Gentamicin, Tobramycin, Amikacin

MOA: inhibit translation by binding 16S of 30S ribosomal subunit, causing misreading and leading to cell death 

Bactericidal

Aminoglycoside (time/concentration), elimination, and bioavailability (where does it go?)

Concentration dependent, very low bioavailability (1 big dose, IV for acute), renal elimination, very short half lifes

Suboptimal penetration of sputum/lung/bone/CNS/abcesses (can be injected directly into CNS for CNS infection) 

Excellent against enterobacteraciae, acinetobacter, pseudomonas, and other GNR

Good vs many GPC in synergy with cell wall active agent 

Elimination of aminoglycosides completely dependent on renal function

Small doses in UTI to avoid toxicity - very small doses will treat UTIs because of renal clearance

Aminoglycosides

7 mg/kg

Check concentration at certain time intervals (time between start of infusion and sample draw)

Increasing age

Hypovolumemia - modifiable by hydrating patient

Concurrent nephrotoxins

Pre-existing renal dysfunction

Onset is variable and can rarely occur with first dose, but it will usually take several days

Gram negative nosocomial infections, mycobacterial infections (streptomycin, amikacin), pseudomonal infections, gram positive synergy in endocarditis

Enzymatic inactivation (enterobacteraciae)

Altered membrane permeability (pseudomonas)

Target site mutation (many organisms) 

Clindamycin, Lincomycin

MOA: inhibits translation by binding 50S subunit and inhibiting peptidyl transferase

Bacteriostatic

~90% bioavailable 

Anaerobes, but not C. diff

Active against staphylococci (including some MRSA), and streptococci, anaerobes

Not good for MRSA pneumonia, not good against atypicals

Altered target site

In gram positives, often cross resistant with macrolides, streptogramins 

Positive D test - susceptible to clindomycin, resistant to macrolide - but will show up as d because macrolide is inducing resistance in clindomycin

Flattening of clindamycin zone = positive D test

Due to expression of erm gene (MOSB phenotype) 

Erythromycin, Clarithromycin, Azithromycin, Troleandomycin, Ririthromycin

MOA: inhibit translation by binding 23S RNA of 50S subunit of ribosome and block exit tunnel

Bacteriostatic 

Achieve high intracellular concentrations, highly bioavailable, excellent lung penetration, poor CNS penetration 

Azithromycin has longest terminal half life 

Elimination: hepatic metabolism or biliary excretion 

Macrolide Spectrum of Activity

Which ones have convenient dosing

Streptococcus, atypical pathogens, some GNR including H influenze and Moraxella 

Clarithromycin - H pylori

Clarithromycin and azithromycin have more convenient dosing than erythromycin 

GI disturbances (N/V/D), particularly with higher doses, rash

Drug Interactions: 

Erythromycin and clarithromycin = inhibitors of CYP 1A2, 3A3/4

Azithromycin has a much lower interaction potential (longest terminal half life too) 

CAP, Upper resp tract infection, MAC, PUD (clarithromycin -- active vs H pylori), promotility (erythromycin)

Efflux pump, altered target site 

Do ketolides instead

Telithromycin (Ketek)

Macrolide analogue with increased S. pneumoniae activity

PO only

Well absorbed, not very soluble

Spectrum, AEs, DIs, similar to macrolides

Additional AE: hepatotoxicity

Main use: CAP (outpatient)

Minocycline, Tetracycline, Doxycycline, oxytetracycline, chlortetracycline, demeclocycline

Inhibit translation by binding reversibly to 30S ribosomal subunit, blocking tRNA from binding ribosome mRNA complex

Bacteriostatic 

(Physically blocks A site)

Atypicals (especially tick diseases), staphylococci including some MRSA, S pneumoniae but resistance in many other strep, Some GNR but limited by resistance (efflux pump), weird organisms: bacillus anthracis, b burgdorferi, y pestis, t pallidum, h pylori

not vs pseudomonas

Highly absorbed

Poor CNS penetration but enough to cause problems (dizziness, confusion, especially in elderly)

AE: tooth discoloration, GI Upset - N/V/borborygmous, photosensitivity (very serious sunburn)

Drug Interaction: multivalent cations --> chelation --> lower absorption 

Cell wall synthesis inhibitors --> disruption of cidal activity 

Has expanded spectrum

Poor absoprtion; very high distribution - low plasma concentrations

Long 1/2 life but dosed q12 hours

Hepatic elimination

Covers many GNR and GPC (including VRE and MRSA), good anaerobic coverage, does not cover pseudomonas or proteus

AE: Significant N/V

Uses: SSTIs, intraabdominal infections (not adequate for HAP)

Good CNS activity but you need cidal activity

Hepatically metabolized through conjugation 

Useful spectrum: streptococci, staphylococci (methicillin sensitive only), enterococci including VRE 

Anaerobes

Some GNR

Gray baby syndrome: neonatal impairment of conjugation -- vomiting/flaccidity/gray color/respiratory distress/metabolic acidosis)

Bone Marrow Suppression

Reversible - dose related

Irreversible - idiopathic 

Elevated phenytoin, phenobarbital, warfarin 

Very uncommonly used in USA

Quinupristin/dalfopristin (Synercid)

MOA: bind to 50S halting protein synthesis

IV only 

Bactericidal against MSSA, MRSA, streptococci

Bacteriostatic vs Enterococcus faecium

Hepatically metabolized 

Some CNS penetration

Hepatically metabolized

Useful spectrum: staphylococci (including MRSA), streptococci (including PCN resistant strains), E. faecium including VRE, but NOT E. faecalis

Phlebitis, severe myalgias, hepatotoxicity, line crystallization when mixed with saline (use D5W only) 

Drug Interactions: CYP450 3A4 inhibitor - causes increased levels of cyclosporine, nefedipine, midazolam, tacrolimus, other agents 

Main Uses: VRE faecium

MRSA infections who can't take other agents

Linezolid, Tedizolid

Binds to 23S of 50S subunit preventing protein synthesis by blocking formation of 70S initiation complex

Bacteriostatic

Highly bioavailable --> PO = IV dosing

Dual hepatic metabolism (not via CYP) and renal elimination 

Weak, reversible inhibitor of monoamine oxidase

Linezolid > Tedizolid (dosed 6x less)

Myelosuppression, thrombocytopenia

Peripheral and optic neuropathy

Serotonin syndrome 

Main uses: MRSA or VRE infections

Resistance due to: altered target site