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Contents
INTRODUCTION........................................................................................................... 1
CHAPTER 1. ANTIBIOTICS: DEFINITION, CLASSIFICATION, MECHANISMS OF ACTION. .3
1.Definition.............................................................................................................. 3
1.2 Main classes of antibiotics................................................................................. 3
Chapter 2. Genetic and biochemical resistance to antibiotics in the main Grampositive and Gram-negative bacterial strains of clinical importance........................10
2.1 Natural resistance vs acquired resistance.......................................................16
2.2. Chromosomal versus plasmidial resistance....................................................20
2.3. Biochemical mechanisms of antibiotic resistance..........................................23
BIBLIOGRAPHY:......................................................................................................... 26
INTRODUCTION
For half a century, antibiotics are the most important weapon in the fight against
dangerous infection-causing bacteria from the ear and the skin infection to the blood infection.
Infectious diseases causing thousands of deaths and much suffering in the past, such as
tuberculosis, are now under control with antibiotics.1
Despite their undeniable importance in modern medicine, these drugs are not always the
best therapeutic solution . There are two main types of germs that cause bacterial infections and
viruses. The most important points to note are:
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q=antibiotice&es_sm=122&source=lnms&tbm=isch&sa=X&ved=0CAcQ_AUoAWoVChMIo7kj4zHxwIVSEAUCh3DvA_O&biw=1024&bih=475#tbm=isch&q=antibiotice+pentru+raceal
a
- Gramicidin
- Bacitracin
- Polymyxins
- Streptomycin
- Neomicima
- Kanamycin
- Nystatin
- penicillin
- grizeofulvin
3. After biogenesis:
- antibiotics derived from amino acids
- from acetate units
- from carbohydrates
4. After pharmacological action:
- Antibacterial antibiotics
- Antituberculosis antibiotics
- Antiviral antibiotics
- Anticancer antibiotics
- Antifungal antibiotics
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&ust=1440690451933819
It may not be administered orally because it is inactivated by stomach acid. It is usually given
intramuscularly, intravenously in severe cases. PenicilinaG can be potassium or sodium. A
patient with heart failure will prefer PenicilinaG potassic, because sodium attracts water and
overweight self circulation. A patient with kidney failure will prefer PenicilinaG sodium
because sodium is eliminated through the kidneys easier.
Penicillins have degenerative bactericidal effect (kills bacteria multiply). Prevents bacterial
wall synthesis.
1.2. Cephalosporins
Broad-spectrum antibiotics are indicated in serious infections that do not respond to other
antibiotics. Some are taken orally: cephalexin, cephalothin, cefuroxime (Zinnat)), others only by
injection (parenteral): Latamoxef, cefepime, cefpirome. If a person had a serious allergic reaction
to penicillin we recommend to avoid cephalosporin because of the risk of cross-allergy .
2. Aminglicozide: Streptomycin, gentamicin, kanamycin, neomycin.
These antibiotics are not used alone, because germs are quickly becoming resistant to them.
Always use together with other antibiotics.
Streptomycin is used to treat tuberculosis TB together with other chemotherapeutic agents.
Gentamicin and Kanamycin is associated with penicilinaG.
If taken digestive, these antibiotics are not absorbed. However sometimes it is administered
digestive to treat intestinal infections (enteritis, enterocolitis). For other infections
(tuberculosis, urinary tract infections, genital infections, bronchitis etc) aminoglycosides are
Antibiotic
Betalactamine
(penicillins, cephalosporins,etc.)
Aminoglycosides
Quinolones
Macrolides
Vancomycin
Tetracilcine
Chloramphenicol
Sulphamides
Trimethoprim
Nitrofurans
Nitroimidazoles
http://europroxima.com/products/antibiotics/nitrofurans/
- intrinsic ability of bacteria to resist certain antibiotics - a greater scientific and clinical
importance is the acquired resistance.
Resistance to antibiotics can occur through natural selection or by mutation (in the
mutagenic effect of environmental factors or uncorrected errors in the DNA replication process).
With emerging antibiotic resistance, gene coding for this character may spread to other cells
through transfer of plasmids. A bacterium can use multiple antibiotic resistance gene, in this case
being called multi-resistant.7
Antibiotic resistance of a microorganism can also be artificially induced , by
transformation techniques (introduction of foreign genetic material into the cell and expression
of encoded characters). This method is useful in genetic engineering and biotechnology for the
selection of bacteria bearing a specific additional character, transmitted along with the gene of
resistance.
