Antimicrobial Agents and Chemotherapy

Classification

Prepared by : Microbiology and Immunology

Department

Objectives of the Lecture

1.   Antimicrobial Agents and Chemotherapy Classification :

q  β-lactams:

q  Macrolides:

q  Lincosamines:

q  Aminoglycosides:

q  Rifampicin:

q  Chloramphenicol:

q  Tetracylines:

q  Polymyxin:

I) β-lactams a) Natural 1- Penicillins

ü Penicillin G (benzyl penicillin) &

ü Penicillin V (phenoxymethyl penicillin).

q  Produced by moulds such as Penicillium notatum and Penicillium chrysogenum

through a fermentation process.

q  Bactericidal to gram-positive cocci and bacilli, Neisseria (pathogenic

gram-negative cocci) and spirochaetes.

q  Not active against most gram-negative rods or T.B.

q  Low toxicity (except hypersensitivity reactions).

Disadvantages of Natural Penicillins: 1- Narrow spectrum.

2- Easily inactivated since it is unstable in solution & is destroyed by

heat, acid, alkali, oxidizing agents….etc.

3- Should be given parentrally because they are partially destroyed in

the stomach due to acidity.

4- Inactivated by penicillinase (β -lactamase).

5- Rapidly excreted in the urine, therefore blood level falls quickly

unless a dose is injected every six hours

b) Semi Synthetic Penicillins:

q  Prepared by acylation of the penicillin nucleus (6- aminopenicllanic acid)

i) Penicillinase-resistant: e.g. Methicillin.

ii) Penicillinase and acid-resistant: e.g. oxacillin, cloxacillin &

flucloxacillin are taken orally.

(Flucloxacillin is the antibiotic of choice for oral administration because of its high absorption).

iii) Broad spectrum and acid-resistant: e.g. Ampicillin and amoxicillin q  are taken orally and are effective against some enteric gram negative bacteria including typhoid, dysentery bacilli, & Haemophilus influenzae. q  Amoxicillin has better absorption than ampicillin. q  Amoxicillin is the drug of choice for upper respiratory tract infections.

iv) Penicillins active against Pseudomonas aeruginosae: e.g. Carbenicillin, carbenicillin-ester & substituted ampicillins (piperacillin, azlocillin, ……..). Carbenicillin is specially used in urinary tract infections. v) Monobactams: Aztreonam is resistant to beta-lactamases and has a great effect against gram negative infections, especially of the meninges, bladder, and kidneys. vi) Carbapenems: Examples: Imipenem - Meropenem

q Have the broadest antibacterial spectrum compared to other β -

lactams.

q Administered I.V. due to their poor oral bioavailability.

q Highly resistant to β -lactamases

vii) β - lactamases inhibitors

q  These drugs are given in conjunction with β -lactam antibiotics to

prevent their degradation by β -lactamases.

Examples: clavulanic acid, sulbactam & tazobactam.

q  Several antibiotic/beta-lactamase inhibitor combinations exist in the

market: e.g

- Augmentin: Amoxicillin/Clavulanic acid

- Unasyn: Ampicillin/Sulbactam

I) β-lactams

2- Cephalosporins q  Resemble penicillins structurally.

q  Stable in acid pH. q  Broad spectrum. q  Many of them are resistant to penicillinase.- Thus, cephalosporins are used as alternatives to penicillin in cases of resistance or penicillin allergy. a- First generation: q  Broad spectrum against Gram-positive cocci and certain Gram-negative rods but resistant to β-lactamases. q Cephaloridine: active against gram-positive cocci, but is nephrotoxic. q Cephalexin: can be given orally.

b- Second generation - Resistant to most enterobacterial β-lactamases. - Cefamandol and Cefoxitin are active against a wide range of gram-negative bacteria and some anaerobes. - Mostly given by injection. c- Third generation - Far more active (up to 100 fold) than first and second generation cephalosporins, and are active against Pseudomonas aeruginosa. Examples: Ceftazidime and Cefotaxime. d- Fourth-generation - Effective against mutants resistant to “third- generation" cephalosporins. Examples: Cefipime penetrates the outer membrane of Gram-negative bacteria faster than third generation cephalosporins. - Administered parentrally.

II- Macrolides

q  Erythromycin: has an antibacterial spectrum similar to that of benzyl penicillin. q  It is a valuable alternative to penicillin in penicillin- hypersensitive patients.

q  Widely used in pediatrics, because its lack of toxicity and its availability in the form of an acceptable oral suspension as base.

q Used as a prophylactic drug against whooping cough.

