Antibiotics--exam 1 Flashcards
Penicillin (prototype)
- β lactam ring forms irreversible covalent acyl-bond w/ transpeptidase enzyme (PBP)
- Prevent x-linking (transpeptidation)
- -cell continues to degrade wall (remodel)→ osmotic lysis
- time dependent killing
- most rapidly excreted drug by normal kidney
- -can be partially blocked → probenecid
- -can exacerbate gout
- one of the most NON-TOXIC and SAFEST drugs
- can produce all 4 types of hypersensitivities
- -**most allergenic of Abx, then Sulfa then cephalosporins
- -all are cross-allergic & sensitizing
- -procaine-penicillin combo is worst
Toxicities (mostly dose dependent)
1) tissue irritation
2) excess Na, K+ from large doses → cardiac & renal toxicity
3) Soft frothy stools & diarrhea → broader spectrum is worse
- overgrowth of staph, pseudomonas, proteus or yeast
4) Superinfection
5) Jarisch-Herxheimer Rxn → severe febrile reaction
- -occurs in syphilis or leptospirosis due to massive killing
Penicillin G potassium (IV, IM)
Penicillin G benzathine (IM depot)
Penicillin G procaine (IM)
Penicillin V (acid resistant → oral)
Natural penicillin
- Penicillin G benzathine → longest acting preparation
- -Treat → Syphilis (DOC) & Rheumatic fever
- -mild/mod infections
- -prophylaxis
- activity against gram positives→ **HIGHEST
- spectrum→ some G-
- activity against anaerobes→ some
- activity against pseudomonas aeruginosa→ none
- penicillinase resistance→ readily inactivated
- acid resistance→ only penicillin V
- main route of elimination→ active transport in kidney
- -no metabolism → no drug interactions
- CNS penetration→ poor penetration (↑ w/ inflammation)
Nafcillin (parenteral)
- Oxacillin (oral)
- Dicloxacillin (oral)
- Methicillin
Penicillinase resistant penicillins*
(Anti-staphylococcal penicillins)
- -**DOC for penicillinase producing staph. auerus
- Methicillin was most common cause of interstitial nephritis
- activity against gram positives→ lower against certain
- spectrum→ some
- activity against anaerobes→ some
- activity against pseudomonas aeruginosa→
- penicillinase resistance→ resistant
- acid resistance→ some & **highly protein bound
- -loading dose → 2x usual dose
- main route of elimination→ **hepatic & renal excretion
Amoxicillin
–Ampicillin
Extended spectrum penicillins* (amino penicillins)
- activity against gram positives→ lower
- spectrum→ extended G- (PeSSkEy, H. influ)
- activity against anaerobes→ yes; w/ penicillinase inhibitors
- activity against pseudomonas aeruginosa→ none
- penicillinase resistance→ susceptible
- acid resistance→ resistant
- main route of elimination→ urinary excretion
- Ampicillin rash → not allergic or itchy
- -can occur w/ EBV
Piperacillin
–Ticarcillin
Antipseudomonal Penicillin
- activity against gram positives→ lower
- spectrum→ same as amoxicillin + some G- enteric bacilli
- activity against anaerobes→ yes; w/ penicillinase inhibitors
- activity against pseudomonas aeruginosa→ YES
- penicillinase resistance→ susceptible
- acid resistance→ sensitive
- main route of elimination→ renal excretion
Aztreonam
Monobactam (same mxn as penicillin)
- relatively resistant to β-lactamases
- Targets → Gram negative rods (including Pseudomonas & Serrate)
- NO ACTIVITY → Gram+ or anaerobes
- Safe in pts w/ Penicillin allergy
Imipenem, Cilastatin
- -meropenem
- -ertapenem
- -doripenem
Carbapenems (same mxn as penicillin)
- broad spectrum → anaerobes, G+, G- rods
- -Pseudomonas may develop res. → add amino glycoside
- Imipenem → inactivated by renal dehydropeptivdases
- -must be given w/ Cilastatin
- -can cause seizures
- Meropenem → resistant to dehydropeptidases
- less likely to cause seizures
- Ertapenem → highly stable against β-lactamases
- particularly effective against Enterobacteriaceae
