Indications Of Antibiotics

β-LACTAMS

1. Mechanism of action  binds and inhibits PBPs. Different antibiotics can inhibit certain PBPs more than others. Inhibition of cell wall synthesis leads to activation of the autolytic system. Bacteria deficient in autolytic enzymes have tolerance to this class of antibiotic.

2. Resistance  decreased penetration to target site by changes in the porin proteins. This is why P. aeruginosa is resistant. Alteration of PBPs might influence binding of the antibiotic. This is resistance in pneumococci, and oxacillin resistance. β-lactamases is the major mech of resistance to β-lactam antibiotics. They can cleave either penicillins, cephalosporins or both. They can be synthesized constitutively or inducible.

3. Side effects 

1. There can be allergic reactions – immmediate (w/in 60 min, anaphylaxis), accelerated (1-72 hrs, urticaria), or late (>72 hrs, skin rash, serum sickness, drug fever). Penicillin G causes anaphylaxis in .01% people. People at risk can be id’d by skin testing with penicilloyl, penicilloate, or penilloate metabolic products. 40-73% of + will have a reaction. Patients with a + skin test can be desensitized with increased doses of drug.

2. Neurologic reactions like encephalopathy, changes in consciousness, seizures. This happens in high dose penicillin therapy particularly renal disease

3. Pulmonary infiltrate with eosonophilia syndrome.

4. Diarrhea (C. difficile colitis)

5. Hypersensitivity hepatitis (oxacillin and nafcillin) Ceftrixone can cause biliary sludge and pseudolithiasis in kids.

6. Renal reactions  methicillin—allergic interstitial nephritis. Glomerulonephritis in association with serum sickness. Ticarcillin can cause sodium overload and hypokalemia.

7. Neutropenias, hemolytic anemia, thrombocytopenia.

8. Vitamin K deficiency

Penicillins

There are two natural penicillins: penicillin G and V. You can also have semisynthetic penicillins which are natural products modified in the lab. Completely synthetic products include the sulfa drugs. Penicillins are sodium or potassium salts. The side chain determines the antibacterial spectrum and properties of each penicillin. All IV penicillins have short t1/2. They penetrate CSF poorly in the absence of inflammation. Nafcillin, oxacillin, doxacillin, and didoxacilin have non-renal routes of clearance so don’t need dose modifications. Ampicillin, mezlocillin, and pineracillin need dose modification when the GFR is <10ml/min.

1. Natural penicillins  work against gram + cocci like streptococci, gram + rods like Listeria, gram – cocci like Neisseria, most anaerobes, treponemal infections. Penicillin G isn’t active against gram – bacilli. Gram + bacteria inhibited by natural penicillins are more susceptible than to semisynthetic.

   1. Penicillin G can’t be given orally. When given in IV it’s cleared every 4-6 hours. Procaine penicillin delays the peak of activity and provides serum and tissue levels for at least 12 hours. Benzathine penicillin is a repository lat can last for 15-30 days.

   2. Penicillin V is given orally in suspension or tablets. Should be given every 6-8 hours. Less active than Penicillin G against Haemophilus, Neisseria, and enteric organisms.

2. Penicillinase-resistant penicillins have less intrinsic activity than penicillin G for most bacteria and are ineffective for enterococci, Listeria, and Neisseria. They are the drugs of choice for penicillin-resistant S. aureus and S. epidermidis.

   1. Methicillin is least active, most likely to cause interstitial nephritis and is not used anymore.

   2. Nafcillin is highly protein bound, given by IV, and is excreted by the liver and kidney.

   3. Isoxazolyl penicillins (cloxacillin, dicloxacin, flucloxacillin, oxacillin) are absorbed orally on an empty tummy. Dicloxacillin has better absorption. Bound to serum proteins and is excreted mostly by the kidney.

3. Aminopenicillins (ampicillin and amoxicillin) have the same spectrum as penicillin G, but are more active against enterococci and listeria. It’s not stable to β-lactamases of gram + or gram – bacteria. They both have the same spectrum, but amoxicillin is better absorbed when given orally and is preferred to ampicillin for oral use, except in shigella.

