(Detailed) Antibacterials By Sarah E.

General Info What is an empirical therapy? One in which the infecting organism is not known Do you use broad or narrow spectrum drugs for this? broad spectrum (OR combo) What is a definitive therapy? One in which the infecting organism is known. narrow spectrum

General Info Name all antimicrobials that are contraindicated in pregnant women. tetracyclines, aminoglycosides, fluorquinolones, sulfonamides, and metronidazole Do you use bactericidal or bacteriostatic drugs in immunocompromised patients? bactericidal

β-lactams Mechanism of action? bind PBPs and inhibit cell wall synthesis Can be used to treat intracellular organisms? No. Do not cross membranes Bactericidal or bacteriostatic? bactericidal for ACTIVELY GROWING BACTERIA Exceptions? Only static for Enterococcus sp. Predominant mode of excretion? kidneys ceftriaxone and anti-Staph penicillins (dicloxacillin- bile)

β-lactams Mechanisms of resistance? β-lactamase production altered PBPs altered porins (gram negatives) Name three organisms that have altered PBPs. pneumococci (ie. Streptococcus pneumoniae), gonococcus, enterococcus Makes them resistant to most β-lactams! Can these be used to treat Neisseria gonorrhoea? Only 3rd generation cephalosporins! Can pregnant women take these drugs? yes!

β-lactams Name 5 organisms that encode plasmid β-lactamases. Haemophilus, E. coli, Neisseria, Salmonella, Klebsiella, Shigella (HEN S(e)KS) Name 2 organisms that have constitutive chromosomal β-lactamases. Bacteroides, Moraxella Name 3 organisms that have inducible or Extended-Spectrum β-lactamases. Pseudomonas, Enterobacter, Serratia

β-lactams Name the 4 categories of β-lactams. Penicillins, cephalosporins, carbapenems, monobactams Name 1 non β-lactam cell wall inhibitor vancomycin

Penicillins Name the 4 categories of Penicillins original, anti-staphylococcal, amino-penicillins, anti-pseudomonal Name 3 places these do NOT distribute. eye, prostate, CNS (unless meninges are inflamed and leaky!)

Penicillins Long or short half-lives? short What three things can lengthen the half-life? kidney failure, probenecid*, aspirin (inhibit renal tubular (and CNS!*secretion) Which category of penicillin is NOT affected by those things? anti-staphylococcals (eliminated via bile, not kidneys) (and also ceftriaxone)

Penicillins Name the major adverse effect of penicillins. allergies!! Anaphylaxis (severe) or rash (mild) Name an adverse effect of oral penicillins. GI distress/pseudomembranous colitis What can these drugs do to the vagina? yeast infections! (flora imbalance) What are the toxic effects of these drugs? seizures (in patients with renal dysfunction or CNS lesions) and hyperkalemia

The Original Penicillins Name the “original penicillin” on our list. Penicillin G When do you use the IV form, these days? treating endocarditis in combo with an aminoglycoside For which disease is the injectable form the DOC? PRIMARY SYPHILIS Which form of the original penicillin can be take orally? penicillin V (acid stable) What do you take penicillin V for? mild gram (+) cocci infection (eg. GAS “strep throat”)

The Original Penicillins Are these useful for most Staphylococcus infections? No (β-lactamases) Intracellular infections? No Most gram negatives? Streptococcus pneumoniae? No (altered PBPs) Spirochetes? YES (syphilis is caused by the spirochete Treponema!)

The Original Penicillins Intracellular Gram negative cocci? Not really (but some N. meningitidis if you can get the drug there!) What do you have to take care to do if giving with aminoglycosides? Administer in separate IV lines

Anti-staphylococcal penicillins Name the one on our list. dicloxacillin Are these broad or narrow spectrum? VERY NARROW What kind of organisms do these treat? Staphylococcus sp. (duh?) with PLASMID ENCODED β-lactamases How are these excreted? in the bile!

Amino-penicillins Name the one on our list. Amoxicillin How does the spectrum compare to the original penicillins? Same for gram-pos, but treats more gram negatives (Broadest spec penicillins) Which gram negatives? Moraxella, Haemophilus, Salmonella, Shigella, E. coli Can these be take orally? yep! (amoxicillin causes minimal GI stress) What do you typically prescribe these for? otitis media, sinusitis, dental infections, etc…

Amino-penicillins Can you use these to treat H. pylori? yes, in combo with clarithromycin When do you use these prophylactically? when you’re worried about endocarditis in high risk patients undergoing procedures Are these active against organisms with altered PBPs? No