-Doripenem → good activity against pseudomonas
Clavulanic acid
- -sulbactam
- -tazobactam
Beta-lactamase inhibitors
- resemble beta-lactam molecule
- weak antibacterial action
- inhibit many, but not all BETA LACTAMASES
- -most active against → plasmid encoded lactamases
Vancomycin
–teicoplanin
Inhibitor of cell wall synthesis (glycopeptides)
- binds terminal D-alanine D-alanine of nascent PG pentapeptide
- → inhibits transglycosylase → no chain elongation
- -**inhibits transpeptidation (cross linking)
- ONLY effective for Gram+
- staph aureus & epidermidis
- strep & enterococci, corynebacterium & clostridium
- penicillin and methicillin resistant staphylococcal (DOC)
- -patient w/ penicillin allergy
- parenteral
- -sometimes oral → GI infections (pseudomem. colitis)
- poor CNS penetration → don’t use for meningitis
Resistance → D-Ala-D-Ala → D-Ala-D-LACTATE
- excreted unchanged in kidney → marked accumulation
- nephrotoxicity in presence of renal insufficiency
- -uremia after high dose may be FATAL
- ototoxic
- red man syndrome → histamine release
Telavancin
Inhibitor of cell wall synthesis (lipoglycopeptide)
- binds terminal D-alanine D-alanine of nascent PG pentapeptide (no elongation or x-linking like vancomycin)
- ↑ membrane permeability (like daptomycin)
- bactericidal → select Gram+, MRSA
- complicated skin & skin structure infections
- take 1x day
- CI → pregnancy & renal insufficiency
Fosfomycin
Inhibitor of cell wall synthesis
- inhibits one of the key 1st steps of peptidoglycan synthesis
- -irreversibly inactivates enolpyruvyl transferase
- -nucleotide precursors accumulate → death & lysis
- active against Gram+ & Gram-
- -uncomplicated lower UTI in women
-taken orally → excreted by kidney
Bacitracin
Inhibitor of cell wall synthesis
- inhibits activation (dephosporylation) of the lipid carrier
- -no transport of peptidoglycan subunits (water soluble) through cell membrane
- accumulate in cytoplasm→ not added to growing PG chain
-mainly target Gram+
-topical or parenteral
–serious nephrotoxicity w/ PE admin
–most commonly use in combo w/ polymyxin B & Neomycin
topically→ prevent superficial skin and eye infection
Cycloserine
Inhibitor of cell wall synthesis
- analog of D-alanine
- competes w/ D-alanine for 2 enzymes (incorporate alanine)
- -inhibits both enzymes & peptidoglycan synthesis
- → weak cell wall & eventual cell lysis
- 2nd line against active pulmonary & extra-pulm TB
- severe CNS toxicity (anxiety, confusion, memory loss, seizures, etc.)
Cephalosporins
- β lactam ring forms irreversible covalent acyl-bond w/ transpeptidase enzyme (PBP)
- Prevent x-linking (transpeptidation)
- -cell continues to degrade wall (remodel)→ osmotic lysis
- has a 7-methyl group → ↑ resistance to β-lactamase
- resistance mxn → same as w/ penicillin
- most have some plasma protein binding
- penetrate most tissues → not eye & CNS
- most excreted unchanged by kidney
- -Probenecid → ↓ excretion & ↑ 1/2 life
- -adjust dosage w/ renal insufficiency
Adverse
- pseudomembranous colitis → ↑ specturm ↑ chance
- dose dependent renal tubular necrosis
- synergistic nephrotoxicity w/ aminoglycosides (esp in elderly)
Properties of ICWS
- activity against gram positives→
- spectrum→
- activity against anaerobes→
- activity against pseudomonas aeruginosa→
- penicillinase resistance→
- acid resistance→
- main route of elimination→
- CNS penetration→
Mechanisms of Bacterial Resistance
- Inactivation by penicillinase (may be inducible)
- ↓ permeability of outer membrane (only G-) → prevents reaching PBP
- Alteration of PBP (mxn if resistant to Methicillin)
- Autolytic enzymes not activated (Listeria & Staph)
- Lack cell wall (Mycoplasma)
- Non-peptidoglycan cell wall (Chlamydia)
Daptomycin
Inhibitor of cell wall synthesis (lipopeptide)
