Antimicrobials

Penicillins

• Bactericidal
• Produced from fungi and molecular modification
• Interfere with bacterial cell wall production (disrupt) cross linking of glycan strands)
• Renally excreted
• Most effective:

• Staphylococci (although now commonly resistant, flucloxacillin prevents the action of beta-lactamases)

• Streptococci 
• Clostridia (Gram positive bacilli)
• Gram negative bacilli such as E. coli and H. influenzae

Cephalosporins

• Bactericidal
• Inhibit bacterial cell wall synthesis
• Broader spectrum than penicillins: effective against beta-lactamase producers

• Later generation agents have effectivity against more Gram negative organisms including pseudomonas and bacteroides

Aminoglycosides: gentamicin

• Bactericidal

• Prevents the first ribosome from joining the mRNA by irreversibly binding to the 30S subunit

• Efficacy: 
• Staphylococci
• Aerobic Gram negatives eg. pseudomonas, proteus
• Not effective against streptococci and anaerobes

• Parenteral administration associated with adverse effects: vestibular, cochlear, renal (rare)

• Amikacin is an aminoglycoside with good Gram negative activity
• Commonly given intravitreally
• Useful for patients with significant penicillin allergy
• Less retinotoxic than gentamicin

• Aminoglycosides do not cross the blood-brain barrier and so do not enter the vitreous
• Not given systemically in endophthalmitis

Tetracyclines

• Bacteriostatic

• Interrupt amino acid attachment during protein synthesis, also by targeting the 30S subunit of the ribosome

• Broad spectrum
• Treatment of choice for chlamydial infections (eg. trachoma), brucellosis, Q fever

• Side effects
• GI upset
• Birth defects
• Permanent teeth staining in children
• Diarrhoea 

Chloramphenicol

• Bacteriostatic

• Prevents peptide chain transfer to other amino acids by targeting the 50S subunit of the ribosome: inhibiting protein synthesis (specifically inhibits peptidyltransferase)

• Potent against staphylococci (hence use for bacterial conjunctivitis)
• Systemic use limited to H. influenzae, meningitis, typhoid
• Can cause potentially fatal aplastic anaemia
• Contraindicated in pregnancy and breastfeeding: grey baby syndrome

Metronidazole

• Disrupts DNA synthesis
• Crosses the blood-brain barrier
• Efficacy: 
• Anaerobic organisms
• Protozoa including trichomonas and giardia

Ofloxacin

• Fluoroquinolone
• Bactericidal 
• Inhibits bacterial DNA gyrase: DNA synthesis inhibitor
• Broad spectrum:
• Pseudomonas
• Chlamydiae
• Mycoplasmas
• Rickettsia
• Enterobacteriaceae 
• Less effective against Gram positives and anaerobes
• Good corneal penetration into the AC
• Systemic use: GI upset and photosensitivity

Vancomycin

• Glycopeptide
• Bactericidal against Gram positives
• Inhibits peptidoglycan assembly and therefore cell wall synthesis
• Good Gram positive efficacy (ineffective against Gram negative)

• Cannot penetrate the outer membrane of Gram negatives

• Poor GI absorption

Amphotericin

• Macrolide polyene antifungal
• Broad spectrum including most fungi that infect humans

• Not absorbed enterally (must be given IV or intravitreally eg. for Candidal endophthalmitis)

• Binds to sterols in cell membranes and has a high affinity for ergosterol: the major sterol in fungal membranes

• Creates ion channels in the membrane leading to loss of membrane integrity
• Adverse effects:
• Anaemia
• Nephrotoxicity

Fluconazole

• Azoles: alter fungal membranes by blocking synthesis of ergosterol leading to cell leakage

• Active against most Candida, Cryptococcus and Histoplasma
• Not effective against aspergillus or mucor
• Hepatotoxic
• Good CNS uptake
• Given intravenously or orally 

Flucytosine

• Disrupts fungal protein and DNA synthesis
• Effective against candida and cryptococcal infections
• Good tissue and CSF penetration
• Marrow aplasia (although not hepatotoxic)
• Fungal resistance is common

Aciclovir

• Acyclic analogue of guanosine

• Activated via phosphorylation by viral thymidine kinase and thereafter inhibits DNA polymerase

• The viral form of thymidine kinase is more effective at this activation than the human form so infected cells are preferentially affected

• Highly specific for HSV and VZV (lesser activity against EBV and CMV).
• Side effects:
• Renal impairment (mild): with intravenous use
• GI upset
• Headache

Ganciclovir

• Acyclic nucleotide analogue with a hydroxymethyl group (cp. with aciclovir)
• Virostatic 
• Inhibits CMV DNA polymerase

• Given intravenously or intravitreally (for CMV retinitis)

• Administered in inactive form which is phosphorylated after uptake by virally-infected cells

• UL97 mutation renders ganciclovir susceptible to resistance
• Side effects

• Haematological (bone marrow suppression: neutropenia (40% of patients), thrombocytopenia (20%)

Foscarnet

• Antiviral: binds to DNA polymerase to prevent nucleotide binding
• Given intravenously or intravitreally
• Side effects: nephrotoxicity

Summary Table: Bacteriostatic vs Bactericidal agents and mechanisms of action

anti-HIV agents

• Ritonavir: protease inhibitor 
• Nausea and diarrhoea
• Zidovudine: reverse transcriptase inhibitor 
• Cytopenia
• Didanosine: reverse transcriptase inhibitor
• Pancreatitis
• Zalcitabine: reverse transcriptase inhibitor
• Peripheral neuropathy

Sulfadiazine

• Blocks the production of dihydrofolate from para-aminobenzoic acid
• Used in the treatment of Toxoplasma gondii

Pyramethamine

• Dihydrofolate reductase inhibitor
• Used in the treatment of Toxoplasma gondii

Antibiotic resistance

• Mutation
• Conjugation
• Plasmid transfer