Amino-penicillins Are these inactivated by β-lactamases? Yes Name 2 things you can co-administer to prevent this. clavulanate or tazobactam (β-lactamase inhibitors) Are amino-penicillins effective against Streptococcus pneumoniae? No (because of altered PBPs) Can these drugs treat Listeria meningitis? yes, if the meninges are inflamed and leaky

Anti-pseudomonal penicillins Name the one on our list. piperacillin How does the spectrum of these drugs compare to penicillin and amoxacillin? Less gram(+), more gram (-) Which gram (-)s? Pseudomonas, Enterobacter, Serratia Are these inactivated by β-lactamases? Yes What can you add to prevent this? clavulanate or tazobactam Are these combinations effective against Pseudomonas species that have inducible chromosomal β-lactamases? No

Penicillins Name the original penicillin. Penicillin G (Oral=Penicillin V, IM = benzthine penicillin G) Anti-staphylococcals? Dicloxacillin (also not on the list, nafcillin, oxacillin) Aminopenicillins? Amoxicillin, (and not on the list ampicillin) Anti-pseudomonals? Piperacillin β-lactamase inhibitors? Clavulanate, tazobactam

Cephalosporins How many generations are there? 4 As generation # increases, resistance to β-lactamases… Increases As generation # increases, activity on gram-positives… Decreases As generation # increases, activity on gram-negatives… increases

Cephalosporins 1st generation cephalosporins (on our list)? Cefazolin, cephalexin 2nd generation? Cefuroxime, cefprozil 3rd generation? Ceftriaxone, cefixime 4th generation? cefepime

Cephalosporins Are any of these drugs effective against MRSA? No Enterococcus sp.? Listeria monocytogenes? Are these drugs more active or less active against gram-negative rods than amoxicillin? More active

Cephalosporins Can you use these drugs in patients with severe penicillin allergies? No In patients with mild penicillin allergies? yes In pregnant women? Are these drugs broader or narrower in spectrum than penicillins? Broader Are oral cephalosporins more or less potent than parenterals? Less potent

Cephalosporins Do oral cephalosporins have a broader spectrum than parenteral cephalosporins? No Which generation achieves therapeutic concentrations in the CNS? 3rd generation Does oral administration reach the CNS? Name the two drugs in the 3rd generation that are on our list. ceftriaxone and cefixime

1st Generation Cephalosporins Name two of these that are on our list. Cefazolin and cephalexin Are these active (generally) against gram positive cocci? Yes, including many Staphylcoccus β-lactamases -Name 3 exceptions. MRSA, Enterococcus, penicillin-resistant pneumococci Are these drugs active against Neisseria? nope

1st Generation Cephalosporins Name the gram-negative rods that these drugs can treat. Proteus mirabiluis, E. coli, Klebsiella pneumoniae (PEcK) Name two indications for cefazolin. Prophylaxis for surgery, anti-staph in mildly allergic patients Name an indication for cephalexin. Substitute for oral penicillins (mild infections)

2nd Generation Cephalosporins Name our 2nd generation cephalosporins. Cefuroxime, cefprozil Do these have more or less activity against gram-positives than generation 1? Less Name the gram-negatives that these cover. Haemophilus, Enterbacter, Neisseria, Proteus, E. coli, Klebsiella, Serratia (HEN PEcKS) Which β-lactmases are these NOT resistant to? Inducible chromosomal lactamases of Pseudomonas, Enterobacter, and Serratia

2nd Generation Cephalosporins Do any of these enter the CNS? Actually yes. Cefuroxime does, but 3rdGCs are better for menigitis and pneumonia Why are these considered the “lost” generation? They aren’t often listed of drugs of first choice, and they are more expensive than 1stGCs as substitutes for oral penicillins

3rd Generation Cephalosporins Name our 3rd generation cephalosporins. Ceftriaxone, cefixime Do these have more or less activity against gram-positives than generation 2? Less Are these active against bacteria with altered PBPs? Yes, many of them! (pneumococcus, eg.) Are these active against Streptococcus sp? Yes! (even though they are generally less potent against gram-positive cocci than 2ndGCs

3rd Generation Cephalosporins Are these more or less active against gram-negatives than 2ndGCs? More active! Particularly which gram-negatives? Enterobacteriacieae Which β-lactamases are these NOT resistant to? Inducible chromosomal lactamases of Enterobacter, Serratia, and Pseudomonas How are these drugs excreted? Through the urine EXCEPT ceftriaxone

3rd Generation Cephalosporins Name two diseases for which this class is the drug of choice. Meningitis (initial treatment in kids over 3 months and immuno-competent adults) Gonorrhea For which kind of bacterial infection (gram+ or gram-) is ceftriaxone a first line drug? Serious gram-negative infections Is ceftriaxone active against Pseudomonas aeruginosa? Nope.

