antibacterials - lecture 31

Over-arching theme with all anti-infectives

therapeutics aim to exploit biochemical differences between the pathogen and host

Selectively inhibit pathogen while minimizing toxicity to similar host pathways

Antibiotics

can be bactericidal or bacteriostatic:

bactericidal

kills bacteria

Work best on organisms with rapid growth (as opposed to those trapped within biofilm)

Of note, these are in vitro distinctions and the efficacy of drugs in vivo in clinical situations is more complex than these definitions imply

bacteriostatic

suppress bacterial growth

In theory require robust immune response to clear

infection

Of note, these are in vitro distinctions and the efficacy of drugs in vivo in clinical situations is more complex than these definitions imply

cell wall inhibitors

b-lactams:

Penicillins Cephalosporins Carbapenems Monobactams

glycopeptides

bacterial cell wall synthesis

Our cells do not have cell walls i.e. bacterial cell walls are an excellent therapeutic target

NAM-NAG are cross- linked by

pentapeptides

Cross-linking is catalyzed by

transpeptidases

In Gram (+) bacteria, the cell wall structure is thick

In Gram (-) bacteria, the cell wall structure is thin

2 classes of cell wall inhibitors

Beta lactams — includes 4 subclasses:

Penicillins

Cephalosporins Carbapenems Monobactams

glycopeptides

beta lactams

Very important drug class — broad spectrum of activity and favorable side effect profile

Mechanism of action (MOA): inhibit the transpeptidase that catalyzes cell wall cross- linking:

Penicillin binding protein (PBP) = transpeptidase

After cross-linking is halted, the bacterial cell wall cannot be completed and the bacterial cell lyses under suitable osmotic conditions (i.e. bacteriocidal)

beta lactams

Beta lactam ring and acyl side group are conserved across all subclasses (red box):

Spectrum of activity is determined by variable side groups that determine specificity for particular organisms

Penicillins developed first; new Beta lactams were developed to combat emerging antibiotic resistance particularly in S. aureus, Pseudomonas, and enteric Gram-negative rods (GNRs) e.g. E.coli, Salmonella, Klebsiella

Beta Lactams: Penicillins

Penicillins — the original beta lactam drugs:

Natural penicillins — penicillin G (parenteral: IV or IM), penicillin VK (oral)

Aminopenicillins — ampicillin (IV), amoxicillin (oral)

Resistance to Penicillins

Beta lactamases are bacterial enzymes that degrade the beta lactam ring. Bacteria that express beta lactamase can therefore destroy natural penicillins and aminopenicillins i.e. such bacteria have resistance to these drugs.

outcome of resistance to b lactams

bacteria continue to grow in the presence of the penicillin, i.e. they are resistant to the drug

outcome of resistance to b lactams: tools to fight resistance

bacteria do not grow in the presence of the drug(s) i.e. there is effective therapy

beta lactams

tools to combat drug resistance

Beta lactamase-insensitive penicillins and combination drugs were developed to combat drug resistance in S. aureus and Gram – rods /anaerobes respectively

Beta-lactamase-insensitive penicillins — oxacillin, nafcillin

Penicillin + beta lactamase inhibitors (BLIs) — combination drug of a broad-spectrum penicillin plus a beta-lactamase inhibitor e.g. amoxicillin-clavulanic acid, pipericillin-tazobactam

Cephalosporins - beta lactams

second subclass developed:

1st generation — cefazolin

2nd generation — cefoxitin

3rd generation — ceftriaxone, ceftazidime

4th generation — cefepime

5th generation — ceftaroline

As generation number increases, the drugs become increasingly useful for treating GNR but less useful for anaerobic organisms

(Remember drug class, not individual drugs)

Carbapenems - beta lactams

third subclass developed, “big gun” subclass for severe or high-risk

infections (e.g. multi-drug resistant bacteria):

Meropenem

Imipenem

Created to treat advanced resistance caused by ESBL (extended spectrum beta lactamases) in GNR and anaerobic organisms

Beta Lactams: Monobactams

“designer drug” class:

Aztreonam

Created to treat Pseudomonas infections in patients with penicillin allergies:

Only active against Gram - aerobes

Shares side group with ceftazidime – consequently patients allergic to ceftazidime maybe allergic to aztreonam

b-lactams

pharmacokinetics:

Absorption: rapid from GI tract (some PCN and cephalosporins only) Distribution: widely distributed but concentrations vary from tissue to tissue (e.g., only some drugs penetrate CSF) Elimination: kidney

adverse effects:

Allergic reactions (most common — rash, rarely anaphylaxis)

