Antibacterial Drugs

No 1 Target Cell wall Family -lactams Class

Penicillins

Sub-class
Penicillins

Examples
Penicillin G (Benzylpenicillin), Penicillin V Flucloxacillin Amoxicillin, Ampicillin Piperacillin Cefradine Cefuroxime Ceftriaxone, Cefixime Cefpirome

Clinical use/Selectivity
Narrow spectrum. Primarily G+, some G-, -lactamase sensitive Staph. infections (MSSA), -lactamase resistant Broad spectrum of G+ & G-, -lactamase sensitive Selected G-, especially P.aeruginosa Gram + : Active Gram - : Some/Moderate Gram + : Less than Gen1 Gram - : More than Gen1 Gram + : Less active Gram - : Very active -lac resistance: Some Gram + : Less than Gen1,2,3 Gram - : Less than Gen1,2,3 -lac resistance: Very high G- Rods (Bacilli) G+ & GG+ * MRSA*

MOA
- Targets PBPs - Each bacterial cell has several types of PBPs

ADR
- Sensitivity/Allergic reactions (NB: Anaphylactic shock) - Rash - Convulsions (IV administration)

Resistance
- Penicillinases (-lactamases) - PBP mutations

Notes

Cephalosporin

Penicillinase -resistant Broadspectrum Antipseudom. Gen1 Gen2 Gen3

- Addition of clavulanic acid (inhibits lactamases)

- C.difficile superinfection (Diarrhoea) - Nephrotoxicity

- Cephalosporinases (-lactamases) - PBP mutations - Decreased membrane permeability

Gen4

Monobactams Carbapenems

Glycopeptides

Aztreonam Imipenem, Meropenem Vancomycin, Teicoplanin, Daptomycin Erythromycin, Clarithromycin, Azithromycin

- Similar to other -lactams - Similar to other -lactams - Nausea & vomiting - Fever - Rash - Ototoxicity - Nephrotoxicity - 50S - Inhibition of elongation & translocation
2+

- Resistant to most -lactamases - Originally resistant to many -lactamases, but resistance starting to emerge - Binding site (mutation)

Protein

Macrolides

Tetracyclines

Tetracycline, Doxycycline, Minocycline

E: similar spectrum to penicillin (ie. mainly G+) C: G+ & GA: Less G+ but more G- than erythromycin Broad spectrum of G+ & G-

- Drug-inactivating enzymes - Binding site (blocked by methylase)

- Excellent alternatives to penicillins (Erythromycin especially)

- 30S r - Inhibition of aminoacyl tRNA binding to ribosome

Aminoglycosides

Chloramphenicol Oxazolidinones 3 Folate Sulfonamides

Streptomycin, Gentamicin, Neomycin, Amikacin, Tobramycin Chloramphenicol Linezolid

Primarily G-, some G+

- 30S - tRNA mismatching

- Ca chelation (deposition into bone & teeth causing staining ) - Teratogenic - Photosensitivity - GI disturbances - Modification to gut flora (B-complex deficiency & superinfection) - Ototoxicity (auditory [Neomycin, Amikacin] & vestibular [Streptomycin, Gentamicin]) - Nephrotoxicity

- influx (plasma-mediated) - efflux pump formation (plasmamediated)

- Useful alternative to penicillins & macrolides (eg. allergy, resistance, etc)

- Drug-inactivating enzymes (plasmamediated)

- Ototoxicity potentiated by concomitant use of other ototoxic drugs (eg. loop diuretics) - Nephrotoxicity potentiated by concomitant use of other nephrotoxic drugs (eg. Gen1 cephalosporins)

Broad spectrum of G+ & GG+ *C.difficile*, *MRSA*, *VRE* T.gondii, P.jirovecii (Co-trimoxazole), IBD (Sulfasalazine), STDs T.gondii, P.jirovecii, Nocardiosis Broad spectrum of G+ & G-

- 50S - Inhibition of elongation - 70S

Trimethoprim

Sulfamethoxazole, Sulfasalazine, Sulfadiazine (*Co-trimoxazole) *Co-trimoxazole

- DHP Synthetase inhibitor (Dihydropteroate Synthetase) - Compete with PABA for DHPS - Targets folate synthesis (DHPS) - DHFR inhibitor (FolateTHF) - Targets folate reduction (DHFR)

