ex 2 Dr. Kuhl chart

Pleuromutilins MOA

inhibits protein synthesis via H-bonds, hydrophobic and Van der Waals interactions with the A- and P-site of the peptidyl transferase center, domain V of the 23S rRNA (50S). The mutilin core closes the binding pocket in an induced fit that prevents correct tRNA positioning. (bacteriostatic/ time-dependent, AUC:MIC)

Lefamulin

pleuromutilins

pleuromutilins spectrum & niche

narrow

resp pathogens only: gram (+) cocci, atypicals, H. influenzae

FDA approved for CAP

take PO on an empty stomach

Pleuromutilins pharm

hepatic metabolism

mix IV only in the citrate-buffered NS bag provided

QT prolongation serious SE

CI: oral only- sensitive CYP3A4 substrates that also prolong the QT interval

Polymyxins MOA

acts as a cationic detergent- binds the cytoplasmic membrane and disrupts the osmotic barrier

(bactericidal/ concentration-dependent killing)

Polymyxin B sulfate

polymyxin class

available as generic injectable

narrow- gram neg bacilli only

MDR GNRs incl Acinetobacter and pseudomonas

reserved for severe, life-threatening infection because of toxicity

colistimethate

narrow

Polymyxins- prodrug - hydrolysed to active form

reserved for severe, life-threatening infections

Polymyxins pharm

excellent tissue penetration except CNS, synovial, pleural, pericardial

renal elimination- dose reduction req

Polymyxin B BW

nephrotoxicity, neurotoxicity, resp muscle paralysis

Polymyxin precautions

feta & infant risk can’t be ruled out

IM/intrathecal- hospital use only

Rifamycins MOA

binds bacterial DNA-dependent RNA polymerases→ inhibits RNA synthesis (bactericidal)

Rifampin

rifamycin (class)

narrow

full pharmacology resistance mechanisms and its interaction burden are taught with TB agents

Rifaximin

Rifamycins

narrow GI flora, non-absorbed

not absorbed orally- for GI disease, not systemic infection

covers gram neg bacilli

Rifaximin uses

for traveler’s diarrhea, hepatic encephalopathy, (decreased ammonia producing bacteria); IBS with diarrhea

rifaximin/fidaxomicin: no renal dose adjustment

fidaxomicin

rifamycins class

narrow- C. diff only

not absorbed orally- C. diff only

use: CDAD

Fosfomycin

UTI agent

narrow

Use: single dose uncomplicated UTI

Fosfomycin MOA

inhibits cytoplasmic enolpyruvyl transferase, an early step in peptidoglycan cell-wall synthesis (bactericidal)

Methenamine hippurate

UTI agent

narrow- not proteus

uses: lower UTI only, chronic prophylaxis

CI: renal insufficiency and severe hepatic disease

Methenamine MOA

converted to formaldehyde at pH <5.5 (toxic to most bacteria) renally concentrated slow reaction- urine must be retained in the bladder, no catheters

methenamine + sulfonamides

do not combine, reacts with the formaldehyde

Nitrofurantoin

macrodantin, furadantin- UTI agent

narrow

use: uncomplicated UTI, chronic prophylaxis

Nitrofurantoin MOA

reduced by the bacteria to its active form, damages DNA and intracellular enzymes (bactericidal) renally concentrated

inadequate levels for systemic disease, works better on acidic urine

nitrofurantoin CI

manufacturer: CrCl <60 mL/min

evidence: short-term use at CrCl: 30-60 mL/min supported by outcomes data

hx of cholestatic jaundice/hepatic dysfunction from prior nitrofurantoin therapy

Pulmonary toxicity, hemolytic anemia (G6PD deficiency, + Coombs)

Nitrofurantoin more CI

CI at term 38-42 weeks during labor/delivery, and in neonates <1 month

Distinct from the G6PD-deficiency hemolysis above: generally considered a first-line UTI option earlier in pregnancy, the risk is specifically near-term.

Thiadiazinane MOA

(dual) heparin- increase antithrombin III activity, prevents catheter-lumen clotting. Taurolidine- no specific, damages cell walls and inhibits microorganisms adherence to biologic surfaces

Taurolidine/heparin

thiadiazinane

N/A not a systemic antibiotic, reduce catheter-related bloodstream infections

not for systemic infection

monitor for heparin-induced thrombocytopenia

monitor for bleeding

Aminoglycosides MOA

irreversibly binds the 30S ribosomal subunit, interfering with the initiation complex of peptide formation → misreading of mRNA (bactericidal/ concentration-dependent killing/ post- antibiotic effect) `

Gentamicin

garamycin IV- aminoglycosides

narrow- gram neg bacilli

aminoglycosides

narrow- gram neg bacilli

renal elimination

poor oral absorption used deliberately for selective GI decontamination

Tobramycin

nebcin

aminoglycoside class

aminoglycoside dosing

traditional: peak by infection type (pneumonia 8–12; serious infection 4–8; UTI/synergy 2–4 mcg/mL), trough goal < 2 mcg/mL. Extended-interval "once-daily" dosing: 5–7 mg/kg q24–48h, interval chosen to allow an undetectable trough for 4–8 h — less nephrotoxic in patients with CrCl > 40 mL/min.

