Antibiotics

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Protein synthesis inhibitors

Protein synthesis inhibitors 30S and 50S inhibitors

30S = aminoglycosides + tetracyclines

50S = chloramphenicol + clindamycin + macrolides (and linezolid = lower-yield, but in FA)

Knowing the above classifications is mandatory.

However the USMLE is going to throw buzz words at you for these, so you need to know their individual MOAs.

Protein synthesis inhibitors Before I get into the specifics of each drug, here are the

“buzz words” you need to associate with the 50S drugs:

Macrolides = “BLOCK TRANSLOCATION STEP” via binding to the 23S rRNA of the 50S subunit.

FA says chloramphenicol and clindamycin both block peptide bond formation, but in terms of the USMLE, they’re going to want you to know that chloramphenicol more specifically “blocks peptidyltransferase.” For clindamycin, it “blocks peptide bond formation.” That’s how it’s seen in questions.

Protein synthesis inhibitors For the 30S buzzwords:

Aminoglycosides = “disrupt initiation complex and cause misreading of mRNA.”

Protein synthesis inhibitors For the 30S buzzwords:

Aminoglycosides = “disrupt initiation complex and cause misreading of mRNA.”

Tetracyclines = “prevent attachment of aminoacyl-tRNA to the A-site” on the 30S.

Aminoglycosides vs macrolides (names) Gentamycin, neomycin, amikacin, tobramycin,

steptomycin (highest-yield ones) = AMINOGLYCOSIDES

Erythromycin, azithromycin, clarithromycin = MACROLIDES

When you see these drug names enough through doing lots of practice questions, you soon won’t have to think twice about their classifications, but at the very minimum, don’t screw these up. I had an easy question my real deal where I had to pick out the aminoglycoside, and they had also listed a macrolide.

Bactericidal vs bacteristatic You’ve gotta know which protein synthesis inhibitors

are bactericidal vs –static.

The 50S ones alone are BACTERISTATIC. That means the macrolides and chloramphenicol + clindamycin are BACTERISTATIC.

Of the 30S, tetracyclines are BACTERISTATIC, but aminoglycosides are BACTERICIDAL.

Tangential: TMP and SMX, individually, are bacteristatic. But TOGETHER THEY ARE BACTERICIDAL.

Aminoglycosides As said before, these inhibit formation of the

initiation complex and cause misreading of the mRNA.

Target AEROBIC GRAM-NEGATIVE RODS.

Therefore require O2 for uptake.

Synergistic with beta-lactams (beta-lactams permit the aminoglycoside to enter the cell)

Neomycin is used for bowel surgery

Aminoglycosides Nephrotoxic with cephalosporins and ototoxic with

loop diuretics. I remembered this through “ALOe.” I thought of aloe vera Aminoglycosides, Loops, Ototoxicity; so that leaves nephrotoxicity for cephs + aminos.

Aminoglycosides Nephrotoxic with cephalosporins and ototoxic with

loop diuretics. I remembered this through “ALOe.” I thought of aloe vera Aminoglycosides, Loops, Ototoxicity; so that leaves nephrotoxicity for cephs + aminos.

FA also mentions that it’s a teratogen. USMLE wants you to know that aminoglycosides can cause congenital deafness. FA (in the embryo chapter) mentions CNVIII toxicity for aminoglycosides.

Aminoglycosides Resistance is via acetylation, phosphorylation,

adenylation. Sounds low-yield, but it’s in FA, and I’ve seen it in two practice questions (perfect example of a 260+ question bc most people won’t make the effort to remember that).

Aminoglycosides (beyond FA) All of the following has rocked up in questions:

Can only be given PARENTERALLY

Can also be given with nafcillin for MRSA endocarditis (remember beta-lactam synergy?)

Neomycin for bowel surgery, right? Well it also kills urease(+) organisms decreased NH3 production decreased NH3 absorption = Tx for hyperammonaemia. FA mentions lactulose for NH3 and the gut, but they don’t mention neomycin.

Aminoglycosides (beyond FA) Contraindicated in myasthenia gravis because it can

cause excessive neuromuscular blockade when used with curariform drugs (curare is a neuromuscular blocking agent at nAChR).

Any kidney damage via aminoglycosides, in terms of USMLE questions, is ATN. They might try to trick you with tubulointerstitial nephritis, but it’s always ATN.

Ampicillin + gentamycin = 1st-line Tx for severe pyelonephritis.

Tetracyclines Like aminoglycosides, 30S, and as said before, they

prevent aminoacyl-tRNA binding to the A-site.

