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Antibiotics

Antibiotics

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Antibiotics

Brief history
Erlich: formulate the hypothesis of selective toxicity for drugs against bacteria 1909 - Salvarsane for syphilis treatment (arsenic compound) 1928- Fleming descovered penicillin 1940 - Florey and Chain – industrial production of penicillin

The photo (courtesy of Merck & Co., Inc.) shows how the growth of bacteria on the agar in a culture dish has been inhibited by the three circular colonies of the fungus Penicillium notatum. The antibiotic penicillin, diffusing outward from the colonies, is responsible for this effect. Today, penicillin is made from cultures of Penicillium chrysogenum that has been specially adapted for high yields.

Definitions
An antibiotic is a substance produced by a microorganism, which, in minute amounts, is able to inhibit other microorganisms. Therefore, this term is properly applied only to compounds directly derived from microorganisms. An antibacterial agent is any compound – natural, synthetic or semisynthetic – that is clinically useful in the treatment of bacterial infections.

Bacteriostatic vs. bactericidal
Bacteriostatic agents (ex. sulfonamides, chloramphenicol) inhibit bacterial growth. Bactericidal agents (ex. penicillin, streptomycin) significantly reduce (99.9%) the number of viable bacteria in the culture (killing effect). Bactericidal effect in vivo is obtained in cooperation with host’s defense mechanisms.

Narrow versus broad spectrum

Narrow spectrum antibacterial agents are preferentially active against either gram-negative or gram-positive bacteria. Broad-spectrum antibacterial agents are active against both gram-positive and gram-negative bacteria.

Concentration versus time dependent antibacterial agents
Concentration dependent antibacterial agents – the antibacterial effect depends on the achievement of high concentrations; it doesn’t matter for how long this concentration lasts (e.g., gentamycin).

Concentration vs. time dependent antibacterial agents
Time dependent antibacterial agents – the antibacterial effect depends on the achievement of active concentrations according with period of time when active concentration > MIC (minimum inhibitory concentration); the raise of the dose doesn’t improve the antibacterial effect (e.g., beta-lactam antibiotics).

Qualities of the ideal antimicrobial drug
 selective toxicity;  broad antimicrobial spectrum;  good diffusion in the tissues;  good persistence in active form;  it should not produce hypersensitivity reactions (allergy or anaphylactic shok*);  bacteria should not develop resistance;  cheap.

* Skin test (+), and an anaphylactic reaction (dyspnea, hypotension, urticaria)

General criteria for effective antibiotic activity
Microorganism Antibacterial agent Host

General criteria for effective antibiotic activity
Microorganism An unique and vital target (specific protein or nucleic acid), that is susceptible to low concentration of the antibacterial agent, must exist in the organism; this target must be sufficiently different from the host’s target in order to minimize side effects (ex. peptidoglycan).

Antibacterial agent
The antibacterial agent must be able to penetrate the bacterial surface and reach the target in its active form. The antibacterial agent needs to reach the infected tissue. (e.g., the treatment of bacterial meningitis is difficult because many common antibacterial agents do not effectively cross the blood-brain barrier).

Antibacterial agent
Infections with intracellular organisms or facultative intracellular organisms are difficult to be treated because many antibacterial agents do not diffuse well into mammalian cells. Tetracyclines, however, are usually effective against intracellular bacteria.

Host
Intact immune system. The immune system of the host must be able to collaborate effectively in the fight against the invading organism. The integrity of the phagocytes is particularly important. Bacterial infections are difficult to be treated in neutropenic patients and in those with primary or secondary immunedeficiencies.

Host - Irrigation and drainage.
Impaired blood supply or drainage of the infected area usually diminishes the efficiency of the antibacterial therapy. Bacterial endocarditis, osteomyelitis, and abscesses are associated with minimal irrigation of the infected tissue.

Host - Irrigation and drainage.
Bronchiectasia (lung disease), kidney stones, and gallbladder stones impair drainage of bronchial secretions, urine and bile, respectively; this may be the cause to extremely difficult to treat bacterial infections, unless the obstruction or anatomical abnormality is surgically removed.

