, which are used in veterinary medicine. However, not all antibiotics mentioned below are necessaily registered for use on animals in Sweden or other countries. As for treatments of specific diseases in different species we refer to The Guidelines of the Swedish Veterinary Association (SVF). There you can find all the general guidelines for antibiotic treatment of animals and specific guidelines for small animals, horses and farm animals.

Bacteria may be resistant to some antibiotics and the resistance may be natural or acquired. Natural resistance means that a bacterium is resistant to an antibiotic due to its natural capacity. Mycoplasmas are e.g. naturally resistant to antibiotics which inhibit cell wall synthesis, because they have no cell wall. Acquired resistance means that a bacterium that was initially sensitive to a certain antibiotic, have developed resistance (by selection) because it has been exposed to this antibiotic. Antibiotic resistance is a very large and, unfortunately, growing problem in all health care because prescription of antibiotics has been too liberal in the past, and this is still the case in some countries, even within the EU.

From the National Veterinary Institut's (SVA's) website you can download the so-called SVARM- and SVARM/SWEDRES-reports, which are published annually by the Public Health Agency and SVA. The SVARM and SVARM/SWEDRES-reports provide a summary of antibiotic consumption and the resistance situation in Sweden in both veterinary and human medicine. The ability of bacteria to survive in the presence of an antibiotic can be tested by so-called susceptibility testing. The result of a susceptibility test is expressed as a MIC (Minimum Inhibitory Concentration) value, which has the unit mg/l (= µg/ml). In order to facilitate the interpretation of a MIC value, bacterial isolates are usually classified as sensitive (S), intermediate (I) or resistant (R) depending on the MIC value in relation to the "normal" MIC distribution of the corresponding bacterial species (see below).

Antibiotics are usually divided into different groups depending on their modes of action and chemical structure. Antibiotics, which are mentioned in the SVFs policy document appear in bold when they are first mentioned in the text below.

I. Inhibitors of cell wall synthesis.

A. Beta-lactams, where the so-called beta-lactam ring is included in the structure.

1. Penicillins (e.g. aminopenicillin amoxicillin, ampicillin, benzylpenicillin, phenoxymethylpenicillin, cloxacillin and methicillin).
2. Cephalosporins (e.g. cephalexin, cephalothin, cefotaxime and cefepime). Cephalosporins should be used very restrictively in the treatment of animals as they are also used to treat life threatening diseases in humans. Use of the third and fourth generation of cephalosporins is regulated in the Swedish Constitution SJVFS 2013: 42, Saknr D9.
3. Cefamycins (latamoxef) is similar to the cephalosporins.
4. Carbapenems (e.g. imipenem, meropenem and aztreonam) are currently banned from use in the treatment of animals as they are also used for the treatment of life-threatening diseases in humans (Swedish Constitution SJVFS 2013: 42, Saknr D9, Annex).

B. Other inhibitors of cell wall synthesis.

1. Glycopeptides (e.g. vancomycin and teicoplanin) block the transpeptidation by binding to -D-alanine-D-alanine- in the side peptide of the peptidoglycan. Glycopeptides are today prohibited to use for the treatment of animals, as they are also used for the treatment of life-threatening diseases in humans (Swedish Constitution SJVFS 2013: 42, Saknr D9, Appendix).

Examples of resistance mechanisms:

A transpeptidase is involved in the synthesis of the cell wall of bacteria. This transpeptidase binds to the dipeptide -ala-ala- and links peptides to be included in the cell wall, into a network. The beta-lactam ring is a structural analogue of -ala-ala- and can, therefore, compete with ala-ala which means that a stable cell wall cannot be formed. Mutations in the transpeptidase or other so-called penicillin binding proteins (PBP) may lead to penicillin no longer binding and, therefore, the bacterium becomes resistant.

Some bacteria are naturally possessing a chromosomal or plasmid encoded penicillinase, i.e. an enzyme that hydrolyzes the beta-lactam ring. In the presence of beta-lactams, these bacteria may be stimulated to increase production of beta-lactamase and if the beta-lactamase gene is plasmid-encoded, it can be transferred to other bacteria.

