Tuesday, March 16, 2010

CLASSES OF ANTIBIOTICS AND THEIR PROPERTIES

Chemical class

Examples

Biological source

Spectrum (effective against)

Mode of action

Beta-lactams (penicillins and

Cephalosporins)

Penicillin G, Cephalothin

Penicillium notatum and

Cephalosporium

species

Gram-positive bacteria

Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly

Semisynthetic beta-lactams

Ampicillin, Amoxicillin

Gram-positive and Gram-negative bacteria

Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly

Clavulanic Acid

Augmentin is clavulanic acid plus Amoxicillin

Streptomyces clavuligerus

Gram-positive and Gram-negative bacteria

Inhibitor of bacterial beta-lactamases

Monobactams

Aztreonam

Chromobacterium violaceum

Gram-positive and Gram-negative bacteria

Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly

Carboxypenems

Imipenem

Streptomyces cattleya

Gram-positive and Gram-negative bacteria

Inhibits steps in cell wall (peptidoglycan) synthesis and murein assembly

Aminoglycosides

Streptomycin

Streptomyces griseus

Gram-positive and Gram-negative bacteria

Inhibits translation (protein synthesis)

Gentamicin

Micromonospora species

Gram-positive and Gram-negative bacteria esp. Pseudomonas

Inhibits translation (protein synthesis)

Glycopeptides

Vancomycin

Amycolatopsis orientalis(formerly designated Nocardia orientalis)

Gram-positive bacteria, esp.

Staphylococcus aureus

Inhibits steps in murein (peptidoglycan) biosynthesis and assembly

Lincomycins

Clindamycin

Streptomyces lincolnensis

Gram-positive and Gram-negative bacteria esp. anaerobic Bacteroides

Inhibits translation (protein synthesis)

Macrolides

Erythromycin, Azithromycin

Streptomyces erythreus

Gram-positive bacteria, Gram-negative bacteria not enterics, Neisseria, Legionella, Mycoplasma

Inhibit translation (protein synthesis)

Polypeptides

Polymyxin

Bacillus polymyxa

Gram-negative bacteria

Damages cytoplasmic membranes

Bacitracin

Bacillus subtilis

Gram-positive bacteria

Ihibits steps in murein (peptidoglycan) biosynthesis and assembly

Polyenes

Amphotericin

Streptomyces nodosus

Fungi ( Histoplasma)

Inactivate membranes containing sterols

Nystatin

Streptomyces noursei

Fungi (Candida)

Inactivate membranes containing sterols

Rifamycins

Rifampicin

Streptomyces mediterranei

Gram-positive and Gram-negative bacteria, Mycobacterium tuberculosis

Inhibits transcription (bacterial RNA polymerase)

Tetracyclines

Tetracycline

Streptomyces species

Gram-positive and Gram-negative bacteria, Rickettsias

Inhibit translation (protein synthesis)

Semisynthetic tetracycline

Doxycycline

Gram-positive and Gram-negative bacteria, Rickettsias, Ehrlichia, Borrelia

Inhibit translation (protein synthesis)

Chloramphenicol

Chloramphenicol

Streptomyces venezuelae

Gram-positive and Gram-negative bacteria

Inhibits translation (protein synthesis)

Quinolones

Nalidixic acid

Synthetic

Mainly Gram-negative bacteria

Inhibits DNA replication

Fluoroquinolones

Ciprofloxacin

synthetic

Gram-negative and someGram-positive bacteria ( Bacillus anthracis)

Inhibits DNA replication

Growth factor Analogs

Sulfanilamide, Gantrisin, Trimethoprim

synthetic

Gram-positive and Gram-negative bacteria

Inhibits folic acid metabolism (anti-folate)

Isoniazid (INH)

synthetic

Mycobacterium tuberculosis

Inhibits mycolic acid synthesis; analog of pyridoxine (Vit B6)

PAS

synthetic

Mycobacterium tuberculosis

Anti-folate

1st generation

The drugs are used predominantly against gram-positive cocci (streptococci and staphylococci). Their spectrum further includes corynabacteria, meningococci, and some community-acquired stems of gram-negative rods like Escherichia coli or Proteus mirabilis. The drugs are active against anaerobes in the extent similar to penicillin.

cefalotin - CLT, cefazolin – CZL (for parenteral administration)

cefalexin - CLX, cefadroxil - CDR, cefaclor – CCL (for oral administration)

(cefaclor has moderate effect against Haemophilus, so it belongs to „one-and-half generation“)

The drugs are predominantly used for treatment skin and soft tissue infections, and for prophylaxis in surgical procedures (except colorectal surgery and situations when methicillin-resistant staphylococci are spread in the surgery department).