Principles of effective antibacterial therapy
Selective use. Antibacterial treatment should be given only when necessary, for the treatment of confirmed bacterial infections. The empirical use of broad-spectrum antibiotics increases, by selection, the prevalence of bacteria resistant to several antibiotics.

Principles of effective antibacterial therapy
Collection of clinical specimens useful for the identification of the etiological agent ALWAYS before the start of the antibacterial therapy.

Principles of effective antibacterial therapy
Criteria for the choice of the antibacterial agent: Clinical criteria: e.g., scarlet fever, erizipelas, are produced only by Streptococcus pyogenes that remains sensitive to penicillin. Epidemiological criteria, showing the prevalence of resistant strains among bacteria isolated in that specific area.

Principles of effective antibacterial therapy
Bacteriological criteria: e.g., microscopic examination, antigenic detection (immediate results) offer some indication (Gram positive cocci, etc) susceptibility tests (results in 48 hours from the collection of the specimen).

Criteria for the choice of the antibacterial agent:
Other criteria: - the site of infection (the drug has to realize active concentrations in the site of infection); - according to the patient: age, pregnancy, immune-depression.

Principles of effective antibacterial therapy
Early treatment: when antibacterial therapy is indeed necessary, it should be promptly initiated. Administration: dose, way, duration. Inadequate use of antibacterials (e.g., doses that are too low; therapy is ended prematurely) is a major factor for the selection of resistant strains.

Principles of effective antibacterial therapy
Special situations: infections in poorly irrigated tissues should be treated with bactericidal antibacterial agents. when abscesses have formed or the infection is associated with obstruction or foreign bodies, surgery is essential to correct the conditions that promote bacterial survival.

CLASSIFICATION
A. Antibacterial agents that inhibit the cell wall synthesis B. Antibacterial agents that alter the function of the cytoplasmic membrane C. Antibacterial agents that inhibit the protein synthesis D. Antibacterials that inhibit the nucleic acid synthesis

CLASSIFICATION
A. Antibacterial agents that inhibit the cell wall synthesis B. Antibacterial agents that alter the function of the cytoplasmic membrane C. Antibacterial agents that inhibit the protein synthesis D. Antibacterials that inhibit the nucleic acid synthesis

Antibacterial agents that inhibit the cell wall synthesis
Beta-lactam antibacterial agents Glycopeptides Phosphomycine Cicloserine Bacitracine

Beta-lactam antibacterial agents

Penicillins Cephalosporines Carbapenemes Monobactam

Penicillins
penicillins are compounds produced and released by fungi from genus Penicillium. Chemistry. All penicillins are derived from 6-aminopenicillanic acid. The antibacterial and pharmacological properties of different penicillins depend on the side chain attached to the nucleus.

Penicillin - Mechanism of action.
The bacterial targets of penicillins are known as penicillin binding proteins (PBP): transpeptidase, carboxy-peptidase, autolytic enzymes. The inactivation of transpeptidases and the activation of autolysins result in the rapid destruction of peptidoglycan and dissolution of the cell wall, which leads to bacterial lysis.

Penicillin and bacterial resistance
Some bacteria produce enzymes that inactivate beta-lactams, known as beta-lactamases.

Penicillins classification
Natural Semi-synthetic penicillins

Antibacterial spectrum
Natural penicillins are narrow spectrum antibiotics that are primarily active against gram-positive bacteria (enterococci are only inhibited), gram-negative cocci, Treponema pallidum and most anaerobes (except Bacteroides fragilis).

Antibacterial spectrum
Penicilinase resistant penicillins (group M penicillins): methicillin, oxacillin, nafcillin, cloxacillin, dicloxacillin. Penicilinase resistant penicillins are preferred for the treatment of Staphylococcus aureus infections, which have a high frequency of beta-lactamase positive isolates. Otherwise, these penicillins have the same spectrum of bacterial susceptibility as the natural penicillins.