Doxycycline is eliminated through feces. Good in ptswith renal insufficiency. They’ll ask you that. They also want you to know that it’s ideal Tx for Lyme disease.

Can’t take tetracyclines with antacids. The same thing goes for fluoroquinolones. I’ve seen both in questions.

Tetracyclines Causes teeth discoloration IN CHILDREN and

photosensitivity IN ADULTS. “guy gets sunburn while on vacation, which drug”.. or girl gets sunburn/blisters while being treated for STD (gottaknow Chlamydia)

VACUUM THe BedRoom vibrio, acne, chlamydia, ureaplasma urealyticum, mycoplasma, tularaemia, H. pylori, Borellia (Lyme disease), Rickettsia rickettsii.

Resistance mechanism is increased efflux or reduced influx. Contrast with aminoglycosides.

Tetracyclines (beyond FA) MINOCYCLINE, like doxycycline, is also fecally

eliminated. Minocycline, like HIPP, can cause SLE-like syndrome.

Tetracyclines can cause pill-induced esophagitis.

Not good for meningitis because they don’t cross the BBB (FA vaguely mentions “limited CNS penetration”)

Demeclocycline causes diabetes insipidus (FA says it probably in the renal chapter but not in the micro chapter, although it’s ridiculously high-yield)

Macrolides Once again, they block translocation via binding to

the 23S rRNA. (elaborate)

Ultra-high-yield: Tx for ATYPICAL PNEUMONIAS.

Prolongs the QT-interval (FA says erythromycin)

DOC for pneumonia in penicillin-allergenic ptskeep in mind we have aztreonam, so why use a macrolide?

GI-discomfort, cholestatic hepatitis, eosinophilia/rash; inhibits P-450. bleeding diathesis in heart valve pt.

Macrolides Resistance is alteration of the 23S rRNA binding site

Macrolides (beyond FA) The reason erythromycin causes acute cholestatic

hepatitis is because it’s the only macrolide eliminated through bile (USMLE would simply ask you for the mechanism of elimination, but if you remember it causes cholestatic hepatitis, it would be easy).

Because erythromycin is eliminated through bile, it also is the only macrolide that doesn’t require dosage adjustment in renal failure pts.

Macrolides are DOC if pt also has post-operative ileus because they are agonists at the motilin receptor (MMCs).

Macrolides (beyond FA) I’ve seen in a practice question where they wanted to

know which drug was most injurious to myocytes. Macrolides was the answer (although protein synthesis inhibitors in general would also be correct). The rationale is that although eukaryotes have 40S/60S (80S) ribosomes, because mitochondria are derived from prokaryotes, they have 30S/50S (70S) ribosomal systems, so muscle, which is heavily mitochondria-dependent, can theoretically be injured by protein synthesis inhibitors.

Macrolides vs tetracyclines I had seen in a practice question that a pt had an

atypical pneumonia and then developed severe sunburn on vacation. They had asked which drug was used. You’ve gotta know that atypical pneumonias are classically mycoplasma, chlamydia or legionella. And you’ve gotta remember that despite macrolides serving as the 1st-line Tx for atypical pneumonias, tetracyclines treat chlamydia, so in this case, the guy had had an atypical chlamydial pneumonia treated with a tetracycline, and he developed photosensitivity.

Chloramphenicol Blocks peptide bond formation, but if you see it in a

question, they want you to know that it knocks out peptidyl transferase.

In turn, resistance is via a plasmid-encoded acetyltransferase that inactivates the drug (FA says this, but on the USMLE, they’ll reword it as “bacterial enzymatic acetylation” to see if you actually know what acetyltransferase means).

Causes aplastic anaemia and grey baby syndrome

Chloramphenicol Used commonly to treat meningitis in the third-

world because of its cheap cost

Chloramphenicol (beyond FA) Kaplan liked chloramphenicol as Tx for Lyme disease

in early pregnancy > doxycycline. However, if near term, doxy is > chloramphenicol. Both drugs carry fetal risks.

Chloramphenicol (beyond FA) Kaplan liked chloramphenicol as Tx for Lyme disease

in early pregnancy > doxycycline. However, if near term, doxy is > chloramphenicol. Both drugs carry fetal risks.

USMLE will ask you to pick out the most lipophilic drug of the bunch. Chloramphenicol, bc it’s great for meningitis due to its BBB penetration, is heavily lipophilic.

Clindamycin Blocks peptide bond formation

Anaerobic infections ABOVE the diaphragm (metronidazole is below)

Good for lung abscesses or aspiration pneumonia

Causes pseudomembranous colitis bc it allows for C. difficile overgrowth

Clindamycin Only real thing I’ve found outside FA for this drug is

that it can also treat MRSA. Or they’ll make pseudomembranous colitis apparent then ask you for the AB-toxin test or MOA of C. difficile-mediated necrosis.

