XV. Respiratory anti-infective agentsA. Introduction • 1. Cell wall synthesis inhibitors • One of the categories of antimicrobials used in the treatment of respiratory infections are the cell wall synthesis inhibitors.
a. penicillins • The feature which all penicillins have in common is a beta lactam ring, and it is this ring that is necessary for the antibacterial activity of the penicillins.
These drugs bind to specific proteins in bacteria called penicillin binding proteins (PBP’s) and then prevent cross links from forming between constituents in the bacterial cell wall.
In addition, they activate enzymes which cause lesions in the cell wall.
There are 3 major categories of penicillins: • “regular penicillins” (Penicillin G, Penicillin V)
Broad spectrum penicillins: amoxicillin, ampicillin, azlocillin, carbenicillin, mezlocillin, piperacillin and ticarcillin
anti S. aureus penicillins: cloxacillin, dicloxacillin, methicillin, naficillin and oxacillin.
None of these are effective against MRSA (methicillin resistant S. aureus). • Over 25% of S. aureus infections are currently classified as MRSA.
Most staphylocci and many gram negative bacteria form beta lactamases (also known as penicillinases), and this is the major mechanism for the bacterial resistance on penicillins.
A possible strategy is to combine an inhibitor of beta lactamase (sulbactam, tazobactam, or clavulanate)) with a penicillin.
Examples of these combination drugs include: • Augmentin (amoxicillin and clavulanate) • Unasyn (ampicillin and sulbactam) • Timentin (ticarcillin and clavulanate) • Zosyn (piperacillin and tazobactam)
Adverse effects of the penicillins include allergic reactions, anaphylaxis, nausea and diarrhea.
b. cephalosporins • Cephalosporins are derivatives of 7-aminocephalosporanic acid.
There are now 5 generations of cephalosporins, based on their introduction into clinical use.
In general, the lower generation cephalosporins are more effective against staphylococcal and streptococcal organisms.
The higher generation cephalosporins are more effective against gram negative organisms (i.e. E. coli species, Klebsiella species, Proteus species).
Examples of cephalosporins include: • For “general use”: cefazolin (Kefzol, Ancef, IV) and cephalixin (Keflex, oral)
For use against anerobes, as in prophylaxis of appendicitis: cefotetan (Cefotan, IV)
For use agains H. influenza: ceftriaxone (Rocephin, IV) and cefuroxime (Ceftin, oral)
For use against meningitis, where penetration of the blood brain barrier into the central nervous system and cerebrospinal fluid is necessary: cefotaxime (Claforan, IV) and ceftriaxone (Rocephin, IV)
Their mechanism of action is similar to that of the penicillins, they bind to PBP’s and inhibit cell wall synthesis.
They are less susceptible to penicillinases due to structural differences that are different from the penicillins.
Similar to, but less frequent than the penicillins, the cephalosporins have a range of allergic effects from skin rashes to anaphylactic shock.
c. monobactams • Monobactams are monocyclic beta lactam antibiotics, and aztreonam is the only commercially available agent here.
It’s mechanism of action is similar to the other beta lactam cell wall synthesis inhibitors.
Aztreonam is most effective against gram negative aerobes such as Pseudomonas aeruginosa and various enterobacter species.
It is administered parenterally, and its adverse effects include GI disturbances, headache, and skin rashes.
d. vancomycin • Vancomycin is active against gram positive, but not gram negative bacteria.
It is indicated for infections caused by MRSA (pneumonia, as well as skin infections, peritonitis, endocarditis).
There are numerous resistant bacilli emerging, including vancomycin intermediate Staphylococcus aureus (VISA) and vancomycin resistant Staphylococcus aureus (VRSA).
Adverse effects include chills, fever ototoxicity and diffuse flushing from rapid intravenous infusion (called red man syndrome).
2. Bacterial protein synthesis inhibitors • There are numberous medications that are inhibitors of bacterial protein, that have applications in the treatment of respiratory infections including:
the tetracyclines • the macrolides and ketolides • the streptogramins • linezolid • the aminoglycosides
Antimicrobial agents that inhibit bacterial protein synthesis have actions that are centered on the ribosome.
In humans, as well as other eukaryotes, there are 80S ribosomes consisting of a small (40S) and large (60S) subunit.
In prokaryotes (bacteria), there are 70S ribosomes consisting of a small (30S) and a large (50S) subunit.
The S stands for Svedberg unit, which measures the rate of sedimentation (S) in a centrifuge, and NOT the size, therefore the fragments are not additive.
These drugs are targeted for the 70S bacterial ribosomes, and do not cause major effects on protein synthesis in humans.
a. the tetracyclines • The tetracyclines are also broad spectrum antibiotics that are the drug of choice in the treatment of infections with Rickettsia, Chlamydia, and Mycoplasma species.