- binds to bacterial membranes → rapid depolarization
- → inhibits protein, DNA, and RNA synthesis → death
- bactericidal → Gram+
- NO MXN OF RESISTANCE
-IV → excreted unchanged by kidneys
Cefazolin (IV)
- Cefadroxil Monohydrate (oral)
- Cephalexin (oral)
First Gen. Cephalosporin (narrow spectrum)
- good activity → Gram + (EXCEPT enterococci)
- -most G+ cocci except → enterocci, MRSA, MRSEpi
- -NO β-lactam is effective against MRSA
- moderate activity → Gram -
- good activity → E. coli, Klebsiella pneum., Proteus marbles
- -1st & 2nd gen. → DOC for E. coli
Cefazolin → surgical prophylaxis
Cefoxitin (IM, IV)
- Cefaclor (Oral)
- Cefotetan (IM, IV)
- Loracarbef (Oral)
Second Gen. Cephalosporin (intermediate spectrum)
- good activity → Gram +
- increased activity → Gram -
- good activity → E. coli, Klebsiella pneum., Proteus marbles
- -1st & 2nd gen. → DOC for E. coli
Cefaclor → serum sickness like SE
Cefotetan & Loracarbef → disulfiram like effect
–inhibits acetyladehyde deydrogenase
Cefotaxime Sodium
- Ceftizoxime
- Ceftazidime
- Ceftriaxone
- Cefixime
Third Gen. Cephalosporin (broad-spectrum)
→ diff from 1st & 2nd gen
- pretty good G+ and G- coverage
- -↓ G+ cocci but ↑ enterobacteriaceae coverage
- even more resistant to B-lactamase
- some will get into CNS → Cefotaxime & Ceftriaxone
- effective against → Pseudomonas
- first line choice → Salmonella
- mostly/half metabolized → liver
- -if it is lipid soluble wont be excreted in kidney and must be conjugated in liver
Ceftriaxone → ↑ hepatic elimination --DOC gonnorhea --penicillin resistant strep. pneumoniae Cefixime → ORAL Ceftizoxime & Ceftazidime → antipseudomonal
Cefepime
Fourth Gen. Cephalosporin
- good G+ and G- (similar to 3rd gen)
- more resistant to some β-lactamases
- anti-pseudomonal (similar to Ceftazidime)
- better activity → Enterobacter & Citrobacter
- reserved for ICU and severe systemic infections
- ↑ penetrvity → Enterobacter & Citrobacter
- reserved for ICU and severe systemic infections
-penetrates CSF
Ceftarolime fosamil
Unnamed gen. Cephalosporin
effective against MSSA, MRSA, & VRSA
- high affinity to → PBP 2A (responsible for resistance)
- -encded by mega
- no antipseudomonal
Organisms not reliably covered by cephalosporins
- Enterococci → Penicillin
- List. Monocytogenes → Penicillin
- MRSA
- Atypicals → Chlamydia & Mycoplasma
Cephalosporins are 1st choice for infections with:
- Moraxella catarrhalis → 2nd or 3rd gen
- Neisseria gonorrhoeae → ceftriaxone, cefixime (oral)
- E. coli, Klebsiella, Proteus → 1st or 2nd gen.
- Salmonella → 3rd gen
- Penicillin resistant Strep. pneumonia → ceftriaxone
MAY be used:
- Gram + infections in penicillin-sensitve patiens
- mixed infections → cellulitis or skin ulcers in diabetic
- surgical prophylaxis → cefazolin
- UTI → excreted & concentrated in urine
Sulfonamide mechanism & uses
Sulfonamide (bacteriostatic)
-competes w/ PABA at dihydropteroate synthase
→ blocks formation of DHF
–folic acid necessary for Purine & DNA synthesis
–susceptible bacteria can’t multiply, grow, or survive
–mammals do not synthesize folic acid like bacteria
-inhibit both Gram+ and Gram-
RESISTANCE
- -↓ sensitivity of target enzyme
- -↑ formation of PABA
- -use of exogenous folate
USES
- DOC→ UTI infections (1st attack & prophylaxis)
- DOC→ Nocardiosis
- Toxoplasmosis & Trachoma
- Pneumocytstis carinii → children and AIDS patients
Sulfonamide distribution, metabolism/excretion, interactions and Toxicity
- good distribution
- -cross placenta and BBB
- Good degree of plasma protein binding → no neg. effect
- ***urine conc. → 10-20x plasma can be reached for UTI
- -at high concentrations → bactericidal
- Metabolized in liver → acetylated products
- Excreted through kidney
- -insoluble (esp. *acidic urine) → crystalluria & renal dmg