Linezolid For this drug, you only need to remember two things:

1) it acts on the 50S subunit (binds to 23S of 50S subunit - same as macrolides/clindamycin)

2) Side-effects are HOT:

H = High risk of serotonin syndrome

O = optic neuritis

T = thrombocytopenia

O = optic neuritis

T = thrombocytopenia

Linezolid I had only ever encountered one question on this drug,

and it was a vignette of someone with serotonin syndrome (flushing, diarrhea, sweating, hyperthermia, agitation, etc.) and blurry vision, and then they wanted to know the drug that caused the Sx.

Sulfonamides vs trimethoprim

Sulfonamides vs trimethoprim Sulfadiazine + pyrimethamine used to Tx

toxoplasmosis are analogous. So if they ask you for the MOA of pyrimethamine, you know it’s like trimethoprim.

Sulfonamides Dihydropteroate synthase inhibitors (PABA analogues)

Simple UTIs

Can treat Nocardia (SNAP)

Simple UTIs

Can treat Chlamydia, as per FA, but I’ve never seen this in a practice question

Simple UTIs

Can cause hypersensitivity rxns (tubulointersititialnephritis; in contrast to aminoglycosides ATN)

Simple UTIs

Haemolysis in G6PD-deficiency (ISPAIN)

Simple UTIs

Haemolysis in G6PD-deficiency (ISPAIN)

Displaces drugs from albumin kernicterus

Sulfonamides (beyond FA) So if a pregnant woman takes a drug and the baby has

jaundice kernicterus sulfonamide.

Sulfonamides (beyond FA) So if a pregnant woman takes a drug and the baby has

jaundice kernicterus sulfonamide.

Because the bilirubin is displaced from albumin, it can cross the BBB kernicterus

Trimethoprim Inhibits dihydrofolate reductase

Once again, sulfonamides and trimethoprim are both BACTERISTATIC, but if combined (TMP-SMX), they are BACTERICIDAL.

Highest-yield for TMP-SMX is Pneumocystis jirovecipneumonia. If high-yield were diarrhea, it would be explosive here.

Can Tx SALMONELLA and SHIGELLA

May cause megaloblastic anaemia or (or any –penia).

Trimethoprim May alleviate TMP-induced megaloblastic anaemia

with “leucovorin rescue” folinic acid

Trimethoprim May alleviate TMP-induced megaloblastic anaemia

with “leucovorin rescue” folinic acid

As stated before, remember the pyrimethamine for toxoplasmosis has same MOA

Fluoroquinolones -floxacin drugs; inhibit bacterial topoisomerase II

(aka DNA gyrase) very very high-yield

Like tetracyclines, cannot be taken with antacids

Can treat a range of organisms (mostly gram(-) rods)

Can cause cartilage damage or tendon rupture

Leg cramps + myalgias in kids (as per FA, but I’ve never seen this in a practice question)

Fluoroquinolones Bacterial resistance is via chromosome-mediated

mutation in DNA gyrase. FA mentions this, but it’s not minutiae. I’ve seen in a couple questions where they want you to know that bacterial resistance is ALMOST ALWAYS plasmid-mediated, but fluoros are the exception because they’re chromosomal.

Fluoroquinolones (beyond FA) First-line Tx for diarrhea due to Shigella + traveler’s

diarrhea

Ciprofloxacin is DOC for UTIs in pts with sulfa allergy. If pt has sulfa allergy and has GERD nitrofurantoin

diarrhea

Kaplan liked that H. influenzae can also be treated by fluoros.

diarrhea

Kaplan liked that H. influenzae can also be treated by fluoros.

GOOD ORAL BIOAVAILABILITY. That rocked up on an NBME exam (Gd knows why), which means it was once (or still is) floating around on the real deal.

Fluoroquinolones (beyond FA) Gatifloxacin causes dysglycaemia (rocked up in GT)

Moxifloxacin causes heart conduction abnormalities

Fluoroquinolones (beyond FA) Gatifloxacin causes dysglycaemia (rocked up in GT)

Moxifloxacin causes heart conduction abnormalities

USMLE might try to re-word the MOA as that which affects the DNA “nicking” process

Metronidazole Forms toxic metabolites that damage DNA

GET GAP Tx for Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes, H. pylori

Metronidazole Forms toxic metabolites that damage DNA

GET GAP Tx for Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, Anaerobes, H. pylori

USMLE will literally give you a classic vignette / presentation of one of the above organisms, then ask for the Tx. They might tell you “clue cells,” for instance, then ask for the Tx, or they’ll tell you a guy went swimming in a lake and now has steatorrhoea, then ask for the Tx, etc.

