Thread by @DrH_flu

Mandell ch. 29:
Macrolides do not have all that great oral bioavailability

Much higher tissue penetration than serum levels

Azithromycin tissue half-life is 2-4 days, so likely retains significant antibacterial activity for 5 days after a 5 day course
1/16

#IDTwitter #idmeded

Macrolides, clindamycin and chloramphenicol all bind at the same site of the 50S ribosome, preventing early chain elongation. They may competitively inhibit each other if used together
2/16

Resistance occurs by several mechanisms:
⚜️ Efflux pumps, one in Enterobacteriaceae (chromosomal) and a different one in Strep & Enterococcus species...the latter is called the M phenotype, is transposable, and only gives resistance to erythro, azithro and clarithro
3/16

⚜️ The other major mechanism of resistance is alteration of binding sites on the 50S ribosome, the MLSb phenotype (Macrolides, Lincosamides, Streptogramin B)

Mediated by erm genes, of which there are many classes (A, B, C, F, etc), on plasmids or transposons
4/16

MLSb is carried by:
⚜️ S. aureus (ermA, C)
⚜️ S. pyo (ermA, B)
⚜️ S. pnuemo, Enterococcus
⚜️ Corynebacteria
⚜️ Bacteroides (ermF)
⚜️ Clostridia
⚜️ Mycoplasma, Legionella
and others.

Watch out, this gets complicated...
5/16

MLSb can be constitutive or inducible, depending on the 🦠 and erm gene.

For example, in S. pyogenes with ermA, the MLSb is constitutive.

But S. pyogenes with ermC has inducible MLSb

If constitutive, it's resistant to clinda...
6/16

If inducible, the in vitro testing will show S to clinda, but in vivo, if clinda is used, it will select for mutants that constitutively make MLSb...

And now the 🦠 will be resistant to clinda. This is especially likely in high bacterial density infections
7/16

In Staph species, clindamycin isn't an inducer; only certain macrolides are, such as erythromycin.

The clinda resistance in vivo occurs because of selection of constitutive mutants when clinda is used, as above, which may lead to treatment failure
8/16

This is where the D test comes in, which is performed when Staph has erythro R and clinda S on in vitro testing, to confirm clindamycin susceptibility

If the erythro resistance is due to a mechanism like efflux pumps, the D test will show susceptibility to clindamycin
9/16

If the erythro resistance is due to inducible MLSb, the erythro will induce clinda resistance to the Staph, leading to the blunted side of the zone of inhibition between the two discs

Photo credit: TUSOM PharmWiki
10/16

(If the MLSb is constitutive, both erythro and clinda will report R on in vitro testing and you wouldn't need a D test)

Nosocomial MRSA is more likely to have constitutive MSLb, as opposed to MSSA and CA-MRSA, which are more likely to have inducible MLSb
11/16

Here's the thing...

In Enterococcus, *all* MLSb antibiotics can induce MLSb if an erm gene is present (usually ermB)

So complete cross resistance is expected whether the MLSb is constitutive or inducible

We will revisit this in the streptogramin chapter...
12/16

Cross-resistance is complete between erythro, azithro and clarithro regardless if the mechanism of resistance is MLSb or M phenotype, etc

Resistance to clinda in S. aureus can also be PhLOPSA (chloramphenicol, clinda, linezolid, streptogramin A) through 23S alteration
13/16

That discussion of MLSb was exhausting, so just a few more tidbits about these familiar drugs:

⚜️ Azithromycin has a profound and prolonged effect on the gut microbiome, more so than beta-lactams

⚜️ Clarithromycin's major metabolite also has good antibacterial activity
14/16

⚜️ B. fragilis group has ⬆️ R to clinda, up to 30-60%

⚜️ Clinda is used for Staph & Strep toxin-producing infections because it inhibits the ribosome and therefore protein (toxin) production; also because it acts on the stationary growth phase, as opposed to beta-lactams
15/16

Clinda has great bone & abscess, but no CNS, penetration.

It has several metabolites with antibacterial activity, including one which is actually more active than clinda, and which concentrates in the bile
16/16