3rd Generation Cephalosporins Should you use these drugs to treat otitis media, respiratory tract infections, or UTIs? No. There are cheaper drugs that work just as well (Note: they ARE recommended for otitis media in regions with resistant infections) Can these drugs treat typhoid fever? Yes Endocarditis? Sometimes Community acquired or nosocomial pneumonia Both when in combination with macrolide or aminoglycoside respectively

4th Generation Cephalosporins Name our 4th generation cephalosporins (that are on the list) Cefepime (there’s only one on our list!) Is this generation resistant to inducible chromosomal β-lactamases? More than the other generations are  What can this treat that 3rd generation cephalosporins can’t? Pseudomonas, Enterobacter, Serratia, (in other words, nosocomial gram-neg infections)

Cephalosporins (name recap) 1st generation cephalosporins (on our list)? Cefazolin, cephalexin 2nd generation? Cefuroxime, cefprozil 3rd generation? Ceftriaxone, cefixime 4th generation? cefepime

All Cephalosporins Name the most common adverse effect for all cephalosporins. Hypersensitivity reactions (identical to penicillin) Name a side-effect that can occur especially in when these are taken in combination with an aminoglycoside. Nephrotoxicity

All Cephalosporins Do these cause “superinfections” more commonly than amoxicillin or clindamycin? No, but superinfections can still occur (resistant gram-positives such as C. difficile) Name two side-effects that occur as a result of the method of administration. Pain with IM, phlebitis with IV

Carbapenems Name the ones on our list. Imipenem-cilastatin Against which species is this class NOT active? MRSA, most Enterococcus sp. (this is the broadest spectrum β-lactam) Is this class resistant to extended spectrum β-lactamases? Yes! Most of them! Name three genera of bacteria that have these. Pseudomonas, Enterobacter, Serratia

Carbapenems Can this class be used to treat Pseudomonas aeruginosa? Yes, but add gentamicin to reduce resistance Can this class be used to treat Aceinetobacter? Yes When should you use these drugs? When there are mixed infections and other drugs can’t be used (ie. Try not to use them) Do these drugs get to the CNS? Yep!

Carbapenems Where is are these eliminated? In the urine Which part of imipenem-cilastatin is the antibiotic? Imipenem What the heck is the cilastatin? Inhibits the renal dihydropeptidase that breaks imipenem into a toxic compound (note, some other drugs in this class are resistant to breakdown by that enzyme all by themselves)

Carbapenems Name 3 adverse reactions. Nausea and vomiting Hypersensitivity seizures in patients with CNS lesions or renal insufficiency Can pregnant women take these? Yes.

Monobactams Name the one on our list. Aztreonam What is the spectrum of this drug? Gram negative aerobes!! (very specific) Name 4 genera included in this category. Pseudomonas, Enterobacter, Serratia, Haemophilus When should you use this drug? In patients severely allergic to penicillins/cephalosporins who have gram-negative aerobe infection

Monobactams Are there adverse effects? VERY FEW (phlebitis, skin rash, abnormal liver test) How are these excreted? Urine Do these cross-react with allergy to penicillins? no

Let’s REHASH THE NAMES Because they all sound the same.

Penicillins Name the original penicillin. Penicillin G (Oral=Penicillin V, IM = benzthine penicillin G) Anti-staphylococcals? Dicloxacillin (also not on the list, nafcillin, oxacillin) Aminopenicillins? Amoxicillin, (and ampicillin) Anti-pseudomonals? Piperacillin β-lactamase inhibitors? Clavulanate, tazobactam

Cephalosporins 1st generation cephalosporins (on our list)? Cefazolin, cephalexin 2nd generation? Cefuroxime, cefprozil 3rd generation? Ceftriaxone, cefixime 4th generation? cefepime

Other β-lactams Carbapenems? Imipenem-cilastatin Monobactams? aztreonam

β-lactams Which are NOT excreted in the urine? Dicloxacillin (and other anti-staph penicillins), and ceftriaxone Which are effective against Pseudomonas aeruginosa? Piparcillin-tazobactam (unless there are ESBLs), cefepime (4th GC), carbapenems, monobactams Which used usually against Streptococcus sp.? Penicillin V (mild pharyngitis infections), cephalexin (1st GCs), cefprozil (2nd GCS—but more expensive), ceftriaxone, or cefixime (if resistant because of altered PBPs, as in S. pneumoniae), or cefepime

β-lactams Which is the DOC for gonorrhea? Ceftriaxone or cefixime (3rd GCs) Which is the initial DOC for meningitis? Ceftriaxone (3rd GC) (immuno-competent and older than 3 months) Tougher question. WHY is this the initial DOC for meningitis? Most common bacterial cause in adults are Strep. pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, and ALL are can be treated with this drug