2nd generation

The drugs contain antibacterial activities of the 1st generation and extend to further community-acquired gram-negative bacteria like Haemophilus influenzae, Moraxella catarrhalis, or less susceptible strains of E.coli or similar patogens.

cefuroxim - CRX, cefamandol – CMN (for parenteral administration)

cefuroxim-axetil (for oral administration)

The drugs are prescribed for treatment respiratory tract infections (bacterial sinusitis or mesotitis, pneumonia), and urinary and hepatobiliary tract infections. They can be used for prophylaxis in surgery as well.

cefoxitin – CXT (only parenteral administration)

It is a representative of cefamycines. These antibiotics are closely related to true cephalosporins differing in one substituent on cephem nucleus. Their common feature is a very good activity against relatively resistant anaerobe Bacteroides fragilis. With its antibacterial activity against other microbes, cefoxitin has been joined to the 2nd generation cephalosporins. Its typical disposal is intra-abdominal, pelvic, and gynecological infections, foot infections in diabetics, infected decubitus ulcers and other mixed aerobic-anaerobic infections. Unfortunately, resistance to cefoxitin raises quickly in departments where this drug used to be given frequently.

3rd generation

The drugs can be divided in two subgroups according to their activity against Ps.aeruginosa:

The subgroup A consists of antibiotics of similar spectrum as 2nd generation but with enhanced activity against gram-negative bacteria and weaker effect against staphylococci.

cefotaxim – CTX, ceftriaxon – CTR (for parenteral administration)

These drugs are used for treatment of severe and life-threatening infections caused by community gram-negative patogens like E.coli, H.influenzae, meningococci, salmonellae etc. The relevant clinical diagnoses are purulent meningitis, epiglotitis, sepsis of urinary or hepatobiliary tract origin etc.

Ceftriaxon is an antibiotic of extreme long half-time (8 hrs) in addition that allows once-daily administration. This feature makes the treatment easier but is of especial importance in treatment of outpatients or in home treatment.

cefetamet-pivoxil, cefpodoxim-proxetil, cefixim, ceftibuten (for oral administration)

The position of these antibiotics is rather problematic. They can be used for treatment of mild or moderate community acquired infections but cephalosporines of 2nd generation suffice in these situations usually. The only rational indication remains infection caused by pathogens of microbiologically verified intermediate sensitivity where 2nd generation cephalosporins perform only a weak effect.

The subgroup B included antibiotics effective against Ps. aeruginosa and other “problematic gram-negative pathogens”. However, the stronger is the anti-pseudomonadal effect, the weaker is the activity against staphylococci and other gram-positive microbes.

ceftazidim – CTZ, cefoperazon – CPR (for parenteral administration)

These antibiotics are used in nosocomial infections/sepsis caused by gram-negative bacteria. Ceftazidim is strongest anti-pseudomonadal cephalosporin. Cefoperazon´s unique feature is predominant excretion via the bile: this advocates for its usage in hepatobiliary tract infections and in renal insufficiency. Cefaperazon is available in a mixture with beta-lactamase inhibitor as well: cefoperazon/sulbactam that can be worthy against Acinetobacter sp. and some “problematic pathogens” owing beta-lactamase activity.

4th generation

Antibiotics of this group have a broad spectrum summarizing the 1st, 2nd and 3rd generation. They can resist some potent beta-lactamases. Nevertheless, their activity against staphylococci is not better than with cephalotin and activity against Ps.aeruginosa is not better than with ceftazidim.

cefpirom, cefepim (only parenteral administration)

These antibiotics are used in nosocomial infections of special resistance pattern (stable derepression of ampC gene) or in nosocomial sepsis of unknown origin where covering the broad spectrum of pathogens is necessary (i.e. febrile neutropenia).