III- Lincosamines

q Clindamycin: is a semisynthetic derivative of Lincomycin , but

better absorbed and much more active.

q Closely resembles erythromycin in most of its properties.

q  Most active against gram positive cocci and anaerobes.

q  Effective alternative to penicillin for use against Streptococcus

pyogenes.

q  Penetrates into bones better than most antibiotics and so used in

treatment of oseteomyelitis.

IV) Aminoglycosides General characters q  Bactericidal to sensitive organisms:

- Primarily active against aerobic gram-negative rods. -Poorly active against gram-positive organisms. - No activity against anaerobes or Streptococci (except when acting synergically with a penicillin).

q  Not absorbed by mouth. q  May be nephrotoxic. q  All are potentially neurotoxic (8th nerve); causing ototoxicity (usually irreversible deafness). q  Of little penetration to the cerebrospinal fluid (CSF).

Most important Aminoglycosides:

1. Streptomycin: was the first effective and it still remains a cheap

first-line drug against tuberculosis. Unfortunately, its ototoxicity and

the rapid development of resistance reduced its usefulness. Usually

used in combination with isoniazid and PAS.

2. Gentamicin: is the most important aminoglycoside & is more

active against a wide range of bacteria, specially Ps. aeruginosa. It is

often used in combination with carbenicillin to delay the

development of resistant Pseudomonas aeruginosa.

3. Neomycin and Framycin (soframycin): are too toxic for

systemic use. Can be applied topically in the form of powder, cream,

ointment or drops, etc. Framycin is especially used in case of burns.

V) Rifampicin q  It is a semisynthetic derivative of one of the naturally occurring rifamycins, which include rifamycins A to E. q The clinical usefulness of natural rifamycins is impaired by their rapid excretion in the bile. q  Rifampicin, in contrast, is well absorbed orally and is less rapidly excreted.

q  It is bactericidal to gram-positive bacteria, some gram-negative bacteria and is the most potent antituberculous agent available, it penetrates well into CSF; thus used in the treatment of tuberculous meningitis. q  Rifamycins should probably never be used alone because of the speed of development of resistant mutants.

Main side effects: Jaundice or GI disturbance.

VI) Chloramphenicol q  Broad spectrum of activity against a wide range of bacteria,

rickettsiae and chlamydiae.

q  Mainly bacteriostatic.

q  Well absorbed orally, and penetrates the CSF more readily than any

other antibiotic.

q  Because of the risk of fatal bone marrow depression (aplastic

anaemia), it is only used for certain life threatening infections e.g.

typhoid fever and meningitis due to Haemophilus influenzae.

q Chloramphenicol drops or ointment are effectively and extensively

used for treating eye infections

VII) Tetracyclines q  A family of closely related antibiotics with four-ringed structure. q  Broad spectrum. Bacteriostatic. q Chlortetracycline, oxytetracycline are still in use in a high dose with frequent gastrointestinal side effects (nausea, vomiting and diarrhea) due to irregular absorption. q Doxycycline and Minocycline (newer tetracyclines)

ü Well absorbed and are slowly excreted so that a daily dose is sufficient. ü An additional property of minocycline is its effectiveness against many staphylococcal and other strains that are resistant to other tetracyclines. ü Permanent yellow staining of teeth limits its use for children during the early years of life or to mothers during the later months of pregnancy. ü  Severe liver damage in pregnant women and teratogenic effects on fetus are reasons for avoiding these drugs during pregnancy.

VIII) Polymyxins

q  They are bactericidal polypeptide antibiotics derived from Bacillus .

q  Effective against Ps. aeruginosa and most gram-negative rods.

q  All are nephrotoxic but the systemic toxicity of polymyxin B and E

is not sufficient to preclude their use, so could be used I.M. when

necessary.

q  They are also used for treatment of intestinal infections since they

are not absorbed from the intestine when given orally.

q  They are used in the form of powders and ointments for the

treatment of wounds and burns.

Quinolones A- Nalidixic acid Active against most G negative bacteria, not G positive. Used for treatment of urinary tract infections when renal function is abnormal. B- Fluoroquinolones Broad spectrum and bactericidal compounds. Much more active than nalidixic acid. It is active against Enterobacteriaceae and Pseudomonas aeruginosa. - Used in treatment of urinary tract infections. Examples: norfloxacin, ciprofloxacin, ofloxacin. They are contraindicated in children and pregnant women and better not to be used unless there is no alternative; due to the suspected risks of damage to the musculoskeletal system and side effects on nervous.