aminoglycoside BW

nephrotoxicity, neurotoxicity/ototoxicity

neuromuscular blockade (decreased ACh release)

-caution in myasthenia gravis

-PGx- MT-RNR1 mitochondrial variant

aminoglycosides CI

avoid concomitant neuromuscular blockers

absolute in pregnancy- fetal ototoxicity

additive nephro-/ototoxicity: loop diuretics, vancomycin, amphotericin B, cisplatin

Amikacin

Amikin aminoglycosides

aminoglycosides class

Plazomicin

aminoglycosides

Macrolides MOA

reversibly binds 50S rRNA, blocking the translocation step of protein synthesis by occluding the peptide exit tunnel. (bacteriostatic/ time-dependent killing)

Azithromycin

Zithromax, Zmax (IV, PO)

long half-life; no significant 3A4 interactions

preferred in pregnancy

Clarithromycin

Biaxin- PO

strong CYP3A4 inhibitor

also renally eliminated- adjust

Erythromycin

macrolide class

strong CYP3A4 inhibitor

macrolides

moderate coverage (gram + cocci, atypicals, & limited gram - coverage)

hepatic elimination- all agents

resistance: esterase hydrolysis; cross resistance with clindamycin

macrolides BW, CI

QT prolongation; Cholestatic hepatitis

CI: colchicine

tetracyclines & glycylcyclines MOA

tetracyclines- reversibly binds 30S rRNA, blocking aminoacyl-tRNA binding at the A site no further amino acids can be added. (bacteriostatic/ time-dependent killing)

Tigecycline/omadacycline/ Eravacycline extend the same with target with structural modifications that evade classic tetracycline efflux/ribosomal protection resistance

Doxycycline

vibramycin, doryx, adoxa- tetracyclines & glycylcyclines

best CNS penetration

Tetracyclines & glycylcyclines

moderate, broader for the newer agents

pregnancy/ breastfeeding- no safe exception for this class

Tetracyclines & glycylcyclines BW & CI

BW: children 8 or less, pregnancy, breastfeeding- bone- growth supression, tooth staining

pseudotumor cerebri (benign intracranial hypertension)

avoid with retinoids

Minocycline

minocin- Tetracyclines & glycylcyclines

Omadacycline

Tetracyclines & glycylcyclines

omadacycline/ eravacycline- no renal dose adjustment

Eravacycline

Tetracyclines & glycylcyclines

Tigecycline

tigecycline/ eravacycline/ omadacycline- expanded gram -, not pseudomonas

expanded gram -, NOT pseudomonas

Lincosamides MOA

reversibly binds 50S rRNA (A-site tRNA positioning + P-site translocation), blocking peptide- bond formation. (bacteriostatic/ time-dependent killing)

Clindamycin

Cleocin- Lincosamides

Lincomycin

lincocin- lincosamides

Lincosamides

narrow- gram + cocci and anaerobes only

no renal dose adjustments

IV dose> PO dose

resistance: ribosomal receptor mutation; cross-resistance with erythromycin

Lincosamides BW & CI

BW: CDAD/ pseudomembranous colitis

do NOT use for meningitis

avoid combining with erythromycin (antagonism) and BCG vaccine

Oxazolidinones MOA

reversibly binds 23S rRNA of the 50S subunit (a unique site), preventing formation of the 70S initiation complex.

Bacteriostatic/ time-dependent killing

Linezolid

Zyvox - oxazolidinones

weak, reversible MAO inhibitor- serotonin syndrome with serotonergic agents

contraindicated within 2 weeks of an MAO inhibitor

Tedizolid

oxazolidinones

oxazolidinones spectrum & pharm

narrow gram + only

hepatic metabolism, not approved for UTI

oxazolidinones SE

myelosuppression if used > 2 weeks

peripheral and optic neuropathy

miscellaneous RNA- chloramphenicol MOA

binds 50S rRNA and inhibits peptidyl transferase, blocking peptide-bond formation. (Bacteriostatic agonist most bacteria; bactericidal against H. influenzae, N. meningitidis, S. pneumoniae)

also inhibits mitochondrial (organellar) protein synthesis- the structural basis of its human marrow toxicity

chloramphenicol

broad

excellent CNS penetration, hepatic metabolism (glucuronidation) immature in neonates

chloramphenicol BW and more

BW: serious/fatal blood dyscrasias

gray baby syndrome

reserve for serious infection with no suitable alternative

Folate antagonists MOA

this is a NUCLEIC ACID pathway, not protein synthesis: sulfonamides competitively inhibit dihydropteroate synthase (a PABA analog, unique to bacteria); trimethoprim/pyrimethamine competitively inhibit dihydrofolate reductase (higher affinity for the bacterial/protozoal enzyme than the human one). Sequential blockade of folate synthesis → ↓ tetrahydrofolate → ↓ thymidine/purine → ↓ nucleic acid synthesis. (Bacteriostatic alone; bactericidal in the SMX-TMP combination / Time-Dependent Killing