β-lactams Which is the DOC for primary syphilis? Penicillin G (single IM injection) Which does NOT show allergic cross reaction with penicillins? Monobactams (aztreonam) Which is used as prophylaxis for surgery (in hospitals WITHOUT high rates of MRSA)? Cefazolin (1st GC) Which are effective on gram-negatives ONLY? Aztreonam (monobactams)

Glycopeptide cell wall inhibitors Name the one drug in this class. Vancomycin!!! What is it’s mechanism of action? Inhibits crosslinking of peptidoglycans by binding D-ala-ala, blocks cell wall synthesis Bactericidal or bacteriostatic? Bactericidal Gram-positives, gram-negatives, or both? Gram-positives only Intracellular, extracellular or both? Extracellular only

Vancomycin Can this be used to treat some kinds of meningitis? Yes, with 3rd GCs. It can cross inflamed meninges. Name one infection for which this is a DOC? MRSA!! (Especially nosocomial MRSA) Which strains of bacteria have shown resistance? Enterococci sp. How is vancomycin eliminated? In the urine

Vancomycin Name 6 recommendations for using vancomycin Treating MRSA Serious gram-positive infection in patients with β-lactam allergies ORAL treatment of C. difficile Endocarditis prophylaxis in patients with β-lactam allergies Prophylaxis for implantation of device in hospitals with high rates of MRSA Initial empiric treatment of pneumoccocal meningitis in areas with resistant S. pneumoniae

Vancomycin Name two relatively common adverse effects. Hypersensitivity (rashes/anaphylaxis) “Red-man” or “red-neck” syndrome-due to massive histamine release What can you do to stop “red-man” syndrome? Slow the IV drip Name two relatively rare adverse effects. Ototoxicity and nephrotoxicity (at high plasma levels) Name one other class of antimicrobial that can further increase the risk of these rare affects aminoglycosides

Last Resort Antibiotics Name 3 antibiotics of last resort. Quinupristin/dalfopristin Linezolid Daptomycin When should you use these? When you can’t use anything else. Otherwise never.

Quinupristin/dalfopristin Are both of these components antibiotics? Yes. They are streptogramins. Bactericidal or bacteriostatic? Bacteriostatic individually, synergistically bactericidal Mechanism of action? Dalfopristin binds 50S ribosomal subunit, conformation change, enhances quinupristin binding to another 50S site, elongation is blocked

Quinupristin/dalfopristin To what other class are these streptogramins related? Macrolides Do these streptogramins inhibit CYP450? Yes. Heads up! What infections are these drugs used to treat? Vancomycin resistant Enterococci (especially faecium), Streptococci, and Staphylococci (including MRSA)

Quinupristin/dalfopristin Is there resistance to these drugs? Yes. Quinupristin is cross resistant with erythromycin and clindamycin Name 4 adverse effects Joint/muscle aches Phlebitis Nausea rash

Linezolid Bacteriocidal or bacteriostatic? Bacteriostatic Oxazolidinone Mechanism of action? Inhibits initiation of protein synthesis Used to treat? VRE (faecium and faecalis), MRSA, MRSE, penicillin resistant pneumococci, and S. aureus with intermediate vanc. resistance

Linezolid Side effects? myelosuppression (but generally a well tolerated drug) Take caution when taking which other drugs? Adrenergic/serotenergic agents because this acts as MAO inhibitor Any resistance to this drug? yes. Some has been observed.

Daptomycin Bactericidal or bacteriostatic? Bactericidal cyclic lipopeptide Mechanism of action? Theoretical insertion of lipophilic tail into bacterial membrane, rapid depolarization and ion efflux, arrest of DNA, RNA, and protein synthesis Side-effects? High doses= increased CPK, muscle discomfort and weakness

Protein Synthesis Inhibitors Name 5 categories of drugs in this class. aminoglycosides, tetracyclines, macrolides, clindamycin (a lincosamide), chloramphenicol Are most of these drugs bactericidal or bacteriostatic? Bacteriostatic Exceptions? The aminoglycosides and sometimes macrolides (concentration dependent)

Aminoglycosides Name the one on our list. Gentamicin (others are amikacin, tobramycin, streptomycin—for TB) Mechanism of action? Irreversible binding to 30s subunit Spectrum? Gram-negative aerobes (bacilli)!! Staphylococci, and some mycobacteria Why? Requires oxygen-dependent transporter to get into cell, and no cell wall (Streptococci have a different transporter) What drug treats gram-negative aerobes only (similar spectrum to gentamicin)? Aztreonam (a monobactam)