Clavulanic acid, which is a structural analogue of penicillins, can inhibit penicillinases by blocking their active centers. Clavulanic acid is particularly active against plasmid born beta-lactamases and is used therapeutically. Clavulanic acid is not an antibiotic in itself, since it only works in combination with certain beta-lactams.

II. Inhibitors of nucleic acid synthesis.

A. The fluoroquinolones (such as ciprofloxacin, difloxacin, enrofloxacin, ibafloxacin, marbofloxacin and orbifloxacin) inhibit the enzymes DNA gyrase and topoisomerase, which are needed for DNA replication. Fluoroquinolones must be used very restrictive for the treatment of animals because they are also used for the treatment of life-threatening diseases in humans. Use of the third and the fourth generation of fluoroquinolones are regulated in the Constitution SJVFS 2013: 42, Saknr D9.

B. Rifampicin inhibits DNA-dependent RNA polymerase, which in turn blocks the protein synthesis since the synthesis of the mRNA is inhibited. Rifampicin must only be used for the treatment of Rhodoccus-infectioner (Constitutional SJVFS 2013: 42, Saknr D9, Annex).

C. Nitroimidazoles (e.g. dimetridazole, metronidazole and ronidazole) reacts with nucleoproteins under anaerobic conditions, which in turn results in breakage of the DNA helix. Metronidazole is one of the few antibiotics that are effective against Clostridium difficile-induced diarrhea in humans and should, therefore, only be used for animals in exceptional cases. Nitroimidazoles are currently not approved for use on animals in Sweden.

Examples of mechanisms of resistance:

Resistance to fluoroquinolones arise by mutation(s) in the genes for the DNA gyrase and/or topoisomerase, which makes the fluoroquinolones unable to block these enzymes.

III. Inhibitors of protein synthesis.

A. Aminoglycosides (e.g., gentamicin, neomycin, streptomycin and dihydrostreptomycin) bind to the 30S subunit of the bacterial ribosomes and cause misreading of the genetic code.

B. Tetracyclines (chlortetracycline, oxytetracycline and doxycycline) interfere with the aminoacylated tRNA chains and prevents binding of amino acids to the growing polypeptide chain. This effect leads in turn to inhibition of protein synthesis.

C. Chloramphenicol (chloromycetin) inhibits the enzyme peptidyl transferase, linking amino acids to the growing polypeptide chain. This inhibition results in blocking of protein synthesis. Chloramphenicol can cause severe side effects and should absolutely not be used in animals that will go to food production.

D. Macrolides (e.g. tylosin and erythromycin) and lincosamides (e.g. lincomycin and clindamycin) binds to the 23S rRNA of the bacterial ribosome and prevents translocation along the mRNA chain. Ketolides belong to the group of macrolides, but they have a broader bacterial spectrum. Azalides (e.g. azithromycin) and streptogramins also belong to the group of macrolides.

E. Pleuromutilins (e.g. valnemulin and tiamulin) bind to the peptidyl transferase of the 50S subunit, thereby preventing amino acids from connecting with the growing polypeptide chain.

F. Fusidic acid is a steroid derivative, which interferes with the release of elongation factor EF-G when amino acids are coupled to the growing polypeptide chain.

G. Oxazolidinones bind to the 23S rRNA of the bacterial ribosome preventing translocation along the mRNA chain. Oxazolidinones are today prohibited to be used for the treatment of animals, as they are also used for the treatment of life-threatening diseases in humans (constitution SJVFS 2013: 42, Saknr D9, Appendix).

Examples of mechanisms of resistance:

Resistance to aminoglycoside may arise by mutations in the ribosomal proteins, so that the macrolide can no longer bind to the ribosome. Some bacteria carry plasmids encoding aminoglycoside modifying enzymes. Such enzymes inactivate aminoglycosides and can easily spread in a bacterial population.

Lincosamide and macrolide resistance can occur by bacterial methylation of a specific nucleotide in the 23S rRNA or by mutations in the 23S rRNA gene, which result in that the macrolide will no longer bind to the ribosome.

IV. Inhibitors of functions in the cell membrane.

A. Polypeptide antibiotics (such as polymyxin B and colistin) affect cell membrane permeability by binding to LPS, and interfering with phospholipids. This allows the essential metabolites to leak out from the bacterial cell.