- –drink more water or alkalize urine
TOXICITIES
- every organ systems may be adversely affected
- Kernicterus in nursing infant → displaces bound bilirubin →CI infants <2 months
- Drug sensitivy (allergy 6%, 2nd to penicillin)
- Blod dyscrasia, leukopenia, granulocytopenia,
- -thrombocytopenia, agranulocytosis
- Kidney & Liver damage
- Stevens-Johnson syndrom (dermal toxic lysis → lose epi)
- Microscopic hematuria→ crystals damage
- PHOTOSENSITIVITY
Sulfasalazine
Sulfonamide (bacteriostatic)
- competes w/ PABA→ blocks formation of DHF
- -prodrug cleaved GI bacteria→ sulfapyridine + mesalamine
- -local actions of melamine → effectiveness of sulfasalazine
- used to treat Ulcerative Colitis
- oral
Silver Sulfadiazine
Sulfonamide (bacteriostatic)
- exact mechanism is unknown→ dent inhibit FA synthesis
- -damages cell membrane and cell wall
- Topical → prevent & treat infections → 2nd/3rdº burns
- Activity against → Bacteria AND yeast
- does not inhibit CA (Mafenide does)
- doesn’t stain dressing or tissue
Trimethoprimp
Folate Antagonist
- inhibits DHF reductase → blocs formation of THF
- -THF needed for carbon transfer → NA, protein synthesis
- -therapeutic does → no human enzyme inhibition
- activity against Gram+ and Gram-
- commonly used systemically for treatment & prophylaxis:
- -uncomplicated UTI
- –alone may be as effective → recurrent UTI
- -traveler’s diarrhea
- SMX or dapsone → pneumocystis carinii
- can be used w/ impaired renal function or if sulfa drugs can’t be tolerated
- may be TERATOGENIC → don’t take during pregnancy
Co-trimoxazole (Bactrim)
Sulfamethoxazole + Trimethoprim (TMP-SMX)
Sulfonamide Combo
- Sulfamethxazole blocks PABA incorporation to DHF
- Trimethoprim prevents reduction of DHF to THF
- -selective for DHF reductase of lower organisms
- fixed 1:5 ratio (TMP-SMX) → 1:20 serum concentrations
- DOC for uncomplicated UTI (except for enterococci)
- -Prostatitis (along w/ doxycycline & fluoroquinolones)
- DOC for Moraxella catarrhalis
- P. jiroveci pneumonia (also TMP + dapsone)
- -respiratory tract pathogens → pneumococcus
- –Haemophilus, Moraxella catarrhalis, Klebsiella pneumonia
- Shigellosis & systemic salmonella infections
- some non TB myco infections
- MSSA & MRSA
- otitis media
- 2nd line for Listeria
Sulfadoxine + Pyrimethamine
Sulfonamide Combo
pyrimethamine → inhibits parasitic DHF reductase
sulfadoxine → antagonizes PABA
–synergistic activity on FA production
- used in combo → malaria treatment
- -not prophylaxis → fatal toxic epidermal necrolysis
Sulfadiazine
Sulfonamide (bacteriostatic)
-competes w/ PABA→ blocks formation of DHF
- oral, intermediate duration
- used w/ Pyrimethamine → toxoplasmosis
- POORLY SOLUBLE in urine → CRYSTALLURIA (most likely)
- -limited use for serious infection
Macrolide Group
Protein Synthesis Inhibitor
- bacteriostatic??
- effective alternative to penicillin → allergy or kidney failure
- among the SAFEST antibiotics
- Clarithromycin & Azithromycin → respiratory, skin & skin structure infections
Eryhthromycin mechanism, uses, resistances
Macrolide
- reversibly binds 50s subunit → blocks translocation (A→P)
- -near binding site for Chloramphenicol → antagonistic
- spectrum similiar to Penicillin G
- most active against → G+ cocci
- active against → G+ bacilli (clostridium
- effective against → Mycoplasma pneumonia
- majority of gram negative → resistant
USE
- most commonly → mixed infections of skin, soft tissue, body cavities caused by Gram-positive organisms
- alternative to penicillin
- Group A strep pyogenes → cellulites, scarlet fever, pharyngitis, erysipelas
- Acute diphtheria
- 1ry pneumonia → M. pneumoniae & chlamydia
- DOC → Legionnaire’s disease (legionella pneumophila)
- -atypical pneumonia ??