Extended spectrum penicillins
This group includes:  aminopenicillins (ampicillin, amoxicillin);  carboxypenicillins (carbenicillin, ticarcillin);  ureidopenicillins (azlocillin, mezlocillin, piperacillin); amidinopenicillins (mecilinam).

Extended spectrum penicillins
They are effective against a great variety of gram-positive and gram-negative bacteria. Some of these broad-spectrum penicillins, such as carbenicillin, piperacillin, are active against Pseudomonas. Broad-spectrum penicillins are penicillinase susceptible. The concomitant use of beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) can reduce this susceptibility.

Beta-lactamase inhibitors
They don’t have important antibacterial effect, but they block the beta-lactamase activity, excepting chromosomal cephalosporinases. E.g., clavulanic acid, sulbactam, tazobactam. Associations: amoxicillin + clavulanic acid; ticarcillin + clavulanic acid; ampicillin + sulbactam.

• • •

17.11

Toxicity
Because the bacterial target of penicillins are enzymes unique to bacteria, generally, the penicillins have very limited toxicity. The most severe side effects are allergic reactions, which depend on individual predisposition (anaphylactic shok).

Cephalosporines - classification
• The cephalosporines are classified into 4 generations, roughly parallel to their chronological development. • First generation cephalosporines. E.g., cephazolin, cephalotin (injectable), cephalexin (oral). • Second generation cephalosporines. E.g., cephamandole, cephuroxime, cefoxitine (injectable), cefaclor (oral).

Cephalosporines - classification
Third generation cephalosporines. E.g., cephotaxime, ceftriaxone (injectable), cephixime (oral). Fourth generation cephalosporines. E.g., cefepime, cefpirome.

Cephalosporines – antibacterial spectrum
Cephalosporines are active against a wide variety of bacteria and are considered wide spectrum antibacterials. Most cephalosporines are resistant to staphylococcal penicillinases. Second and third generation cephalosporines are resistant to most beta-lactamases produced by gramnegative bacteria.

Cephalosporines – antibacterial spectrum
Only some second-generation cephalosporines are active against anaerobes (e.g., cefoxitine, cefotetane). Some third and fourth generation cephalosporines are active on Pseudomonas aeruginosa (e.g., ceftazidime, cefoperazone, cefepime, cefpirome).

Cephalosporines – toxicity
Because the structures of cephalosporines and penicillins are similar, 10-15% of the patients allergic to penicillin may be allergic to cephalosporines, too. Cephalosporines are more toxic than penicillins; the most toxic are the first generation cephalosporines.

Other beta-lactam antibacterial agents
Carbapenems (Imipenem, Meropenem). These agents have a very broad antibacterial spectrum (grampositive and negative, aerobic and anaerobic organisms). They are resistant to betalactamases. They are not active on methicillinresistant staphylococci.

Other beta-lactam antibacterial agents
Monobactams (Aztreonam) are effective against a narrow spectrum of aerobic gram-negative bacteria, including Pseudomonas. They are resistant to beta-lactamases.

Cycloserine
Mechanism of action: inhibits incorporation of D-alanine into an oligopeptide in the cytoplasm. Cycloserine is rarely used, as a second line antimycobacterial drug. It is ototoxic (particularly when given parenterally) and should not be used unless absolutely necessary.

Glicopeptides (vancomycin, teichoplanin)
Mechanism of action: they block incorporation of new subunits in the peptidoglycan molecule.

Glicopeptides (vancomycin, teichoplanin)
Antibacterial spectrum and administration: Vancomycin is the first choice antibiotic in infections produced by methicillin resistant staphylococci (MRSA) and penicillinase producing enterococci. Glicopeptides are macromolecules and can’t cross the gram-negative membrane.