The emergence of antibiotic resistance is a evolutionary phenomenon, caused by selective
pressure of environmental factors. Antibiotics are a selection factor and the bacteria that suffers a
benefical mutation (the emergence of resistance to antibiotic) will survive and will possibly send
these characters to descendants. The increasingly frequent use of antibiotics to treat infections
resulted in emergence of a growing number of bacterial strains resistant to a growing number of
antibiotics.
There are several mechanisms by which this phenomenon may occur:
o inhibition of penetration of the antibiotic into the cell - for example the resistance
mechanism of E. coli to macrolide
o Eliminating antibiotic (active efflux) - seen in some species of E. coli and S. aureus.
The natural result of the discovery of this phenomenon was the continuous search of new
antibiotics capable of inactivating microorganisms resistant to antibiotics already available.
However, it was found that after a certain time from the introduction of a new semi-synthetic
antibiotic, or a new class of antibiotic, the existance of resistant bacterial strains is, due to the
fact that antibiotic resistance is an evolutionary phenomenon. 9
Among the examples of continual evolution and adaptations of pathogenic bacteria to new
antibiotics, are increasingly frequent cases of multi-resistant tuberculosis and infections with
methicillin-resistant Staphylococcus aureus.
The concept of microbial resistance defines the ability of pathogenic germs to survive
and multiply in the presence of antibiotics. The germs are resistant or become "indifferent"
("tolerant") to antibiotics, thereby avoiding desired antibacterial effect through various ways ,
following multiple usual non-toxic doses . When exposed to an antibiotic, the bacteria is the
8
Conform http://www.britannica.com/science
9
selected for resistance . This natural biological process leads to the survival of the resistant
strains (FEDES, 2000).
After HEINEMANN (1999), antimicrobials are approaching the end of their
effectiveness. Although evolution of resistance to these drugs was expected, mechanisms by
which genes conferring resistance will spread were not intuited . Therefore antimicrobial agents
used in the future must avoid effects caused by pathogens.
Clinical resistance
Clinical resistance is more complex than microbiological resistance, since it is linked to
the likelihood of response to antimicrobial therapy. Prior to treatment, information concerning
the susceptibility of the bacteria involved in the infection are received from specialized
laboratories, although not fully reflects the antibacterial activity of antibiotics in clinical
conditions (Swartz, 2000).
Pseudo-resistance or false resistance
It represents the failure of antibiotic treatment due to characteristics of the host organism
and of the infection and especially incorrect use of antibiotics. Pseudo-resistance is a temporary
phenomenon, reversible, which shall be exercised only in vivo. In clinical terms, the
development of resistance is facilitated by pharmacokinetic characteristics of different classes of
antibiotics and an incorrect treatment (insufficient dose , too short duration of treatment or longterm use of antibiotics), as well as inefficient active concentration of the antibiotic at the place of
infection (hard sterilizable outbreaks,serous barriers, avascular tissue, inactivation of antibiotics,
unfavorable pH etc.). Another cause of treatment failure is relative resistance to
pathogens,sensitive in vitro, but became insensitive, usually temporarily, in vivo (persisters,
germs with reduced metabolism).
Moreover, other factors such as the immune status of the patient may affect the
therapeutic response. In most patients, antibiotics do not totally destroy pathogens, but assists the
immune system in an attempt to eliminate the infection. An enormous selection force is the large
amount of antibiotics used in agriculture as well as the therapy and prophylaxis of human and
veterinary medicine (HARDY, 2002; CROMWELL, 2002; DIBNER et al., 2005).
Microbial resistance to antibiotics can be natural and acquired: natural resistance is the
resistance of all members of a bacterial species to one or more antibiotics present in the
maximum dose tolerated by the treated body without risk, doses that can inhibit growth or
destroy other bacterial species . After ENGELKIRK Burton (2002), natural resistance is the
intrinsic property of the species thus total, genetically fixed. For instance, the resistance to
penicillin G of the strains of Salmonella;
Pseudomonas aeruginosa is naturally resistant to chloramphenicol; Proteus genus species
are resistant to tetracycline; anaerobes (Bacteroides, Clostridium, some streptococci) and Serratia
genus are resistant to aminoglycosides. Acquired resistance refers to the state arising from
naturally sensitive species after the entering of an antibiotic into therapy and consists in
decreasing or cancellation of antibiotic sensitivity.10
This is a phenotypic character correlated with an altered genetic material. In practice, the
bacteria is considered resistant when there is an subunitary ratio between medium serum levels
supported by the patient and minimum inhibitory concentrations of the antibiotic or antibacterial
(TODAR, 2002). Until now several acquired resistance types are known, and are classified by
various criteria:
a. The moment infection is installed
The primary resistance, the state of resistance of the bacteria at the initiation of the
infection. Secondary resistance, state acquired by infected strain during treatment.