C) Carbapenems

They are very potent antibiotics of extremely broad spectrum including majority of gram-positive and gram-negative patogenes. These antibiotics resist effect of many beta-lactamases, too. The group of not affected microbes embraces methicillin-resistant staphylococci, Clostridium difficile, Stenotrophomonas maltophilia, Pseudomonas cepacia and some exceptionally resistant strains of enterococci, Acinetobacter, or Pseudomonas.

imipenem, meropenem (only parenteral administration)

These antibiotics are reserved for extreme resistant nosocomial infections/sepsis.

D) Monobactams

Monocyclic beta-lactams are active against Enterobacteriaceae, Pseudomonas, and other gram-negative aerobic microorganisms. They resist many bacterial beta-lactamases.

aztreonam (only parenteral administration)


This antibiotic is reserved for nosocomial infections/sepsis caused by resistant gramnegative bacteria. Because of its lack of cross-reactivity, it can be given patients with allergy to penicillin or cephalosporins.

Table 1: Evolution of antibiotics/chemotherapeutics: Discovery of the first important preparations till 1950.

antibiotic

natural source

first description as anti-infective drug

discoverer

sulfanilamide

(prontosil)

-

1932

G.Domagk

penicillin

Penicillium notatum

19411

A.Fleming, Florey, Chain

streptomycin

Streptomyces griseus

1944

S.A.Waksman

cephalosporin

Cephalosporium acremonium

1945

G.Brotzu

bacitracin

Bacillus subtilis

1945

B.A.Johnson

chloramphenicol

Streptomyces venezuellae

1947

I.Ehrlich

polymyxin

Bacillus polymyxa

1947

C.G.Ainsworth

chlortetracyclin

Streptomyces aureofaciens

1948

B.M.Duggar

neomycin

Streptomyces fradiae

1949

S.A.Waksman

oxytetracyclin

Streptomyces rimosus

1950

A.C.Finlay

colimycine

Bacillus colistinus

1950

Y.Koyama

1 Penicillin was discovered by A.Fleming in 1928 but the first therapeutic usage was realized by Florey only in 1941.

Table 2: The much-feared resistant bacteria

Nosocomial environment

• MRSA = methicillin resistant Staphylococcus aureus1

• MRSE = methicillin resistant Staphylococcus epidermidis

• VISA/GISA = vancomycin or glycopeptide intermediate (resistant) Staphylococcus aureus

• VISE/GISE = vancomycin or glycopeptide intermediate (resistant) Staphylococcus epidermidis

• VRE = vancomycin resistant enterococci

• high-level gentamicine-resistant enterococci

• gram-negative bacteria producing ESBL (= extended spectrum beta-lactamase)2

• multiresistant gramnegative bacteria3

Community environment

• Streptococcus pneumoniae resistant to penicillin

• Streptococcus pneumoniae resistant to macrolides

• Streptococcus pyogenes resistant to macrolides and to lincosamides (partially crossed resistance)

• MRT = multiresistant Mycobacterium tuberculosis

1 MRSA strains are resistant to virtually all beta-lactams and usually resistant to macrolides and lincosamides: the only reliable antibiotics for empiric therapy are glycopeptides.

2 The highest frequency of ESBL producing strains are in Klebsiella species, nevertheless this pattern of resistance was reported in E.coli and other gram-negative microbes as well.

3 The most important multiresistant strains occur in following species: Pseudomonas, Acinetobacter, Serratia, Burkholderia, and Stenotrophomonas. However, remember that resistance in gram-positive bacteria became a hot problem nowadays.

MECHANISMS OF RESISTANCE

1) enzymatic destruction of ATB

easy to transfer and to spread

several genes bond in one plasmide

2) block of ATB penetration into cell

3) efflux of ATB

4) change of the target molecule

MRSA, MRSE

difficult to develop


MAIN MISTAKES IN ATB TREATMENT

1) usage in diseases of non-bacterial origin

(x non-antiinfective effect of ATB !)

2) not taking material for cultivation before

starting ATB treatment

3) uncorrect interpreting ATB failure

patients compliance ?

4) uncorrect answer to ATB failure

change ATB ?

cultivation attempt ?

5) blind confidence in various studies results




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