RESISTANCE (mostly plasmid encoded)
1) Drug efflux by active pump
2) **Methylase enzymes→ modify ribosomal target; ↓binding
- -cross resistance w/ all members of group
3) Hydrolysis by esterases from enterobacteriaceae
4) Chromosomal mutations → alter a 50s ribosomal proein
Eryhthromycin metabolism, toxicity, adverse reactions, and drug interactions
- Gastric acid → rapidly destroy erythromycin base
- crosses placenta, penetrates prostatic fluid
- no CNS penetration
- Primarily fecal excretions (large amounts lost)
- -some in bile → reabsorbed
- Intravenous → E. Gluceptate & E. Lactobionate when large doses needed
ADVERSE
- GI disturbances
- DIARRHEA → stimulates motilin
- -may help constipation
- QT prolongation, torsades de pointes
- -worst in group, but all do it
- transient hearing loss → ototoxicity
INTERACTIONS
- inhibits CYP3A4 → ↑ serum [ ] of other drugs
- -→ serious QT prolongation and cardiac arrhythmias w/
- -Cispride, Pimozide, Sparfloxacin or Grepafloxacin
- changes GI flora → ↓ estrogen enterohepatic circulation
- ICWS are made ineffective → they need growth to work
- statins -> rhabdomyolysis
Clarithromycin
Macrolide
-binds to 50s subunit → protein synthesis inhibition
- most common use → infections of respiratory tract
- penetrates lung tissue & macrophage > Erythromycin
- -**effective against MAC
- H. pylori-associated duodenal ulcer
- community-acquired pneumonia in children
- inhibition of CYP3A4 → ↑ serum [ ] of other drugs
- less QT elongation than Erythromycin
- well tolerated → no disabling nausea & vomiting
- other adverse reactions similar to erythromycin
- best oral of macrolides
Azithromycin
Macrolide
-binds to 50s subunit → protein synthesis inhibition
- not metabolized by liver & excreted into bile
- → less interactions & inhibition of P450
- can be dosed → 1 daily
- less GI intolerance than Erythromycin
- reaches higher intracellular concentrations
- -↑ efficacy & duration of action
USES
- active against same organisms as erythromycin
- STD → Chlamydia & gonorrhea combine w/ Ceftriaxone
- pediatric otitis media, pharyngitis, MAC prophylaxis
- IV for initial treatment of CA pneumonia & PID
Telithromycin
Ketolide
-binds 50s subunit → inhibits protein synthesis
- greater antibacterial killing than macrolides
- good against respiratory pathogens
- -**erythromycin & penicillin resistant pneumococci
- activity → intracellular and atypical bacteria
- metabolized by CYP3A4
- diarrhea, nausea, vomiting → most common SE
- serious hepatoxicity
Clindamycin
Inhibitor of Protein synthesis
-binds 50s subunit → inhibits protein synthesis
- **effective anti-aerobic antibiotic
- -MOST anaerobes → G+ & G-
- w/ pyrimethamine → toxoplasmic encephalitis in AIDS
- strep (not enterococci) & staph → very susceptible
- topically for acne → inhibits lipase-producing organism
- -↓ FFA in sebum → inflammatory lesion w/ acne
- well absorbed orally → high [ ] **BONE, bile, and urine
- -poor CSF concentrations
- well know cause → pseudomembranous colitis (c. dificile)
Dalfopristin; Quinupristin (Synercid)
Streptogramin
- irreversible block ribosome functioning
- -Dalfopristin → 70s or 50s → inhibits early phase
- -Quinupristin → 50s → inhibits late phase
- combo has up to 16x activity of each agent alone
USE (IV infusion)
- **Vancomycin resistant enterococcus faecium bacteremia
- Complicated skin and skin structure due to staph aureus
- nausea, vomiting, pain, puritis, rash
- inhibits CYP 3A4 (↓ cyclosporin, midazolam, nifedipine)
CI → pregnancy, children, breast feeding, hepatic disease
Linezolid
Oxazolidinones
-binds 50s → prevents formation of functional 70s initiation complex → blocks translation
**-reversible, non-selective inhibition → MAO!!
- predominant activity → aerobic gram positive
- -bacterial pneumonia
- -skin & skin structure infections
- -Vanco resistant enterococcal infections
- -MRSA
-CI → pheochromocytoma or hypersensitivity
Isoniazid
Primary Antimycobacterial agent
- inhibits biosynthesis of Mycolic acid
- can reach intracellular bacteria (streptomycin can’t)
- prodrug activated by Mtb protein (KatG → resistance)
- -develops quickly when given alone
- ALWAYS combo w/ rifampin, streptomycin or ethambutol for ACTIVE TB
- given SOLO for LATENT TB
- bactericidal → actively growing bacilli
- bacteriostatic → latent or dormant infection
- combo w/ Rifampin → bacteriocidal
- most atypical mycobacteria → resistant to INH
TOXICITY:
- CNS stimulation (convulsions
- peripheral neuritis → slow acetylators (↓ by Pyridoxine)
- liver damage → fast acetylators (MUST test liver enzymes)
- Hemolysis → G6PD
- Lupus like syndrome
Rifampin
Primary Antimycobacterial agent
- inhibits DNA-dependent RNA polymerase
- -resistance → mutation rpoB gene
- primarily used for TB in combo w/ other anti-TB drugs
- effective against TB & some atypical in very low [ ]
- inhibits growth → G+ cocci and some G-
- **bactericidal → active, latent, intra-/extra-cellular bacilli
- -can be used alone for latent TB
- prophylaxis for TB → HIV pts (Rifabutin if taking protease inhibitors)
- Asymtomatic carriers of N. meningitidis (not for usual infxn)
- ***strong bactericidal activity → Leprosy
- excreted primarily through Bile
- induces CYP3A4
- ↓↓ effectiveness of oral contraceptives
- ↑ requirement of methadone
- make tears, urine, and sweat harmless ORANGE
Rifabutin
Primary Antimycobacterial agent
-inhibits DNA-dependent RNA polymerase
- very lipophilic → wide dist. (5-10x [ ] in lungs than serum)
- → substantial intracellular accumulation
- Alternative to Rifampin
- -LESS potent inducer of CYP → HIV pts on HAART
- alternative to Clarithromycin or Azithromycin for 1ry MAC prophylaxis in HIV pts.