Aminoglycosides Name the gram negatives that these treat. Pseudomonas aeruginosa, Enterobacteriaceae What combo broadens the spectrum? Combine with a cell wall synthesis inhibitor (like a β-lactam or vancomycin) Is the therapeutic index of these drugs low or high? Very low

Aminoglycosides Name 2 common adverse effects. Ototoxicity (dose dependent, cumulative use, potentiation by other ototoxic drugs, irreversible) Nephrotoxicity (accumulates in and kills renal tubule cells, reversible, dose dependent) Name 1 rare adverse effect Curare-like neuromuscular blockade at high doses Can pregnant women take these. No

Aminoglycosides Are these drugs often used alone? No. combos reduce toxic effects Name a combo to treat endocarditis. Gentamicin + penicillins Name a combo to treat septicemia or nosocomial pneumonia. Gentamicin + 3rd GC Name a combo to treat MRSA Gentamicin + vancomycin

Aminoglycosides How are these drugs excreted? In the urine Are these absorbed from the GI tract? No. They are too polar Do these drugs enter the CNS? No The eye? Eukaryotic cells?

Aminoglycosides What is the primary mechanism of resistance? Inactivating bacterial enzymes How do Enterococcus sp. resist? Mutations in 30s binding site Pseudomonas? Decreased transport into bacterium Do the aminoglycosides show cross resistance with each other? Sort of, but not totally. Inactivating enzymes are identical

Tetracyclines Name the one on our list. Doxycycline Bactericidal or bacteriostatic? Bacteriostatic Mechanism of Action? Reversible binding of 30s subunit Most common mechanism of resistance? Drug efflux 2 other mechanisms of resistance? Modified ribosome binding site, drug modification

Tetracyclines Do these drugs get into cells? Yes Do these drugs get into the CNS? Nope Are these drugs broad spectrum? They used to be, but there’s a lot of resistance now Can pregnant women take them? No-interferes with calcium deposition/bone development Can kids take them? Not under age 8 for the same reason

Doxycycline Does this drug have a long or short half-life? long, (once a day dose is ok) Can this be taken orally? Yes Does food interfere with the absorption? Generally no, but di and tri-valent cations can chelate it and prevent absorption How is doxycycline excreted? Feces How are other tetracyclines excreted? urine

Tetracyclines Name 8 diseases that tetracyclines are used to treat. Lyme disease (spirochetes) Syphilis (spirochetes) Mycoplasma pneumonia Cholera (V. cholerae) Legionella Rickettsia CA-MRSA in patients allergic to TMP-SMX These are used as prophylaxis for which disease? Malaria (reasons unknown for why this prevents)

Tetracyclines Name 4 adverse effects other than the bone/teeth thing. GI distress Intestinal/vaginal superinfection Skin photosensitivity Vestibular reactions (high doses)

Macrolides Name the two on our list. Erythromycin and azithromycin Mechanism of action? Binds 50s subunit Bactericidal or bacteriostatic? Bacteriostatic (cidal if high enough concentration) Name 4 mechanisms of resistance. Reduced permeability, increased efflux, enzymatic hydrolysis, modification of ribosomal binding site

Macrolides Do these drugs show cross resistance with other classes? YES. Clindamycin and streptogramins (like Quinupristin!) Can these drugs be taken orally? Yes Does food interfere with absorption? YES

Macrolides Do these get into phagocytes? Yes (MACs get in MACs) Do these get into the CNS? NO Are these active against gram-positives? Yes Are these active against gram-negatives? A few Which ones? Legionella, Bordatella, Haemophilus, Neisseria, H. pylori

Macrolides Do these treat intracellular bacteria? Yes Name 3. Chlamydia, Mycoplasma, Mycobacterium Do these treat spirochetes? yes Name 2. Borrelia, Treponema

Macrolides For which diseases are macrolides the DOC? CA-pneumonia (pneumococcus, Mycoplasma, Legionella), Legionnaire’s disease, corynebacterial infections (diphtheria), and chlamydia

Erythromycin v. Azithromycin Which is better tolerated orally? Azithromycin How does erythromycin affect the intestines? Directly affects motility Which has a shorter half-life? Erythromycin (about 90 minutes) What is the half life of azithromycin? 2-4 days

Erythromycin v. Azithromycin Which one is metabolized in the liver? Both Which one inhibits P450 oxidation of other drugs? Erythromycin (Azithromycin does NOT) Which one can’t be taken with digoxin? Erythromycin Why? Kills off intestinal bacteria that inactivate digoxin and inhibits P-glycoprotein efflux, increases serum levels

Erythromycin v. Azithromycin Which one accumulates in tissues 10-100 times higher than in serum? Azithromycin What is the advantage of this? Once-daily dosing and single-dose treatment of some infections Which infections can be treated with a single dose of Azithromycin? Chlamydia urethritis or pharygitis