Glicopeptides (vancomycin, teichoplanin)
They must be given parenterally in the treatment of systemic infections because it is poorly absorbed by the intestinal mucosa. They realize active concentrations in CSF. Vancomycin can be given orally for the local treatment of intestinal infections (e.g., pseudomembranous colitis produced by Clostridium difficile). Toxicity. Vancomycin is more toxic than penicillins, especially for kidneys

Bacitracin
Inhibits peptidoglycan synthesis by interfering with the recycling of the phosphorilated lipid carrier. It is active against gram-positive bacteria. Bacitracin is nephrotoxic and ototoxic when given parenterally; therefore it is mainly used in topical ointments (only local).
Def: Ototoxicity is damage of the ear (oto), specifically the cochlea or auditory nerve and sometimes the vestibulum, by a toxin (often medication like antibiotics).

Vancomycin and beta- lactams like penicllin interfere with cell wall synthesis (1)

CLASSIFICATION
A. Antibacterial agents that inhibit the cell wall synthesis B. Antibacterial agents that alter the function of the cytoplasmic membrane C. Antibacterial agents that inhibit the protein synthesis D. Antibacterials that inhibit the nucleic acid synthesis

Antibacterial agents that alter the function of the cytoplasmic membrane

Antibacterial agents that alter the function of the cytoplasmic membrane

Polymyxines are polypeptides with big molecular weight. E.g., polymixine B, polymixine E (colistine).

Antibacterial agents that alter the function of the cytoplasmic membrane

Mechanism of action They modify the structure of the cytoplasmic membrane, which disturb the active transport of some molecules through it. They are bactericidal.

Antibacterial agents that alter the function of the cytoplasmic membrane

Antibacterial spectrum Gram-negative bacilli and cocobacilli (aerobic or facultative anaerobic).

Antibacterial agents that alter the function of the cytoplasmic membrane

Administration: orally in enteritis; parenterally in urinary tract infections. They don’t penetrate the blood-brain barrier (not efficient in meningitis). Toxicity: nephrotoxic, neurotoxic.

CLASSIFICATION
A. Antibacterial agents that inhibit the cell wall synthesis B. Antibacterial agents that alter the function of the cytoplasmic membrane C. Antibacterial agents that inhibit the protein synthesis D. Antibacterials that inhibit the nucleic acid synthesis

Antibacterial agents that inhibit the protein synthesis
1. 2. 3. 4. Aminoglycosides Tetracyclines Chloramphenicol Macrolides – lincosamides – streptogramines (MLS group)

Aminoglycosides
Natural aminoglycosides  produced by Streptomyces: streptomycin, neomycin, kanamycin, tobramycin, spectinomycin;  produced by Micromonospora: gentamycin, sisomycin. Semisynthesis aminoglycosides: kanamycin derived: amikacin; sisomycin derived: netilmycin.

Aminoglycosides
Mechanism of action: Aminoglycosides bind the 30S ribosomal subunit, which disturbs the protein synthesis and produce nonfunctional proteins.

Aminoglycosides

Aminoglycosides - Antibacterial spectrum.
Aminoglycosides are bactericidal. They are active on facultative anaerobic gramnegative bacilli and on staphylococci. Gentamycin, tobramycin, amikacin and netilmycin are also active on Pseudomonas aeruginosa. Streptomycin is particularly active on mycobacteria, Yersinia pestis and Brucella.

Aminoglycosides - Antibacterial spectrum.
Spectinomycin is given in gonococci infection with beta-lactamase producing strains. Neomycin is mostly used in topical ointments and in oral preparations. Aminoglycosides in association with penicillins or vancomycin are synergistic against enterococci and viridans streptococci.

Aminoglycosides
Administration: aminoglycosides are not absorbed from the digestive tract; thus, they are given parenterally. They may be given locally in meningitis. Toxicity: ototoxic, nephrotoxic, except spectinomycin. Gentamycin, tobramycin, amikacin, netilmycin have lower toxicity levels. Aminoglycosides realize concentrations very close to the toxic ones (their serum concentrations have to be checked).

Tetracyclines
Natural tetracyclines: chlortetracycline, oxytetracycline. Semisynthesis tetracyclines: tetracycline, doxycycline, minocycline.

Tetracyclines - Mechanism of action
Tetracyclines are bacteriostatic. They fix on the 30S ribosomal subunit, blocking the binding of tRNA on the complex mRNA-ribosom; thus, they stop peptide elongation.