B. Cyclic lipopeptides (such as daptomycin) bind to the bacterial cell membrane, which is then depolarized. This leads to inhibition of DNA, RNA and protein synthesis.

V. Inhibitors of different steps in the metabolism.

A. Folic acid antagonists

1. Sulfonamides (eg, sulfa and sulfadoxine) inhibits the synthesis of folic acid by competing with the structural analog para-aminobenzoic acid. Folic acid is a coenzyme required for the synthesis of certain amino acids and nucleotides and which eukaryotic cells can take up from the environment.
2. Trimethoprim inhibits the enzyme dihydrofolate reductase. Sulfa and trimethoprim are often combined to counteract the emergence of resistance.

B. Furantoins (such as nitrofurantoin and furadantin) are transformed by bacterial flavoproteins to reactive intermediates, which inhibit bacterial energy metabolism as well as the synthesis of DNA, RNA, proteins and the cell wall. Furantoins affect so many different steps in of bacterial metabolism and, therefore, resistance does not easily arise. Consequently, furantoins are used against urinary tract infections in primarily dogs to reduce the use of aminopenicillins, against which resistance is more easily incurred. Resistance against furantoins occurs, but is uncommon.

Examples of mechanisms of resistance:

Point mutations in the genes for some of the enzymes involved in the synthesis of folic acid may lead to resistance because these modified enzymes are no longer blocked. Enterococci are naturally resistant to sulfonamides because they absorb folic acid from the environment.

VI. General mechanisms of resistance:

By decreased permeability or increased efflux, bacteria can develop resistance mechanisms, which are effective against different types of antibiotics. Decreased uptake may be due to mutations in porins and increased efflux may be due to mutations in the so-called efflux pumps. Efflux pumps are protein complexes which can pump the drugs out of the cell by active transport. Most often, the natural substrates of efflux pumps are bile salts, adhesins, toxins and other proteins.

VII. Abbreviations

ESBL, means "Extended-Spectrum Beta-Lactamases", which implies that the bacterium has a beta-lactamase with extended spectrum (can hydrolyse different kinds of beta-lactams). ESBL is sometimes used, a bit sloppy, for a group of multi-resistant bacteria, but is actually a name given to a group of enzymes, which are present in some multi-resistant bacteria. ESBL confer resistance to penicillins and many cephalosporins. ESBL are often plasmid encoded and may be transmitted between gram negative bacteria.

ESBL-CARBA (or ESBL_CARBA), is the term for a mechanism of resistance in enteric bacteria, which causes resistance to most penicillins, cephalosporins and carbapenems. In Sweden, findings of ESBL_CARBA in animals are notifiable to the County Administrative Board and the Board of Agriculture.

MRS means Methicillin Resistant Staphylococci. MRS is a designation for staphylococci in general, which is resistant to all penicillins (such as methicillin) and cephalosporins. In Sweden, findings of MRS in animals are notifiable to the County Administrative Board and the Board of Agriculture.

MRSA means Methicillin Resistant Staphylococcus Aureus. MRSA is the designation of Staphylococcus aureus strains, which are resistant to all penicillins (such as methicillin) and cephalosporins. In Sweden, findings of MRSA in animals are notifiable to the County Administrative Board and the Board of Agriculture.

MRSP means Methicillin Resistant Staphylococcus Pseudintermedius. MRSP is the designation of Staphylococcus pseudintermedius strains, which are resistant to all penicillins (such as methicillin) and cephalosporins. In Sweden, findings of MRSP in animals are notifiable to the County Administrative Board and the Board of Agriculture.

VRE means Vancomycin Resistant Enterococci.

VIII. More information

More information about the antibiotic resistance situation and antibiotic consumption in various European countries (including Sweden) can be obtained on the website of the European Centre for Disease Prevention and Control when clicking on "Health Topics" and then select "Health Topics A-Z" and then "Antimicrobial resistance". There you can select e.g., "Antimicrobial resistance interactive database (EARS-Net)" under Interactive Databases. Another important source of information on antibiotic susceptibility in the form of MIC values is the website EUCAST (European Committee on Antimicrobial Susceptibility Testing), where you can search a database for a specific antibiotic or a particular bacterium.