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

1^st 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).

2^nd generation

The drugs contain antibacterial activities of the 1^st 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 2^nd 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.

3^rd 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 2^nd 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 2^nd generation suffice in these situations usually. The only rational indication remains infection caused by pathogens of microbiologically verified intermediate sensitivity where 2^nd 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.

4^th generation

Antibiotics of this group have a broad spectrum summarizing the 1^st, 2^nd and 3^rd 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