- alternative to Rifampin for TB/TB prophylaxis in HIV pts if resistant to isoniazid
- discoloration → URINE, tears, sweat, feces, saliva, sputum
- thrombocytopenia (not significant)
Pyrazinamide
Primary Antimycobacterial agent
- requires conversion to active form
- -resistance → mutation pncA
- Mechanism not well understood
- bacteriostatic/bacteriocidal
- HIGH risk of hepatic injury
- hyperuricemia
- -CI if any degree of hepatic dysfunction
Ethambutol
Primary Antimycobacterial agent
- inhibits arabinosyl transferases → cell wall synthesis
- -inhibits arabinogalactan synthesis
- -resistance → mutation in embCAB
- bacteriostatic
-about 1/2 excreted in urine unchanged
- ↓ visual acuity
- loss of green-red perception → retrobulbar neuritis
- -not recommended for children < 13 yrs.
Streptomycin
Aminoglycoside (Primary Antimycobacterial agent)
-Protein synthesis inhibitor → 30s (bactericidal)
(para-)Aminosalocylic acid
Secondary Antimycobacterial agent
-ORAL→ absorbed from GI and dist. widely (not CSF)
- Anorexia, nausea, diarrhea
- peptic ulcer, hemorrhage
- kidney & liver damage
- Thyroid injury → goiter w/o myxedema
- Drug fever, joint pain, rashes, granulocytopenia
Ethionamide
Secondary Antimycobacterial agent
-ORAL
- GI irritation, neurological complications
- resistance rapidly develops (give in combo)
Rifapentine
Secondary Antimycobacterial agent
- inhibits DNA-dependent RNA polymerase
- has longer 1/2 life than rifampin and rifabutin
- once weekly dosing
- intermediate induction of CYP
Capreomycin
Secondary Antimycobacterial agent
- IM injection
- Kidney damage (most serious)
- nitrogen retention
- 8th nerve deafness & vestibular disturbances
Clofazimine (off market in USA)
Secondary Antimycobacterial agent
-binds preferentially to mycobacterial DNA (high GC)
→ ↓ reproduction & growth
- bactericidal → TB, M. marinum
- slowly bactericidal → leprosy
- bacteriostatic → MAC
Thalidomide
Anti-leprosy agent
- ↑ degradation of TNF-α mRNA encoding protein
- → ↓ TNF-α
- treatment of choice → Erythema nodosum leprosum
- TERATOGENESIS (most regulated Rx in US)
- -CI in pregnancy and breastfeeding
Dapsone
Anti-leprosy (similar to sulfonamide)
- PABA antagonist → bactericidal
- part of MDT for leprosy
- -given alone Leprosy always develops drug resistance
- bacteria disappear very slowly
- -after 5 yrs of treat → 1/2 pts have positive smears
Treatment for MAC
1) include either Clarithromycin or Azithromycin
2) include Ethambutol
3) add third oral drug (rifabutin, rifampin, clofazimine, cipro)
4) Include IV amikacin in certain cases (resis. clarithromycin)
Amino glycoside group
- -Gentamicin
- -Tobramycin
- -Amikacin
- -Streptomycin
- -Neomycin
- -Kanamycin
- -Paromomycin
- inhibit protein synthesis → inhibts 30s subunit
- -block initiation of protein synthesis
- -block further translation → premature termination
- -promote usage of incorrect AA → bactericidal
- transport into cell req. O2 → no effect anaerobic
- Polarity responsible for properties
- NONE is absorbed adequately orally
- NONE penetrate CSF
- kidney rapidly excretes ALL
- -accumulate w/ renal failure → ↓ dose
- more active at ALKALINE pH
- used almost exlusively for:
- -***Gram- enteric bacteria (enterobacteriaceae)
- -suspicion of sepsis or endocarditis (combine w/ penicilin)
- Ototoxicity → auditory and vestibular (8th CN)
- Nephrotoxicity
- neuromuscular weakness
- resistance is plasmid mediated (R-factor derived)
- -enzymes that adenylate, phosphorylate, or acetylate
- killing → concentration dependent
- adverse effects → time dependent
Streptomycin
Aminoglycoside
- Tularemia
- Bubonic plague
- Only TB drug that is injected
- endocarditis
- inhibit protein synthesis → inhibts 30s subunit
- -block initiation of protein synthesis
- -block further translation → premature termination
- -promote usage of incorrect AA → bactericidal