Antibiotics that act at the level of the elongation phase of protein synthesis

How antibiotics work:

For example vancomycin and b- lactams like penicllin interfere with cell wall synthesis (1). Erythromycin and tetracyclin disrupt protein synthesis at the ribosome (2). Quinolones inhibit enzymes involved in DNA synthesis (3) and sulfonamides also interfere with DNA synthesis by mimicking naturally-occurring building materials.

Erythromycin and tetracyclin disrupt protein synthesis at the ribosome (2)

Tetracyclines - Antibacterial spectrum
Tetracyclines are broad-spectrum antibacterials, active on gram-positive and gram-negative, aerobic and anaerobic organisms. They are also active on: spirochete, mycoplasmas, chlamydia, rickettsia. They are not active on Pseudomonas aeruginosa.

Tetracyclines - Administration.
When given orally, they are well absorbed. They don’t realize active concentrations in CSF. They are not eliminated by urine, so, they are not effective in urinary tract infections. Doxycycline, minocycline are long acting tetracyclines and require less frequent administration.

Tetracyclines - Side effects
They produce brownish staining of the teeth and they affect the growth of long bones in children. That’s why they are counter-indicated in children less than 8 years old and in pregnant women. Tetracycline administration encourages candidiasis as a result of the loss of the normal flora.

Chloramphenicol
Chloramphenicol is the first antimicrobial compound synthesized in the laboratory. Tianphenicol is a less toxic derivative. Mechanism of action: it blocks protein synthesis by fixing on the 50S ribosomal subunit and inhibiting the peptidiltransferase.

Chloramphenicol

Chloramphenicol - Antibacterial spectrum.
Chloramphenicol is bacteriostatic against most bacteria, but it is bactericidal against Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae.

Chloramphenicol - Antibacterial spectrum.
The antibacterial spectrum is similar to that of tetracyclines. It is active against intracellular bacteria (it is the first choice antibacterial in the treatment of typhoid fever, Rocky Mountain spotted fever). It is also useful in H. influenzae meningitis because it penetrates the blood-brain barrier. It is effective against anaerobes.

Chloramphenicol - Administration
Chloramphenicol can be given orally or in injections, realizing good concentrations in tissues, even in CSF. It is conjugated in the liver, the resulted inactive compound being eliminated by urine.

Chloramphenicol - Toxicity.
In newborn or premature, chloramphenicol produces gray baby syndrome because the liver is incapable to conjugate the compound. In adults, there is a dose-dependent toxic effect on the bone marrow, which is reversible. In a very low number of patients (1: 25000), a dose independent toxic effect may appear – the irreversible, lethal bone marrow aplasia.

Macrolides – lincosamides – streptogramines (MLS)

Macrolides
Erythromycin Roxitromycin Clarithromycin Azithromycin Spiramycin Josamycin

Macrolides
Mechanism of action: macrolides bind to the 50S ribosomal subunit, immobilize peptidyl tRNA and cause premature peptide chain termination.

Macrolides
Antibacterial spectrum: erythromycin is active against gram-positive cocci and bacilli, including anaerobes, Legionella pneumophila*, Bordetella pertussis*, Campylobacter jejuni* (* = Gram negative bacilli), mycoplasmas, chlamydia. Erythromycin is the alternative to penicillin in the treatment of group A streptococcal infections.

Macrolides
The new macrolides (clarithromycin, azithromycin) are also active on gram-negative bacteria: Moraxella catarrhalis, Haemophilus influenzae. Clarythromycin is active in the treatment of Helicobacter pylori gastritis and in infections with Mycobacterium avium-intracellulare.

Macrolides
Administration: macrolides are given orally and realize good concentrations in tissues, but not in CSF. They are eliminated predominantly by bile. Toxicity: macrolides have low toxicity. They may cause gastric intolerance.

Lincosamides
Ex: Lincomycin Clindamycin Antibacterial spectrum: lincosamides are active against staphylococci, gram-positive and gram-negative anaerobes, including Bacteroides fragilis. Adverse effects: lincosamides encourage, more than other antibacterials, the pseudomembranous colitis with Clostridium difficile.