b. The number of antibiotics to which resistance is installed. Mono-resistance - microbial
resistance to a single antibiotic. Multi-resistance - microbial resistance to several antibiotics.
c. The rate of installing resistance to antibiotics. Streptomycin fast resistance type ,
consists of a single stage (single mutant, interesting only one gene). Penicillin-type progressive
resistance constituted in several steps (successive mutations, interesting multiple processes)
d. The presence of antimicrobial factor. Inducible resistance - expressed only in the
presence of antibiotic resistance. Constitutive resistance - the ability of a gene to continuously
express their resistance independent of the presence or absence of the antibiotic.
e. Other types of resistance. Cross-resistance - the ability of some strains to manifest
resistance to some antibiotics related by chemical structure. Adaptive resistance - a condition
which, without interesting the genome is sometimes transmitted to successive generations and
which appears under the influence of subinhibitory doses of antibiotic, bacteria returning to its
previous state after several generations from the disappearance of inducing factor
(ANGELESCU, 1998; Swartz, 2000).
10
11
Swartz, 2000
For children with symptoms like fever, fatigue, muscle pain or irritated throat, do not quickly
conclude that they contacted bacteria . Most often, it is a common cold, against which antibiotics
have no effect. Carry out a pediatric inspection and help children fight viral infection by
- Prolonged bed rest;
- Additional hydration by water, fruit juices, soups and tea;
- Anti-inflammatory drugs based on ibuprofen;
- Nasal sprays with saline solution and cough syrup;
- Steam baths;
Prevention of antibiotic resistance depends largely on healthcare professionals, who are
the only ones authorized to issue prescriptions on which patients can purchase antibiotics. They
must:12
- Prescribe antibiotics correctly (crop sampling, performing sensitivity testing, establishing the
required dosage and administration period, issuing the prescription after the patient has been
tested properly).
- To document on the dose, timing and indications on the prospectus of antibiotics sold in
pharmacies.
- constantly worrying about the high degree of risks in the preading of antibiotic resistant
bacteria in the medical unit in which they work.
- Attend and support all measures taken by hospital practices and authorities, to discourage
improper antibiotic prescriptions for patients.
- Respect all rules of hygiene and other infection control measures with each patient treated.
- Inform patients about the dangers they face when abusing antibiotics.13
12
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13
Swartz, 2000
14
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Efflux phenomena
This system occur naturally in certain bacteria. Also in P. aeruginosa, such a system
largely explains the high natural resistance against a large number of antibiotic molecules. This
system exists in staphylococci against quinolones.
Gained resistance
First resistance efflux acquired by E. coli was reported in 1980. It was the tetracycline excretion.
Since then, this resistance mechanism has been revealed to:
- E coli, P. aeruginosa and Staphylococcus aureus against quinolones;
- staphylococci against macro-LIDE ;
- P. aeruginosa against beta lactams;
This may involve acquiring resistance genes as a result of introduction of a plasmid or, most
often, a mutation engaging existing chromosomal gene overexpression but little or no casted.
15
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257838/
16
Swartz, 2000
After cell penetration of the antibiotic, there is a stage of target recognition.This type of
resistance occurs at the remembered level. It's either a natural resistance with a weak affinity of
certain antibiotics for targets, or a resistance acquired with the modification of targets and the
affinity loss to antibiotics for these targets.
Natural resistance
Various molecules in the family does not have all the same affinity for the bacterial targets.
Aztreonam (monobactams) has weak affinity for the PLP of Gram-positive and rigorous
anaerobic bacteria , which explains their natural resistance against this antibiotic.17
Likewise, first-generation quinolones (nalidixic acid and pipemidic) have only weak affinity for
DNA gyrase Staphylococcus.
Acquired resistance
This type of mechanism is responsible for a large number of acquired resistance. We quote
Staphylococcus resistance against beta-lactams. It is about the acquisition of genetic material
(mecA gene). This gene encodes the synthesis of a new PLP: PLP 2a or 2 'which possesses a
weak affinity for beta-lactams, whatever the molecule, also explaining cross-resistance against
the whole family.
Similarly, Streptococcus pneumoniae, sensitive to penicillin G is no longer sensitive
(only in 40% of the cases in France). The acquisition of foreign genes by transformation from
other streptococci or pneumococcus is responsible for this resistance.
17
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257838/
Quantitatively and qualitatively, this type of mechanism is certainly the most important.
Many classes of antibiotics and virtually all bacterial species are concerned. To be active, the
antibiotic must reach its target intact. If there is modification of the antibiotic by enzymes present
in bacteria, at any level, modified form of the antibiotics molecule is most often inactivate.