Erythromycin v. Azithromycin Of the two, which is the better for treating CA-pneumonia? Azithromycin Which can be used to treat Mycobacterium avium complex? Which drug is more expensive? Arithromycin

Erythromycin Name a side-effect associated with IV administration. Phlebitis Name 3 rare side-effects. Hypersensitivity reaction, hepatitis, reversible deafness Can this drug cause seizures and arrythmias? yes, when taken with other drugs that are metabolized by P450 (such as anticonvulsants and antihistamines)

Lincosamides Name the one on our list. Clindamycin Mechanism of action? Acts at same 50s site as the macrolides Is this drug absorbed orally? Yes Does this drug get into the CNS? No Bactericidal or bacteriostatic? bacteriostatic

Clindamycin Does this drug show cross-resistance with other drugs? Yes. With macrolides. Does this drug get into phagocytes? Yes. Does this drug penetrate abscesses? Yes! How is this drug eliminated? By the liver

Clindamycin Which gram-positive organisms does this treat? Strep, staph, pneumococci, anaerobes Which gram-negative organisms does this treat? Bacteroides sp. And other anaerobes Seeing a theme? Anaerobes! Name some organisms that are resistant to clindamycin. Gram-neg aerobes, C. difficile, enterococci

Clindamycin When is this used for prophylaxis? By dentists to prevent endocarditis Name two infections in AIDs patients that this treats. Pneumocystis pneumonia, toxoplasmosis Name 2 important side effects. hypersensitivity rash, diarrhea (10% of all patients get resistant C. difficile pseudomembranous colitis)

Clindamycin When is this used for prophylaxis? By dentists to prevent endocarditis Name two infections in AIDs patients that this treats. Pneumocystis pneumonia, toxoplasmosis Name 2 important side effects. hypersensitivity rash, diarrhea (10% of all patients get resistant C. difficile pseudomembranous colitis) For what infections is this the DOC? Anaerobic infections (as well as Metronidazole)and CA-MRSA (as well as TMP-SMX)

Chloramphenicol (Yet another drug) Mechanism of action? Binds 50s at or near where clindamycin does Mechanism of resistance? Bacterial enzyme production (chloramphenicol acyl-transferase – CAT) Does this get into the CNS? Yes!

Chloramphenicol Is this drug broad or narrow spectrum? Freakishly broad spectrum (gram+/-, aerobic/anaerobic, intracellular and not) For which infections is this the DOC? None. This is never a first choice drug. So when do you use it? In patients with resistant infections or who can’t take other drugs Name 2 examples. CF patients with Burkholderia cepacia, and meningitis in patients with severe penicillin allergy

Chloramphenicol Name a common adverse effect. Dose-dependent reversible bone marrow suppression (due to possible inhibition of mitochondrial protein) Name a rare side effect (the one that keeps this drug from being used). Dose-INDEPENDENT aplastic anemia (fatal if not treated with bone marrow transplant, 1/30,000 patients get this)

Chloramphenicol What can this cause in infants? “Gray baby syndrome” How does this work? Infants can’t conjugate enough of the drug with glucuronic acid, toxic levels reached How is this drug eliminated? Liver Does this drug inhibit P450? Yes

Anti-folates What’s on our list for these? Trimethoprim-sulfamethoxazole (TMP-SMX) Are both components antibiotics? Yes What is the mechanism of action of TMP? Inhibits dihydrofolate reductase (and THF synthesis) What is the mechanism of resistance to TMP? Reduced permeability or mutant DHFR

Anti-folates What is the mechanism of action of SMX? Competes with PABA (as do other sulfonamides), blocks DHF synthesis What is the mechanism of resistance to SMX? Reduced permeability, overproduction of PABA, mutant enzyme, ability to use exogenous folate Are these drugs ever used separately? Not in the US

Anti-folates Can pregnant women take these? No Can these drugs be taken orally? Yes Do these get into the prostate? Do these get into the CNS? Do these get into the fetus? yes

Anti-folates Where are these eliminated? More than half in urine, some liver Are these active against anaerobes? No Aerobes? Typically yes Gram-negative cocci? Yes Enterobacteriaceae? yes

Anti-folates Are these active against Ps. Aeruginosa? No Most strep and staph? Yes Exceptions? S. pyogenes, MRSA Are these active against most enterococci? no

Anti-folates For what diseases are these the first-line treatment? Adult sinusitis, lower UTI, chronic bronchitis, prostatitis, Pneumocystis pneumonia, CA-MRSA Name 4 diseases for which this is an alternative treatment. Shigellosis, traveller’s diarrhea, acute otitis media, typhoid fever