Streptogramines

-

Ex. : Pristinamycin Virginamycin Antibacterial spectrum. Streptogramines are active against staphylococci, including methicilin resistant strains (MRSA).

Antibacterials that inhibit the nucleic acid synthesis
1. Sulfonamides - Sulfizoxazole - Sulfamethoxazole etc.

Sulfonamides
Mechanism of action. Sulfonamides are bacteriostatic. They inhibit the folic acid synthesis by inhibiting dihidropteroate synthetase. Antibacterial spectrum. Sulfonamides are active on:  Gram-positive and gram-negative bacteria, except Pseudomonas aeruginosa;  Actinomyces israelii, but not other anaerobes;  Chlamydia.

Sulfonamides
Administration: orally, resulting in good concentrations in tissues. Elimination by urine. Adverse effects:  hypersensitivity reactions, especially after local administration;  acute hemolytic anemia in patients with G6PD deficiency;  increased concentrations of nonconjugated bilirubine in newborn.

Trimethoprim
Mechanism of action. Bacteriostatic. It inhibits folic acid synthesis by blocking dihidrofolate reductase. Antibacterial spectrum. Similar to sulfonamides. Adverse effects. It may produce skin rash or bone marrow depression.

Cotrimoxazol,
Trimethoprim + sulfamethoxazole (5/1) = cotrimoxazol, a synergistic combination. Each component is bacteriostatic, but the combination is bactericidal. It is particularly useful in the treatment of genitourinary tract infections, bacterial gastro-enteritis and it is frequently used in the long-term prophylaxis of bacterial infections in immune-compromised hosts.

Quinolones
First generation: Nalidixic acid Pipemidic acid etc. Second generation (Fluoroquinolones):- Norfloxacin - Pefloxacin - Ofloxacin - Ciprofloxacin - Sparfloxacin

Quinolones
Mechanism of action. Bactericidal; they inhibit DNA gyrase. Antibacterial spectrum. First generation quinolones are active only on Enterobacteriaceae. Fluoroquinolones have extended spectrum, being also active on Ps. aeruginosa, staphylococci, gram-negative cocci and coccobacilli, Legionella pneumophila, chlamydia and mycoplasmas. They are inactive on streptococci and anaerobic bacteria.

Quinolones
Administration. Nalidixic acid is given orally, but it realizes active concentrations only in the kidneys. Fluoroquinolones are systemic quinolones, which, after oral administration, realize active concentrations in tissues and CSF, having good penetration in the cells. They are eliminated predominantly urinary. Adverse effects. Fluoroquinolones determine photosensitivity after exposure to the sunlight. They have limited applications in children.

Rifampin
Mechanism of action. Bactericidal; it inhibits RNA polymerase DNA dependent. Antibacterial spectrum. Mycobacteria, gram-positive cocci (staphylococci), gram-negative cocci and coccobacilli, Legionella pneumophila, chlamydia, rickettsia.

Rifampin
Administration. After oral administration, it realizes active concentrations in tissues, including CNS. It concentrates in phagocytes and has billiary and urinary elimination. Adverse effects. Hepatic disorders.

Metronidazol
 Mechanism of action. After penetration in the bacterial cell, intermediate metabolism compounds interact with DNA.  Antibacterial spectrum. Protozoa, anaerobic and microaerophilic bacteria.  Administration. After oral administration, it realizes active concentrations in tissues and CSF. Urinary elimination.  Adverse effects. They are, generally, well tolerated.

Antimycobacterial agents
Conditions for an effective antimycobacterial therapy: The antimycobacterial agents have to be active against extra- and intra-cellular bacilli, including the dormant ones. To prevent relapses by a long-term therapy. To prevent the resistance phenomenon by using at least three associated therapeutical agents. The antimycobacterial agents are classified: First line therapy – important antimycobacterial effect and low toxicity

Isoniazid
 Mechanism of action. Bactericidal by inhibition of the mycolic acids synthesis. It is effective against extra- and intracellular bacilli.  Administration. Orally given, it realizes active tissue concentrations. Urinary elimination.  Adverse effects. Hepatotoxicity, neurotoxicity (especially in elderly patients, diabetics, alcoholics).