These enzymes occurr naturally or acquired at bacteria of clinical interest .
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certain bacteria produce enzymes that inactivate aminozide.This is the case of Serratia marcescensus , that inactivates tobramycin, netilmicin and amikacin, as the Providencia stuartii that
inactivates gentamicin, tobramycin and netilmicin.19
Accquired resistance
Following the beta-lactams described, it is clear that it is important to detect MECA-resistant
organisms through the acquisition of enzymes. Geneticaly , beta-lactamases should distinguish
the plasmid origin from the chromosomal origin. In most cases, it is a genetic material
acquisition through plasmids. We are talking about plasmid resistance . Depending on their
spectrum of activity, we organize:in penicillinases, as staphylococci; in broad spectrum senior
penicillinases and beta-lactamases, as the enterobacteria.
If we talk about aminozide, there arevnumerous inactivating enzymes of plasmid origin .
Depending on their type, they are responsible for the inactivation of one or more molecules used
in clinical gentamicin, tobramycin, netilmicin or amikacin. They are frequent in
Enterobacteriaceae, Pseudomonas and, more frequently, in staphylococci.
Another mechanism of acquiring resistance is often seen in Gram negative bacteria. This is betalactams. This is no longer foreign gene, but mutations in genes that govern the synthesis of
natural cephalosporinase. This is no longer synthesized at low levels, but at a very high level,
responsible for inhibiting a greater number of molecules of beta-lactams.
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%2Fext1731.html&ei=ieHdVZq5DMW5UcaXuegN&psig=AFQjCNFZyG666dmesjr5qT2Qae2l0L
R5OQ&ust=1440690949701197
21
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and are final. However, the number of resistant mutants will decrease after the end of exposure to
the antibiotic (Swartz, 2000).
In a population exposed to an antibiotic, development of chromosome resistance is
usually a gradual process, careful monitored, carried out through several consecutive mutations;
However, for some antibiotics a single mutation may determin resistance resulting in an intense
increase of MIC. The emergence of resistant mutants is much less frequent in vivo than in vitro,
probably because mutations leading to resistance are usually associated with other cellular
changes that may be disadvantageous for bacteria. For this reason, some scientists see the
development of resistance determined by mutations on chromosome as a small problem
compared with transferable resistance. However, in practice, these mutations have little
significance due to the fact that rarely occur (10%) (Jackson et al., 2004).
Transferable resistance.
Bacteria have extremely efficient genetic transfer systems capable of exchanging and
accumulating resistance genes. Some genes, including genes which encode resistance, can move
between the elements of chromosomal and extrachromosomal DNA of the bacteria.
Extrachromosomal mutations are more frequent (90%), so of great practical importance. Genes
can be transmitted between bacteria of the same species or different species or different genres of
bacteria (horizontal transfer), that have common habitat in the body. Interspecies transfer means
that, once transferable resistance gene have occurred, the bacteria carrying the gene will remain
a potential donor for other bacterial genes (Agerso et al., 2005).
The most important carrier for the transfer of resistance genes in bacteria are plasmids,
transposons and integrons (Swartz, 2000). As specified by McDermott (2002), in recent years a
number of resistance genes have been associated with the massive transfer of extrachromosomal
DNA elements called plasmids, which can be other mobile DNA elements such as transposons
and integrons.
It has been shown that these mobile elements transmit genetic determinants of
antimicrobial resistance mechanisms and they matter in the dissemination of resistance genes
between different bacteria. Plasmids are extrachromosomal DNA molecules, replicable, which
may contain resistance genes (MARBLE, 1999). Replication is independent of chromosomal
DNA.22
They are important in the development of bacterial plasmids, since they affect the
replication, metabolism, bacteria fertility, as well as resistance to bacterial toxins (bacteriocins),
antibiotics and bacteriophages, thus ensuring a better chance for survival and propagation.
However, the general plasmids are not strictly necessary for the survival of the bacteria. They
have been identified in the majority of bacterial species, having the ability to be transferred
(conjugative), or co-transferred (non-conjugative) from a bacterium to another, thereby leading
to a wide dissemination of the plasmid-encoded characteristics within an ecosystem.
The genes encoded by the plasmid is inherently more mobile than chromosomal genes
because plasmids can be transferred within a bacterial species or between different species
(Swartz, 2000). R-plasmids are plasmids containing the resistance gene (AOKI, 1993, KIM. Et
al., 1996, Diaz et al., 2006). The purchase of new resistance determinants may occur more
rapidly than the R-plasmid genetic mutation.