Kanamycin
Neomycin
Paromomycin
Gentamicin
Aminoglycoside (30s)
-Kanamycin & Neomycin → pre-op suppression of enteric aerobic flora
- Neomycin → hepatic encephalopathy
- -kills GI bacteria that make ammonia
-Paramomycin → intestinal amebiasis
Neomycin & Gentamicin → topical application
Streptomycin → Gentamicin → Tobramycin → Amikacin → Spectinomycin →
Neomycin →
Kanamycin →
Paromoycin →
Streptomycin → tuberculosis (enterococcal endocarditis) *Gentamicin → gram neg, combination *Tobramycin → gram neg, combination *Amikacin → gram neg, combination Spectinomycin → gonorrhea
*effective against p. aeruginosa
Neomycin → oral, topical
Kanamycin → rarely used
Paromoycin → cryptosporidium parvum, amebiasis, tapeworm
Chloramphenicol
mxn, resistance, distribution, metabolism, toxicity
Broad Spectrum (protein synthesis inhibitor)
- binds 50s → inhibits peptide bond formation
- -usually bacteriostatic
- -bactericidal → common meningeal pathogens
resistance → acetyl transferase → acetylate & inactivates
- orally → ALL tissues, (including eyes and CNS)
- conjugated w/ glucuronic acid (90%)
- -toxic levels w/ hepatic insufficiency
- 10% active drug excreted by glomerular filtration
- reversible BM depression & hematopoietic problems
- can inhibit mitochondrial protein synthesis
- -*FATAL APLASTIC ANEMIA
- Gray baby syndrome → unable to conjugate and excrete
- -glucuronyl transferase deficiency
Chloramphenicol
uses, interactions
- NOT used as DOC for any bacterial infection
- DO NOT use for minor infection, viral, URT, or w/o careful follow up
- Typhoid fever
- Meningitis
- Eye infections
- infections from Gram-negative organisms
- Rickettsia, Brucellosis, RMSF
- not effective → Entamoeba histolytic or pseudomonas
- inhibits metabolism→ Tolbutamide & Chlorpromaide
- may interfere w/ Warfarin metabolism
- -→ ↑ hypoprothrombinemic effect
- inhibits P-450 (phenobarbital & phenytoin)
- ↓ plasma [ ] by use w/ phenobarbital, phenytoin, rifampin
- can displace erythromycin from binding site
Tetracycline (group)
Tetracycline
- bind 30s → prevent access of aminoacyl tRNA to receptor site → prevents addition of AA to growing chain
- bacteriostatic
- resistant mutants → transport drug out of cell
- poor solubility→ unabsorbed modifies intestinal flora
- -overgrowth → yeast, enterococci, proteus, pseudomonas
- chelates Ca++, Fe++ and Al++ → ↓ solubility
- wide list. → except CNS and JOINTS
- -deposited in bone and teeth
- should not be given to pregnant women or children <8
- may impair hepatic function → liver necrosis
- may cause renal tubular acidosis
- photosensitization
Tetracycline uses
Drug of Choice:
- mycoplasma pneumonia
- chlamydia (DOC → azithromycin)
- rickettsiae
- some spirochetes
- H. pylori → combo w/ metronidazole & bismuth
- alternative for gonococcal infection
- plauge, tularemia, brucellosis → combo w/ aminoglycoside
- Entamoeba histolytica, plasmodium falciparum
Doxycycline
Long acting Tetracycline
- more active than tetracycline HCl
- absorption not sig. affected by food
- slowly excreted → mostly in bile
- good tissue penetration → esp. prostate
Minocycline
Long acting Tetracycline
- hich concentration in saliva and tears
- meningococcal carrier state (DOC rifampin)
- absorption not sig. affected by food
- slowly excreted → mostly in bile
-viestibular ototoxicity
Demeclocycline
Tetracycline
- Blocks ADH receptor function in collecting tubules
- used for SIADH
Tigecycline
Glycylcycline
- binds 30s → bacteriostatic
- developed to circumvent resistance mxns
- -bad substrate to pump
- similar activity to tetracyclines → active against resistant
- MRSA, MRSE, PRSP, and VRE
- IV → complicated skin/structure, intra abdominal infxn
Nitrofurantoin
UTI drugs
- interferes w/ bacterial enzymes
- activity higher in ACIDIC urine → keep < 5.5
- used for UTI (often used in elderly)