folate antagonists

sulfonamides, trimethoprim, pyrimethamine

folate antagonist coverage & pharm

moderate gram + / - coverage

incl MRSA-CA and several “unusal” pathogens

fixed ratio 1:5 TMP: SMX; excellent CNS penetration

avoid concomitant leucovorin in HIV positive pts being treated for PCP

Sulfamethoxazole- trimethoprim

folate antagonist

bactrim, septra

folate antagonist SE & CIs

hypersensitivity rash, SJS/TEN

bone marrow suppression: hemolytic anemia

hyperkalemia

CI: dofetilide

Folate antagonist precautions

timing-dependent, not absolute: 1st trimester→ congenital malformation risk, near-term→ kernicterus

increase INR with warfarin; photosensitivity

CI: methotrexate

caution ACEi/ ARB + spironolactone

nitroimidazoles MOA

the nitro group is reduced by anaerobes and protozoal species, activating pyruvate-ferredoxin oxidoreductase, which removes electrons from NADPH and produces reduced cytotoxic compounds that bind proteins, membranes and DNA. Bactericidal/ time-dependent killing

Metronidazole

flagyl

nitroimidazoles drugs

metronidazole, tinidazole & secnidazole

metronidazole

narrow & in an unusual direction- anaerobic and protozoal (Class)

IV: PO ~ 1:1 excellent CNS penetration

Nitroimidazoles BW & SE

BW: carcinogenic- class effect, incl tinidazole

SE: dysgeusia - metallic taste

nitroimidazoles precautions

CI: 1st trimester of pregnancy; disulfiram (acute psychosis) & lithium (increased lithium levels)

avoid alcohol during and within 3 days

DDI: 3A4 (moderate); 2C9 (strong) → increase INR on warfarin

Fluoroquinolones MOA

gram - primarily inhibits topoisomerase II/ DNA gyrase, which uncoils DNA; inhibition supercoils DNA & blocks transcription/replication. Gram + primarily inhibits topoisomerase IV, which decatenates replicated DNA into daughter cells; inhibition blocks replication. (bactericidal/ concentration- dependent killing/ post-antibiotic effect)

ciprofloxacin

cipro- fluoroquinolone

DDI: P-gp (strong)

CI: do not give with tizanide

Not reliable for S. pneumoniae; best pseudomonas coverage

renally eliminated

Levofloxacin

levaquin- fluoroquinolones

respiratory quinolones

renally eliminated

Moxifloxacin

Avelox- fluoroquinolones

respirarory quinolones

not renally eliminated

prolongs QTc the most

fluoroquinolones other (drugs)

delafloxacin- SSTI indication only

ofloxacin, finafloxacin/ gatifloxacin - topical use only

fluoroquinolones spectrum & pharm

broad

renal elimination

divalent/ trivalent cations (dairy, antacids, iron, zinc)- decrease absorption

excellent tissue penetration

resistance- generally confers class resistance

fluoroquinolones BW

BW: tendinitis/ tendon rupture, peripheral neuropathy, CNS effects, myasthenia gravis exacerbation, aortic aneurysm/ dissection

QT prolongation

arthropathy (articular cartilage erosion)

fluoroquinolones precautions

pregnancy: a cartilage/ arthropathy concern, not an absolute ban

triazaacenaphthylenes MOA

inhibits type II topoisomerases— bacterial topoisomerase II (DNA gyrase) and topoisomerase IV— at a site distinct from the fluoroquinolones binding site, blocking DNA replication. (bactericidal)

that distinct site is why it holds up against FQ-resistant organisms— FQ target- mutation resistance doesn’t cross-react

Gepotidacin

Blujepa- triazaacenaphthylenes

Po- 1500 mg BID x5 days

narrow

Blujepa spectrum & pharm

for uncomplicated UTI

approved for pts 12 or older and more than 40 kg

avoid GFR < 30 ml/min and child-Pugh C

gepotidacin SE & DDI

QT prolongation

DDI: CYP3A4; acetylcholinesterase inhibitors

Spiropyrimidinetriones MOA

first-in-class spiropyrimidinetrione— binds DNA gyrase/ topoisomerase IV at a site distinct from the fluoroquinolone binding site, blocking DNA replication— same rationale as gepotidacin: holds up against FQ- resistant gonorrhea. Bactericidal approved 2025-12-12

Zoliflodacin

Spiropyrimidinetriones class

very narrow- single dose oral treatment of uncomplicated gonorrhea

single dose therapy with a limited SE profile overall

zoliflodacin CI

concomitant use moderate/ strong CYP3A4 inducers- including rifampin