Nephrotoxicity

Neurotoxicity (high doses induce seizures) Hepatotoxicity (PCN/BLI, ceftriaxone)

drug interactions:

few

glycopeptides

Cell-wall inhibitors that treat resistant Gram (+) organisms

MOA:

Block cross-linking of pentapeptides and prevent cell wall synthesis

Bactericidal

Drug: vancomycin

glycopeptides

pharmacokinetics:

Absorption: none, given IV only (important

exception: C. difficile infections of the gut)

Distribution: widely distributed (including CSF when meninges are inflamed e.g. meningitis)

Elimination: kidneys

adverse effects:

Vancomycin-flushing (previously Red-man) syndrome - extreme flushing due to direct release of histamine from mast cells. Remedy: decrease infusion rate, administer diphenhydramine as necessary

Nephrotoxicity

drug interactions:

none indicated

protein synthesis inhibitors

Aminoglycosides (Gentamicin)

Tetracyclines (Doxicycline)

Macrolides (Azithromycin)

Lincosamides (Clindamycin)

Oxazolidinones (Linezolid)

protein synthesis inhibitors

MOA: inhibit bacterial ribosome

Bacterial and mammalian ribosomes are similar but different enough that drugs are selective for the pathogen:

protein synthesis inhibitors

Includes drugs that act on the 2 subunits of the 70S bacterial ribosome:

30S inhibitors:

Aminoglycosides

Tetracyclines

50S inhibitors:

Macrolides Lincosamides Oxazolidanones

Adverse Reactions/Drug Interactions of 30S inhibitors

Aminoglycosides (eg gentamicin)

Not useful against anaerobes

Very effective antibiotics but the toxicity of

aminoglycosides limits their clinical use

Ototoxicity

Nephrotoxicity

Tetracyclines (eg doxicycline)

Particularly useful against intracellular organisms

Tetracycline is incorporated into calcifying structures

(not used in children <8 yrs)

Allergy, superinfection

Hepatotoxic and nephrotoxic

Photosensitivity

Metal cations, like Zn2+, Ca2+, Mg2+ (found in

antacids, dairy products, dietary supplements) impair absorption in GI tract

Adverse Reactions/Drug Interactions of 50S inhibitors

Macrolides (eg azithromycin)

Cholestatic Jaundice

Antagonize other antibiotics targeting 50S

(commonly stated to decrease the effectiveness of oral

contraceptives: false)

CYP 3A4 inhibitor (i.e. many drug-drug interactions)

Cardiac arrhythmias

Lincosamides (eg clindamycin)

Can precipitate antibiotic-associated diarrhea

(C. difficile pseudomembranous colitis)

Oxazolidinones (eg linezolid)

Very useful in ICU settings for resistant Gram + infections eg MRSA, VRE

Myelosuppression, CNS effects

Folic acid synthesis inhibitors

Sulfonamides

Trimethoprim

folic acid

Bacteria must synthesize folic acid for growth

Sulfomamides and trimethoprim are competitive inhibitors of distinct steps in the bacterial synthesis of folic acid

Combined together (e.g. trimethoprim- sulfamethoxazole, Bactrim) because resistance to individual drugs is widespread

Folate Synthesis Inhibitors

Pharmacokinetics

Absorption: rapid absorption from the GI tract

Distribution: widely distributed including CSF

Elimination: renal

Adverse Effects

Rashes

Bone marrow suppression (mostly seen in folate deficient patients)

Nephrotoxicity

Drug interactions

CYP 3A4, CYP 2C8 and CYP 2C9 inhibitors (consequently many drug-drug interactions)

Bacterial replication inhibitors

Quinolones, Fluoroquinolones (Ciprofloxacin)

Nitroimidazoles (Metronidazole)

Fluoroquinolones e.g. Ciprofloxacin

Mechanism of Action:

Inhibit DNA topoisomerase and/or gyrase activity (unique

to bacteria) and hence DNA synthesis

Fluoroquinolones

Pharmacokinetics

Absorption: rapid absorption from the GI tract

Distribution: widely distributed (including CSF)

Elimination: kidney

Adverse Effects

Achilles tendon rupture Cardiac arrhythmias

Drug interactions

Absorption markedly reduced when given with antacids

Nitroimidazoles e.g. Metronidazole

Mechanism of action— complex, unique

Metabolites of nitroimidazoles affect DNA/RNA synthesis and protein synthesis in bacteria

-- bacteriocidal

Spectrum of activity

-- Anaerobes (Gram – and Gram +), some protozoa

Adverse effects

-- Disulfiram (Antabuse)-like reaction with alcohol use

-- Neuropathy

Superinfection

appearance of a secondary infection as a result of treating a primary infection, e.g. C. difficile after Clindamycin treatment

"wont test us on anything after this"

"wont test us on anything after this"