- Pancytopenia - Grey Baby Syndrome - Thrombocytopenia - Diarrhoea - Nausea - Bone marrow toxicity - ARF - Renal crystals - Hepatitis - Folate deficiency (megaloblastic anaemia)

- Drug-inactivating enzymes [Acetyltransferase] (plasma-mediated) - Linezolid is a non-selective MAO-I, precautions to be taken (5HT, serotonin syndrome) - Increased PABA production - Binding site (DHPS mutation) - Humans are unable to synthesise folate (from diet) and are thus not affected by anti-folates - Potentiation of effects with Trimethoprim (Cotrimoxazole) - Bacterial DHFR many times more sensitive to Trimethoprim than Human DHFR - Potentiation of effects with Sulfamethoxazole (Co-trimoxazole)

DNA Synthesis

Fluoroquinolones

Ciprofloxaxin, Levofloxacin, Nalidixic Acid (Narrow spectrum)

- Topoisomerase II Inhibitor (Bacterial DNA Gyrase) - inhibits transcription & replication (supercoiled DNA) - Binds to bacterial DNA and forms unstable molecule - Bacterial RNA Polymerase inhibitors

Metronidazole 5 RNA Synthesis RNA Polymerase Inhibitors

Rifampicin

Anti-protozoa, Anaerobic bacteria Anti-TB, & Broad spectrum of G+ & G-

- C.difficile & MRSA superinfection - Theophylline toxicity (inhibition of P450 enzymes with ciprofloxacin & theophylline) - Arrhythmias - Convulsions - Disulfiram-like action (avoid alcohol) - Potent inducer of P450 enzymes - Liver disease - Orange-pink colouration

- Decreased influx - Binding site (mutation)

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Antibiotic Contraindications:
1) Crossover allergy
i. ii. iii. iv. v. vi. vii. Cephalosporins & penicillins Tetracyclines Penicillins: Rash Anaphylactic shock Aminoglycosides: Ototoxicity & Nephrotoxicity Macrolides: Nausea, Long QT, Venotoxicity Sulfonamides: Hypersensitivity, SJS, BM toxicity, Hepatitis, ARF & renal crystals Tetracyclines: Crossover allergy, Photosensitivity, Teratogenecity, Ca2+Deposition Chloramphenicol: Pancytopenia, Grey Baby Syndrome Fluoroquinolones: Superinfections (C.difficile & MRSA), Arrhythmias (torsades), Convulsions

Combination therapy
- Advantage:
1) 2) 3) 4) 1) 2) 3) 4) Wider spectrum & potency Reduce dosage Prevent resistance Empirical/Temporary treatment pre-diagnosis Antagonistic effects (Bacteriocidal vs Bacteriostatic) Drug-drug interactions Toxicity Cost

2) Toxicity

- Disadvantage

Antibiotic Resistance:
- Can arise by:
1) Mutation 2) Gene transfer a) Plasmid exchange b) Bacteriophage (Viruses that injects its DNA into bacteria)

Antibiotic Interactions
- Synergism:
1) Penicillins & Aminoglycosides 2) Sulfonamides & Trimethoprim - Both bacteriocidal - Successive multi-step inhibition - Antagonises each others function

- Antagonism:
1) Penicillins & Bacteriostatic antibodies

- Caused by:
1) Low dose 2) Long course

- Prevented by:
1) High dose 2) Short course 3) Combination therapy

- Common mechanisms of antibiotic resistance:

1) Reduced intracellular drug levels a) efflux (overproduction of existing protein pumps) b) influx 2) Drug inactivation by enzymatic destruction 3) Alteration in drug target structure 4) Increased DNA repair 5) Endogenous inhibitors of apoptotic signalling - Tetracycline - Gram - bacteria - -lactamase, ESBL, Acetyltransferases, Kinases - PBPs, 30S ribosome (Streptomycin), RNA Polymerase (Rifampicin) - Fluoroquinolones

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