Anti-folates Name 3 common adverse effects. Hypersensitivitym, GI distress, photosensitivity What are the rare adverse effects? Precipitate in urine and form crystals, hepatotoxicity in patients with G6PDH deficiency!!, blood disorders What can sulfonamides do to the fetus? 3rd trimester, can cause kernicterus (bilirubin encephalopathy)

Anti-folates Are the side effects ameliorated somewhat if the patient has AIDS? No. The side effects get worse Do these drugs inhibit P450? YES and the BIND ALBUMIN (a double whammy)

Fluoroquinolones What’s on our list for these? Ciprofloxacin Bactericidal or bacteriostatic? Bactericidal Mechanism of action? Nucleic acid synthesis inhibitor, blocks topoisomerase Elimination? Kidney in same manner as penicillins Name 2 chemicals that slow excretion Probenecid, aspirin

Ciprofloxacin Mechanisms of resistance? Decreased permeability or mutant topoisomerase Broad or narrow spectrum? Very broad Active against aerobes, anaerobes, or both? Pretty much just aerobes Who else is just aerobes? Aminoglycosides!

Ciprofloxacin Is this drug well distributed? Yes To where? Prostate, bone, urine, macrophages, PMNs Does this drug treat gram-positives? Some Exceptions? MRSA, enterococci, variable against streptococci

Ciprofloxacin Does this drug treat gram-negatives? Yes. The AEROBIC ones Intracellular organisms? Some Which ones? Legionella, Mycoplasma, Brucella Name the major clinical use. Upper and lower respiratory infections

Ciprofloxacin Name some other clinical uses. Traveler’s diarrhea, osteomyelitis, prostatitis, resitant-TB, MAC Name two examples where this drug is used prophylactically. Menigitis and inhalation anthrax in neutropenic patients Name two organisms which are becoming more and more resistant. S. pneumoniae and Ps. aeruginosa

Fluoroquinolones Can pregnant women take these? No. No pregnant women or kids under 18 Why not? Drug damages developing cartilage, leading to arthropathy Name a few other adverse effects. GI distress, headaches, dizziness, skin rashes, abnormal LFTs. Reports of possible tendon rupture???

Fluoroquinolones Can you use antacids or mineral supplements when taking these orally? No. Chelation occurs and the drug becomes less bioavailable What other drugs chelate in the digestive tract? Tetracyclines Do these inhibit P450 enzymes? yes, possibly What happens when you take these with NSAIDS or theophylline? Increased risk of seizures

Metronidazole Mechanism of action? Prodrug, converted to active form via a nitroreductase, binds DNA Spectrum? Anaerobes only! (and some protozoa)…they have the nitroreductase Which ones in particular? Bacteroides, Clostridium, Trichomonas, Giardia, Entamoeba

Metronidazole For which diseases is this the DOC? Pseudomembranous colitis from C. difficile What’s the 2nd choice for C. difficile? Oral vancomycin Name a few other diseases that Metronidazole can treat. Bacterial vaginosis, abdominal and pelvic infections, gas gangrene, tetanus, with TMP-SMX for diverticulitis, and for Bacteroides brain abscesses

Metronidazole Name 3 common adverse effects. Nausea, dry mouth, taste alteration Name a rare side effect. Peripheral neuropathy (STOP DRUG) Is this drug mutagenic? In bacteria and rodents, but no human data Can pregnant women take this? Not during 1st trimester, avoid during whole pregnancy if possible

Metronidazole Does this drug inhibit P450? Yes Do other drugs affect this drug’s half-life? Yes. Ones that affect P450 What can happen when this is taken with disulfiram or ethanol? Acute psychosis

Anti-mycobacterial drugs Name 4 reasons that mycobacterial infections are hard to treat. Lipid rich cell wall is impermeable to most drugs (β-lactams definitely won’t work) Primarily intracellular Slow growing/dormant Notorious for resistance

Anti-tuberculosis drugs Name 5 first-line drugs to treat TB infections Isoniazid Rifampin Pyrazinamide Ethambutol Streptomycin

Anti-tuberculosis drugs Name 2 other drug CLASSES that can be used as 2nd line treatment (note these are not the ONLY other classes that can be used.) Aminoglycosides (such as amikacin), fluoroquinolones (such as ciprofloxacin)

Anti-tuberculosis drugs Describe the CDC recommended regimen for TB therapy (for active disease). Start on 4 first-line drugs (INH, rifampin, PZA, ethambutol) for 2 months When you find out susceptibilities, eliminate ethambutol if susceptible to INH and rifampin Continue INH, rifampin, and PZA for 2 more months Eliminate PZA because it is most active on extracellular organisms Continue with INH and rifampin for 4 more months