Rifamycins - Rifampicin, Rifabutin and Rifapentine

Rifampin and ansamycine
Bactericidal; active on extra- and intra-cellular mycobacteria and bacilli with slow multiplication.

Antimycobacterial agents
Pyrazinamide Structural analogue of nicotinamide. Bactericidal, especially o intracellular bacilli. Oral administration; it realizes good concentrations in tissues and CSF; renal elimination.

Antimycobacterial agents
Ethambutol Bacteriostatic by inhibiting the transfer of mycolic acids from the cytoplasm to the cell wall. Active only on extra-cellular bacilli. Oral administration; it realizes good concentrations in tissues and CSF; renal elimination. Adverse reactions: periferic neuropathy. Streptomycin Bactericidal on extra-cellular bacilli.

Second line antibiotics used
Cycloserine Broad spectrum antibiotic This blocks the synthesis of peptidoglycan by inhibiting D-alanine racemase and D alanine ligase. Fluoroquinolones Broad spectrum antibiotics Interact with DNA gyrase and DNA topisomerase which means that supercoiling and replication are altered.

Second line antibiotics used
Capreomycin and viomycin Viomycin inhibits cell free translation systems Capreomycin may inhibit protein synthesis P-aminosalicylic acid Discovered 1946 but now rarely used Possibly competes with p-aminobenzoic acid or with salicylate dependent biosynthesis of iron chelating mycobactins

Second line antibiotics used
Thiacetazone A thiosemicarbazone with unknown action but may involved in inhibiting mycolic acid synthesis Ethionamide Produced from 1966 Kanamycin or amikacin Affect ribosomal proteins Produced from 1957

Second line antibiotics used
Ofloxacin Produced from 1987 onwards A drug that interacts with DNA gyrase Quinolones Affect DNA gyrase and also DNA replication Acridinones May involve inhibition of RNA synthesis

Second line antibiotics used

Oxazolidinones Inhibit bacterial protein synthesis
Gangamycin Synthetic antibiotic Inhibit cell wall synthesis

Mechanisms of natural bacterial resistance:
Low permeability of the cell wall. E.g., resistance of mycobacteria to the antibacterial agents active on nonacid fast bacteria; natural resistance of gram-negative bacteria to glicopeptides.

Mechanisms of natural bacterial resistance:
Absence of the antibiotic’s target. E.g., resistance of mycoplasmas to the cell wall synthesis inhibitors. Enzymatic inactivation of antibiotics by constitutive enzymes. E.g., natural resistance of Yersinia enterocolitica to aminopenicillins.

Antimicrobial Drug Resistance
A. Principles and Definitions 1. Clinical resistance to an antimicrobial agent occurs when the MIC of the drug for a particular strain of bacteria exceeds that which is capable of being achieved with safety in vivo.

Genetic transfer

Antimicrobial Drug Resistance
Resistance to an antimicrobial can arise (1) by mutation in the gene that determines sensitivity/resistance to the agent or (2) by acquisition of extrachromosomal DNA (plasmid) carrying a resistance gene.

Antimicrobial Drug Resistance
Resistance that appears after introduction of an antimicrobial agent into the environment usually results from a selective process, i.e. the agent selects for survival of those strains possessing a resistance gene. Resistance can develop in a single step or it can result from the accumulation of multiple mutations.

Antimicrobial Drug Resistance
2. Cross resistance implies that a single mechanisms confers resistance to multiple antimicrobial agents while multiple resistance implies that multiple mechanisms are involved. Cross resistance is commonly seen with closely related antimicrobial agents while multiple resistance is seen with unrelated antimicrobial agents.