- wide spectrum against G+ and G-
- -most Proteus and Pseudomonas are resistant
-highly protein bound → no effect in blood
ADVERSE (mainly long term or renal impairment)
- colors urine BROWN
- Interstitial pulmonary fibrosis
- neurological disorders
-CI → pregnancy & impaired renal function and allergy
Methenamine Mandelate
UTI drug
- Decomposes in urine → formaldehyde & ammonia
- Formald. → binds amino groups → inactivates proteins
- -CHEMICAL rxn → no receptor → NO RESISTANCE
-CHRONIC suppressive treatment of UTI (esp e. coli)
- essentially NON-TOXIC
- CI → renal and hepatic insufficiency
Ciprofloxacin
- -Levofloxacin
- -Ofloxacin
2nd gen fluoroquinolone
- inhibition of DNA gyrase → alter DNA’s structure & function
- -bactericidal
- resistance → mutation of topoisomerase enzyme
- -plasmid mediated → Qnr proteins protect gyrase
- -acetyltrasferase → modify fluoroquinolones
- CROSS RESISTANCE
- UTI (pseudomonas)
- travelers diarrhea (trimethoprim)
- soft tissue infections
- prophylaxis of inhalational anthrax
- Mg++ (antacids) → interfere w/ absorptions
- poorly penetrates CSF
ADVERSE
- GI disturbances
- Seizures
- ↑ QT interval (macrolides–Azithromycin)
- transient ↑ serum transaminase, LDH, alk phos
- cartilage erosion → tendon rupture
- CI → pregnant women & children <18
Shortcomings of Ciprofloxacin
- limited activity against S. pneumonia
- poor CNS penetration
- not effective against anaerobes
Moxifloxacin
- -Gatifloxacin → only TOPICAL
- -Gemifloxacin → approved for CAP
3rd gen fluoroquinolone
-inhibits DNA gyrase → alters DNA structure & function
- oral ONCE a day
- ↑ activity penicillin-susceptible/resistant PNEUMOcocci
- ↓ activity → pseudoonal & enterobacteriaceae
- ↑ activity anaerobes
- treatment of acute exacerbations of:
- chronic bronchitis, acute sinusitis, and pneumonia
- good penetration → respiratory tissue & CNS
- metabolized → glucuronide & sulfate conjucation
- -CI w/ hepatic insufficiency
Norfloxacin→
Ciprofloxacin→
Olfloxacin→
Levofloxacin→
Moxifloxacin→
Gatifloxacin→
Gemifloxacin→
Norfloxacin→ UTI and prostatitis
Ciprofloxacin→ systemic infections, UTI
Olfloxacin→ prostatitis, STD (not syph), some systemic, TB
Levofloxacin→ CAP
Moxifloxacin→ penicillin resistant S. pneumoniae
Gatifloxacin→ Ocular application only
Gemifloxacin→ penicillin resistant S. pneumoniae, CAP
Metronidazole
- reduced metronidazole disrupts DNA helical structure
- -inhibts NA synthesis → bactericidal
- selective for ANAEROBES
- DOC → c. dificie
- metallic taste
- disulfiram-like effect → don’t use alcohol
Fidaxomicin
-inhibits protein synthesis → binds RNA pol
- active → G+ aerobe and anaerobe
- -NO gram neg activity (vancomycin)
- negligible systemic absorption → high [ ] in feces
- 3rd line treatment for C. difficile colitis
1) metronidazole 2) vancomycin 3) fidaxomicin
Mupirocin
- inhibits protein & RNA synthesis
- → reversible binds isoleucyl-tRNA synthetase
- bacteriostatic → low [ ]
- bactericidal → high [ ]
- little potential for cross-resistance
- TOPICAL administation to skin or nares
- imetigo → staph aureus, β hemolytic strep (pyogenes)
Polymyxin B; Polymyxin E
Poypeptide antibiotic
- disturbs cell membrane → ↑ permeability → loss of metabolites essential to bacteria existence
- -bactericidal
- mostly for Gram-neg infections
- -very effective against G- bacilli (pseudomonas and coliform organisms)
- topically → wounds, burns (pseudomonas)
- UTI, septicemia, bacteremia
- used when other Abx are INEFFECTIVE of CI
- no GI absorption → no oral use
- poor dist after parenteral
- bind very well to plasma proteins
- Nephrotoxiciy → CI kidney disease
- Paresthesia (respiratory arrest), ataxia, dizziness
Polymyxin drug interactions
Aminoglycosides → ↑ risk of renal dysfunction & respiratory paralysis
Cephalothin → ↑ risk nephrotoxicity
Non-depolarizing muscle relaxant → enhance blockade