Anti-tuberculosis drugs Wow. How many months was that? 8! (And that’s for the non-fancy susceptible TB!) Name 3 reasons to deviate from this regimen. TB infection is resistant Patient can’t tolerate 1st line drugs Patient is already taking drugs that have significant interactions with rifampin (we’ll get to this)

Isoniazid (aka INH) MOA? Inhibits synthesis of mycolic acids (pro-drug converted to active drug by bacterial enzyme) Resistance? One mutation away! Is this drug potent against TB? It is the most potent anti-TB agent we have Can you use it alone? Prophylaxis only. Never to treat active disease

Isoniazid (aka INH) Name 3 relatively common adverse reactions Allergy Hepatitis (stop drug if jaundice!) Peripheral neuropathy How can you prevent the neuropathy? B6 supplementation What’s the name of B6? (for a bonus) Pyridoxine!

Isoniazid (aka INH) Name 2 rare adverse effects. Systemic lupus erythematosus CNS toxicity-memory loss, psychosis, seizures (reverse with B6) Does this drug inhibit P450? yes

Rifampin MOA? Binds RNA polymerase, blocks RNA sythesis Resistance? Mutation of RNA pol, can occur quickly Can you use this drug alone? Prophylaxis only. Not to treat. Is this drug absorbed orally? Yes Where does this drug distribute? Mostly everywhere (CNS, phagocytes)

Rifampin How is this drug eliminated? Metabolized in liver, excreted in bile Is this drug active only against TB? No. Active against gram-pos and gram-neg cocci, chlamydia, some enteric bacteria, other mycobacteria For what is this a DOC? Neisseria meningitidis and H. influenzae prophylaxis

Rifampin Other uses/combos: Leprosy: Rifampin+dapsone +/- clofazimine Legionella: Rifampin + erythromycin M. kansasii: Rifampin +INH MRSA: Rifampin+vancomycin+gentamicin S. pneumoniae (resistant strain): Rifampin +vancomycin

Rifampin Name 3 adverse effects. Harmless orange color to body fluids Flulike symptoms Jaundice (can be FATAL) Does this drug inhibit P450 metabolism. No! It induces it!! Decreases ½ life of other drugs This includes some anti-retrovirals, so HIV patients with TB should take rifabutin instead of rifampin

Ethambutol MOA? Inhibits mycobacterial cell wall sythesis and enhances actions of rifampin/other lipophilic drugs Elimination? 50% in urine Does this drug get in the CNS? Only when meninges are inflamed. Clinical use? Only in combo therapy for TB

Ethambutol 2 Adverse effects? Reversible visual disturbances (loss of acuity and red/green colorblindness) Hyperuricemia/gout

Pyrazinamide (aka PZA) MOA? Unknown Spectrum? Active only against M. tuberculosis Name 2 clinical uses. With ciprofloxacin, resistant TB prophylaxis With INH, rifampin, ethambutal for TB treatment

Pyrazinamide (aka PZA) Name 2 adverse effects. Hyperuricemia (occurs in most patients, can cause gout) Hepatotoxicity (requires periodic liver function tests

Streptomycin MOA? It’s an aminoglycoside (the original!), so irreversible 30S binding Gets into CNS? No Gets into cells? No! Useful for extracellular TB only! Used clinically for? Combo therapy for very serious TB infection

Streptomycin Adverse effects? Ototoxic and nephrotoxic (like other aminoglycosides)

Anti-leprosy drugs Name 3. Dapsone Clofazimine Rifampin

Dapsone MOA? antifolate—related to sulfonamides Absorbed by GI? Yes Distribution? Very well distributed Elimination? Bile and urine

Dapsone Name 2 clinical uses. Pneumocystis pneumonia prophylaxis in AIDS patients Combo with clofazimine and rifampin for leprosy 1 common adverse effect? Allergy 1 rare adverse effect? Hemolysis, especially in patients with G6PDH deficiency

Clofazimine MOA? A dye that binds DNA Can be taken orally? Yes Where does this drug accumulate? Reticuloendothelial cells and skin Adverse effects? Skin discoloration (reddish to darkish brown)

Clofazimine 2 good things about this drug other than it’s antibiotic effect? Anti-inflammatory (could also be a bad thing) and prevention of erythema nodosum leprosum Clinical use? With dapsone and rifampin for leprosy Weak activity against M. avium

Atypical Mycobacterial infections Most common cause? Mycobacterium avium Is normal treatment for TB effective for this? No. Recommended treatment? Azithromycin or clarithromycin plus ethambutol +/- cipro or rifabutin Use azithro, clarithro or rifabutin as monotherapy prophylaxis for AIDS patients with low CD4 counts