4. Carboxy penicillins (carbenicillin, ticarcillin) are like aminopenicillins but they can also penetrate the porin channel of gram – bacteria. They are more resistant to β lactamases like enterobacter, pseudomonas, proteus.

5. Extended-spectrum ureidopenicillins  mezlocillin and pineracillin are derivatives of ampicillin and cover the same spectrum as carboxypenicillins. They are more active against klebsiella, enterococci, and bacteroides fragilis. These drugs are all basically the same so choices are made by cost considerations.

6. Β-lactam and β lactamase inhibitor  clavulonic acid and penicillanic sulfone derivatives like sulbactam and tazobactam are β-lactamase inhibitors. They basically make the enzyme inactive so the β-lactam they’re administered with can do its work. They are most efficient against plasmid encoded β-lactamses made by S. aureus, influenza, B. catarrhalis, bacteroides, serratia. They do not work against chromosomal lactamases of serratia, c. freunsii, enetreobacter, P. aeruginosa, and enterobacteriaceae.

   1. Amoxicillin-clavulanate  works against S. aureus, H. influenza, enterobacteriaceae, and anaerobes

   2. Ampicillin-sulbactam works against enterobacteriaceae and acinetobacter. It’s broader spectrum but less potent than clavulanic acid.

   3. Timentib, Zosyn has a spectrum like sulbactam but a potency like calvulonic acid. Works against S. areus, inflenza, gonorrhoeae, enterobactericaea, and anaerobes.

Cephalosporins

Active against gram+ and – bacteria and are not destroyed by penicillinase. Most forms are semi-synthetic derivatives of cephalosporin C. There are 4 gnerations based on spectrum of activity against aerobic and facultative gram – bacilli. First and second generation don’t penetrate the CSF barrier well and shouldn’t be used for meningitis. Third generation ones should be used.

1. 1^st Generation  cefazolin, cephapirin they are active against gram + cocci, anaerobes. They are not active against gram -.

2. 2^nd 

   1. activity vs. H. influenza – cefruxime and cefamandole

   2. activity vs. bacteroides – cefotoxin and cefotetan

3. 3^rd  1) bad vs. P aeruginosa – cefotaxime, ceftriaxone, ceftizocime 2) good vs. p. aeruginos ceftazidime and cefoperazone

4. 4^th  cefepime

Carbapenems

Imipenem, Meropenem, Entapenem. Resistant to plasmid and chromosomal β-lactamases. Work against gram +, gram -, and anaerobic bacteria. They are not active against s. maltophelia, B. cepacia, E. faecilium, oxacillin resistant staphylococcci, and JK diphtheroids. They are effective against P. aeruginosa through a different channel than normal. It causes resistance easily when the drug is used as a single agent. Imipenem-cilastatin has been associated with CNS toxicity. Meropenem has a lower risk of producing seizures. Ertapenem has a longer half-life and can be administered once daily, but it has a narrower spectrum of activity.

Monobactams

Aztreonam has good activity against most gram – aerobic and facultative bacteria. There is no cross-allergenicity with other β-lactams.

GLYCOPEPTIDES

Vancomycin, teicoplanin, and daptoomycin. Should be given IV over 1hr. absorbed poorly from GI. Eliminated by glomerular filtration. T1/2 is 6-8 hours.

1. Mechanism of action  bind to D-ala-D-ala and prevent further gylcosylation.

2. Resistance  There at least 3 genes reesponsible )called van A, B, and C). A is the most common and is induced by vancomycin or teiciplanin and can be plasma encoded. It makes the code D-ala-D-lactate so vancomycin doesn’t fit anymore. B is inducible by vancomycin, but bacteria with this are still susceptible to teicoplanin. C is on the genome and is constitutive. VISA (S. aureus) resistance is due to excessive production of cell wall material , and these bacteria are usually also resistant to teicoplanin.

3. Side effects most common are fever, chill, and phlebitis. There can also be hearing loss, reversible nephrotoxicity, rashes, leukopenia, thrombocytopenia, eosonophilia, and lacrimation.

Category: Pharmacology Notes