Antimicrobial Drug Resistance
B. Mechanisms of Resistance 1. Altered permeability of the antimicrobial agent - Altered permeability may be due to the inability of the antimicrobial agent to enter the bacterial cell or alternatively to the active export of the agent from the cell. 2. Inactivation of the antimicrobial agent Resistance is often the result of the production of an enzyme that is capable of inactivating the antimicrobial agent.

Antimicrobial Drug Resistance
3. Altered target site - Resistance can arise due to alteration of the target site for the antimicrobial agent. 4. Replacement of a sensitive pathway - Resistance can result from the acquisition of a new enzyme to replace the sensitive one.

Modification of the cell wall permeability:
E.g., resistance of Pseudomonas aeruginosa to carbapenems; resistance of Mycobacterium tuberculosis to isoniazid, etionamide, cycloserine, PAS.

Modification of the target:
biochemical modification of the PBP, which diminishes the enzyme’s affinity for that antibiotic. E.g., resistance of pneumococci to penicillin, resistance of staphylococci to methicillin; resistance to trimetoprim and sulfonamides; resistance to rifampicine by modification of the RNA polymerase affinity; resistance to quinolones by modification of their affinity to DNA girases.

Structure of a Low-affinity Penicillinbinding Protein from Enterococcus Faecium

Penicillin-binding proteins (PBPs) are membrane proteins involved in the final stages of peptidoglycan synthesis and represent the main target for b-lactam antibiotics. Enterococcus faecium strains are resistant to penicillin through the overproduction of low-affinity penicillin-binding protein PBP5.

Structure of a Low-affinity Penicillinbinding Protein from Enterococcus Faecium Only one structure of a penicillin sensitive PBP has been solved (PBP2x from Streptococcus pneumoniae). The availability of the structure of a resistant PBP such as PBP5 is of the utmost importance for the understanding of the resistance mechanism developed by the bacteria. It should lead to the development of new antibiotics designed to specifically bind to this protein active site.

Efflux of the antibacterial agent outside the bacterial cell:
E.g., resistance to tetracyclines.

Enzymatic inactivation of antibiotics:
Aminoglycosides – acetyltransferases; adenil-transferases, phosphorilases; Chloramphenicol – chloramphenicolacetyl-transferase; Beta-lactams – beta-lactamases; Chromosomal cephalosporinases – they are not inactivate by betalactamase inhibitors.

Enzymatic inactivation of antibiotics:
 Beta-lactamases inactivated by inhibitors: sulbactam, clavulanic acid, tazobactam. E.g., staphylococcal penicilinase. R plasmids have one or several resistance determinants that can spread epidemically by conjugation or transduction, among the same species or among species. Several resistance determinants are transposable elements.

ANTIBIOTIC ASSOCIATIONS
Indications: severe infections, before the identification of the etiological agent; in joint infections; to obtain a synergistic effect, to surpass bacterial resistance in severe infections or to reduce the dose of a toxic antibiotic; to prevent selection of resistant mutants in the treatment of severe infections (e.g., tuberculosis).

ANTIBIOTIC ASSOCIATIONS
An antibiotic association can be:  synergistic: the activity of the association is bigger than the sum of the individual activity of the antibiotics:  antagonistic: the activity of the association is smaller than the activity of each separated antibiotic;  additive: the activity of the association is equal to the sum of the activities of the two antibiotics;  indifferent: the association has a smaller activity than the most efficient antibiotic of the association.

Rules for the association of the antibiotics
It is avoided the association of aminoglycosides or with polymixines (the toxic effects are summed). It is avoided the association of a bacteriostatic by inhibition of the protein synthesis (tetracyclines, macrolides) with a bactericidal antibiotic (penicillins, aminoglycosides) (antagonistic effect). It is indicated the association of antibiotics that block successive steps of a metabolic pathway (e.g., trimetoprim + sulfamethoxazole).

Rules for the association of the antibiotics
It is indicated the association of an antibiotic with another one that encourages its penetration in the bacterium (e.g., penicillin + aminoglycosides against enterococci). It is indicated the association in which one antibiotic is protected from enzymatic effects by the other one (e.g., ampicillin + sulbactam).

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