Metronidazole Disulfiram-like rxn with EtOH headache /

metallic taste in the mouth

Metronidazole Disulfiram-like rxn with EtOH headache /

metallic taste in the mouth

Once again, clindamycin = anaerobes ABOVE diaphragm; metronidazole = BELOW

Metronidazole (beyond FA) FA doesn’t say it for metro at the end of the micro

chapter, although it does under C. difficile, but metronidazole is a TREATMENT FOR pseudomembranous colitis. Vancomycin and metro are both Txs for it, but if a question has both as answer choices, metro is always correct > vancomycinbecause of the scare of vancomycin-resistant organisms. Another thing: vanco is always given IV (poor oral bioavailability), but for pseudomembranous colitis, IT’S GIVEN ORALLY (makes sense bc it stays confined to the gut).

Metronidazole (beyond FA) I’ve also seen it in a practice question: USMLE likes

metronidazole CREAM as Tx for acne rosacea. But erythromycin CREAM is Tx for acne vulgaris.

Polymyxins USMLE for some reason likes you to know the

structures/MOA of these drugs really well. Know that they have a long hydrophobic tail and that they are cationic and basic. They act as detergents on the cell membrane and DISRUPT ITS OSMOTIC PROPERTIES.

Polymyxins USMLE for some reason likes you to know the

structures/MOA of these drugs really well. Know that they have a long hydrophobic tail and that they are cationic and basic. They act as detergents on the cell membrane and DISRUPT ITS OSMOTIC PROPERTIES.

They’re used only when a pt is resistant to practically all other Txs very high neuro- and nephrotoxicity

Polymyxins You’ll find them in the THAYER-MARTIN medium

used to culture N. gonorrhea. TM medium = “VPN client” = vancomycin (hits gram+), Polymyxin = colistin (hits other gram-), nystatin (hits fungi)

Daptomycin Don’t be fooled by the name. It’s not an

aminoglycoside, nor is it a macrolide.

You’ve gotta know that it creates membrane channels that result in depolarization and **disruption of the membrane potential.**

Its notable side-effect is myopathy with increased CPK (so contraindicated with statins/fibrates)

It is only effective against gram(+)s.

Cannot be used for pneumonia bc pulmonary surfactant inhibits it.

Anti-TB drugs

Anti-TB drugs Prophylaxis = isoniazid. High-yield.

Tx = RIPE = rifampin, isoniazid, pyrazinamide, ethambutol

Anti-TB drugs Prophylaxis = isoniazid. High-yield.

Tx = RIPE = rifampin, isoniazid, pyrazinamide, ethambutol

All are HEPATOTOXIC, except for ethambutol, which causes VISUAL CHANGES.

Rifampin Inhibits DNA-dependent RNA-polymerase. USMLE

really likes that. And they’ll really nail it. They’ll literally list “RNA-dependent DNA-polymerase” and other types of similar polymerases to trick you, but you need to remember that rifampin inhibits DNA-dependent RNA-polymerase. That means it prevents RNA synthesis. The way I remembered this was “RDR” = rifampin-DNA-RNA. Whatever works for you. Just find a way to remember it.

Rifampin FA says that rifampin delays resistance to dapsone

when used for leprosy. I’ve never actually seen a question on this though.

As said prior, isoniazid, NOT rifampin, is the prophylaxis for TB. But you need to remember that rifampin is the prophylaxis for N. meningitidis and H. influenzae type-B.

I’ll summarize that last point bc it’s so important:

TB prophylaxis = isoniazid

TB Tx = rifampin, isoniazid, pyrazinamide, ethambutol

N. meningitidis / H. influenzae prophylaxis = rifampin

N. meningitidis Tx = ceftriaxone (FA says ceftriaxone or penicillin G, but in terms of USMLE questions, I’ve only ever seen ceftriaxone)

Rifampin (contd) Upregulates P-450 (very high-yield)

Can cause orange tears/sweat/urine (high-yield); harmless side-effect, but pt will be concerned

Rifampin (beyond FA) Since rifampin upregulates P-450, you don’t want to

give it to HIV pts on protease inhibitors bc you’ll increase the rate of the latter’s degradation, so you instead give rifabutin. USMLE will list both as Txs for TB in the same question, but the answer is rifabutin if the pt is HIV(+) bc you need to assume he/she is on HAART.

USMLE wants to know WHY rifampin is prophylaxis for N. meningitidis.