One R-plasmid may encode resistance simultaneously to more than 10 different
antibiotics. There have been found many different r-plasmids. A single bacterial cell may contain
several different plasmids and each plasmid may have more resistance genes. Plasmids isolates
from human and veterinary seem to be very similar, suggesting even their transmission from
animals to humans (WRAY C. et al., 1986) or from humans to animals (Sannes et al., 2004).
Dissemination of plasmids can occur through clonal distribution and intra- and inter-species
transfer, leading to a gradual increase in the proportion of microorganisms in a bacterial
community transporting one or more factors R.23
Transmission of plasmids from one bacteria to another is done in several ways: conjugation (recombinant) - by sexual pili; - Transducing phage - the plasmid is taken from a
bacteriophage, and transferred to a plasmid-free bacteria; - Transformation - the plasmid is taken
22
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23
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3257838/
Gene cassettes are elements that include a single gene and a place ("Site") of
recombination. More than 40 cassettes have been identified, , and all but 5 of them contain the
resistance gene (Agerso et al., 2005). One of the conserved regions of integrons contains
integrase gene, which is responsible for specific insertion at the place ("Site") in the boxes
(Swartz, 2000). Integrons can be located in chromosomal DNA, but more often are located in
plasmids (Diaz et al., 2006) or transposons and are therefore mobile. For example, the
chromosome resistance characteristic pattern of Salmonella typhimurium DT104 is associated
with the presence of integrons (Swartz, 2000).
Bacterial resistance to antibiotics, both the natural and acquired resistance, is achieved
through a variety of mechanisms (ANGELESCU, 1998):
1.Enzymatic inactivation of antibiotics, resistant plasmids and, more rarely, the
chromosomes, encodes enzymes of antibiotics inactivation . We know several categories of
genes encoded plasmid phosphotransferase or transposable elements that often gives them a high
level of resistance. Aminoglycosides are modified by these enzymes at the level of amino and
hydroxyl groups especially through mechanisms of phosphorylation, acetylation or adenilare,
and these changes lead to inactivation of antibiotics.
Inactivating enzymes of chloramphenicol. Resistance is likely a plasmid and is due to the
production of an enzyme by the bacterium, acetyltransferase, causing antibiotic acetylation,
resulting its inactivation.
2. Antibiotic resistance through bacteria changes a. modifying the permeability of bacterial
coatings
Structural alterations of bacterial coatings - outer membrane permeability reduction by
reducing the synthesis of porins so as decreasing the number of functional porins applicable
gram-negative bacteria which are in this manner impermeable to betalactamine and quinolones development of impermeable cell walls due to extremely narrow porins for example
Pseudomonas aeruginosa compared to multiple antibiotics - strengthening the barrier function of
the outer membrane proteins by producing additional intercalated protein in its complex
structure. thus producing E. coli tetracycline resistance - reducing bacterial wall permeability
through the loss of a outer membrane protein . resistance of bacteria compared to
chloramphenicol - reducing bacterial permeability deficient in intracellular penetration of
antibiotics is performed compared to sulfonamides, trimethoprim, nitrofurans, nitroimidazoles
modification of active antibiotics transport systems through bacterial coatings for example
Pseudomonas aeruginosa compared to aminoglycosides
b. alteration of headquarters - the target of inhibitory activity of the antibiotic - modification of
PBP (penicillin binding proteins), inserted proteins on the external membrane of the cell, as
action target: betalactamine - ribosomal protein modification target: aminoglycosides,
tetracyclines - macrolides, lincosamides, glycopeptides also determined the modifying of the
target of action - reducing the affinity of action for quinolones is caused by a structural change in
DNA gyrase. 25
25
c. Active efflux of antibiotics in the bacterial cell - impedes the effective concentrations of
antibioticsin the cell : tetracycline, fluoroquinolones (Staphylococcus aureus), erythromycin
d. modifying enzymes: dihidropterat synthase (DHPS) for sulfonamides and dihydrofolate
reductase (DHFR) to trimethoprim, so that the chemotherapeutic agents can not achieve
competition with the enzymes involved in folate synthesis
e. lack of action of some enzymes: nitrofuran-reductase in the case of nitrofurans and nitroreductase in the case of nitroimidazoles
f. the acquisition by the bacteria of some enzymes - esterase, nucleotidiltransferases, enzymes of
plasmid origin, changes macrolides and lincosamides .
g. metabolite increased production of the antimicrobial agent is in competition - increasing
paraaminobenzoic acid synthesis (APAB) cancels competitive inhibitory action of sulfonamides.
Therefore, given the complexity of resistance to antibiotics and continued growth of this
phenomenon, constant surveillance is needed, involving medical- veterinary laboratories and the
empowered authorities worldwide.
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