..it penetrates the respiratory tract wall and prevents meningococcal pharyngeal colonization.

Rifampin (beyond FA) Rifampin binds the beta-subunit of DNA-dependent

RNA-polymerase. Retarded, but it showed up in a question (lord knows why). This is an example of how everyone needs a little luck on the real deal.

USMLE might tell you the pt’s contact lenses were rusty colored as an indirect reference to the orange tears a little trickier

Why is isoniazid used over rifampin for TB prophylaxis?

..bc rifampin is way more hepatotoxic.

Isoniazid (INH) Decreases synthesis of mycolic acids (high-yield)

KatG (catalase-peroxidase) needed to convert INH to active metabolite

Although hepatotoxic, USMLE loves that INH is a common cause of vitamin B6 deficiency. Quite HY.

They’ll tell you a person with TB was treated and now has paresthesias (or sometimes seizures) B6 def.

Isoniazid (beyond FA) KatG needed to convert INH to active metabolite does

so via acyl-carrier and ketoacyl-carrier protein synthesis. So KatG is a catalase-peroxidase enzyme that carries out acyl-carrier and ketoacyl-carrier protein synthesis.

Isoniazid (beyond FA) KatG needed to convert INH to active metabolite does

so via acyl-carrier and ketoacyl-carrier protein synthesis. So KatG is a catalase-peroxidase enzyme that carries out acyl-carrier and ketoacyl-carrier protein synthesis.

USMLE loves to ask about metabolism of INH. If they show you a bimodal curve of INH metabolism, you’ve gotta know that people demonstrate phenotypic variation regarding fast vs slow acetylation.

Isoniazid (beyond FA) I’ve seen a practice question where the hepatotoxicity

of INH was presented as fever, anorexia and nausea, WITHOUT jaundice. Effects can be acute. If they throw neurotoxicity at you, it will be the paresthesias. If its hepatotoxicity, you’ll get the former Sx (just think, in paracetamol poisoning, does jaundice develop?)

Isoniazid (beyond FA) USMLE wants you to know WHY isoniazid causes B6

deficiency.

It’s bc INH inhibits pyridoxal kinase, so B6 cannot get activated (normally pyridoxine pyridoxalphosphate).

deficiency.

INH can cause D/NE/E deficiency (secondary to the B6 deficiency)

deficiency.

INH can cause D/NE/E deficiency (secondary to the B6 deficiency)

Seizures secondary to B6 deficiency and INH occur bcof decreased GABA (bc you need B6 to decarboxylateglutamate to GABA!).

Pyrazinamide Knocks out mycobacterial fatty acid synthase I

Effective in the acidic pH of phagolysosomes

Pyrazinamide Knocks out mycobacterial fatty acid synthase I

Effective in the acidic pH of phagolysosomes

Although it causes hepatotoxicity, it also causes gout (hyperuricaemia). On my real deal, I was asked the lower-yield side-effect of a drug (hint hint).

Pyrazinamide (beyond FA) Like INH, pyrazinamide requires activation by TB

FA mentions that pyrazinamide is most effective in the acidic pH of phagolysosomes, but what this means is that pyrazinamide is the most effective intracellularTB medication that’s how they’ll ask it. The other drugs still penetrate the cell, but pyrazinamide is simply the best at killing TB that have already been engulfed by macrophages.

Ethambutol Decreases carbohydrate polymerization of the

mycobacterial cell wall by blocking arabinosyltransferase.

Ethambutol Decreases carbohydrate polymerization of the

mycobacterial cell wall by blocking arabinosyltransferase.

So they want you to know that ethambutol knocks out carbohydrate synthesis but that pyrazinamide knocks out fatty acid synthesis. Isoniazid hits mycolic acid synthesis directly, and rifampin inhibits nucleic acid synthesis.

Ethambutol Causes optic neuropathy. FA says red-green color

blindness for ethambutol, but I’ve seen it in questions as decreased visual acuity and central scotoma.

Although, of RIPE, RIP are hepatotoxic, ethambutolcauses VISUAL PROBLEMS, so if they list “hepatotoxicity” and “central scotoma” as two answers, the latter is right, even though FA only says red-green color blindness.

Tangential: sildenafil instead causes blue-greencolor blindness.

TB drugs in general RIPES can also be used instead of RIPE. If they ask

about an aminoglycoside, streptomycin has shown some use against TB.

TB drugs in general RIPES can also be used instead of RIPE. If they ask

about an aminoglycoside, streptomycin has shown some use against TB.

I’ve seen in a practice question cycloserine as general TB Tx. It is a broad-spectrum TB drug and can cause CNS effects/seizures.

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