Concentration dependent killing
Vs.
Time dependent killing
Kill based on peak concentration (optimal above 10x MIC)
Kill based on amount of time concentration above MIC
Inhibitors of cell wall synthesis
Penicillins Carbapenems Cephalosporins Aztreonam Vancomycin Bacitracin Cycloserine
Inhibitors of protein synthesis/structure
Aminoglycosides Chloramphenicol Erythromycin, clindamycin, lincomycin Tetracyclines Streptogramins/linezolid
Interference with cell membrane function
Polymixin B, colistin
Azole and polyene (antifungals)
Interference with DNA/RNA synthesis
Rifampin
Fluoroquinones
Inhibitors of metabolism
Isoniazid, ethambutol
Sulfonamides, trimethoprim
Guidelines for selecting and using antimicrobial agents
Confirm presence of infection
Determine site of infection
Determine causative organism(s)
Select drug
Follow response and alter therapy as necessary
Select a drug based on
Sensitivity of the microorganism
Physiochemical properties
Toxicities of the drug
Patient characteristics
Reasons to start empiric abx coverage
Site of infection difficult to culture
Serious or life threatening infections
Notes: culture site before starting
Gram stains - quick and very informative for selecting
Penicillins/cephalosporins
Mechanism of resistance
Beta-lactamases
PBP changes
Porin channel changes
Aminoglycosides
Mechanism of resistance
Enzyme inactivating
Macrolides
Mechanism of resistance
Methyltransferases that alter drug binding sites on 50s ribosomal subunit
Tetracyclines
mechanism of resistance
Transport systems that pump drugs out of the cell
Sulfonamides
Mechanism of resistance
Increased PABA formation
Target enzyme sensitivity
Fluoroquinones
Mechanism of resistance
Target enzyme changes
Drug efflux
Gram positive class
Staphylococcus
Streptococcus
Enterococcus
Gram negative
Piddly
Haemophilus Morexella Morganella Shigella Salmonella (Providencia, neisseria)
Gram negative
Fence
Proteus
Eschericia coli
Klebsiella
Gram negative
SPACE
Serratia Pseudomonas Acinetobacter Citrobactor Enterobactrer
Atypical class
Chlamydia
Mycoplasma
Legionella
Anaerobes class
Peptostreptococcus
Bacteroides
Clostridium
Post Antibiotic Effect (PAE)
Persistent effect on bacterial growth following brief exposure of organisms to a drug
Aminoglycosides & fluoroquinones
Penicillin G
Binds PBP & blocks crosslink peptidoglycan
Strep, some enterococcus
Acid labile
Rheumatic fever prophylaxis
Penicillin VK
Binds PBP
Strep, some enterococcus
Acid stabile
Absorption not slowed by food
Anti penicillinase penicillin (anti staph)
Methicillin, nafcillin, oxacillin (IV drugs)
cloxacillin, dicloxacillin (PO drugs)
Nafcillin - hepatic elimination
Strep and beta lactamase staph
Ampicillin
Bind PBP
Strep, ENTEROCOCCUS, and PEK gram neg
Diarrhea is major side effect
Amoxicillin
Bind PBP
Strep, enterococcus, PEK gram neg
Absorb not slowed by food
Diarrhea less so than amp
Carbenicillin
Bind PBP
Strep, PEK and SPACE gram neg (pseudomonas requires high concentrations)
Absorption not delayed by food
High urine but low systemic concentration
Ticarcillin
Bind PBP
Strep, PEK and SPACE gram neg (pseudomonas req. high concentration)
High sodium load!! (CHF, renal fail, hypernat.)
Pipercillin
Bind PBP
Strep, enterococcus, PEK and SPACE gram neg
Sodium load but much lower than ticarcillin
Adding beta lactamase inhibitor to penicillin
Augmentin- amox/clavulanic acid
Unasyn- amp/sulbactam
Zosyn- pipercillin/ tazobactam
Adds staph and anaerobes
Cephalosporins (general)
Bind PBP inhibit peptidoglycan crosslink
Oral admin - rapid, thorough absorption
Most renal excretion
Probenecid interaction: prolonged excretion if tubular secreted
Warfarin: potentiates bleeding
Cephalosporins (General)
Binds PBP and inhibits peptidoglycan crosslink
Oral admin - rapid, thorough absorption
Probenicid: prolong excretion of tubular secreted drugs
Warfarin: potentiation of anticoagulant effects
1st Gen. Cephalosporins
Cephalexin, Cefazolin
Coverage: strep, staph, piddly
cefazolin - surgical prophylaxis, long 1/2 life
minor skin and soft tissue infections
2nd Gen. Cephalosporins
Cefaclor, Cefuroxime
Coverage: strep, staph, H. Flu., M. Cat., PEK
Cefaclor - serum-like sickness in kids
2nd Gen. Cephalosporins (Cephalomycins)
Cefotan, Cefoxitin
Coverage: strep, staph, H. Flu., M. Cat., PEK, Anaerobes
Cefotan has NMTT group (alcohol & bleeding)
Used for abdominal/GI surgery, more severe skin and sot tissue infections
3rd Gen. Cephalosporins
Ceftriaxone
Coverage: strep, H Flu, M Cat, PEK, SACE
Good choice for meningitis but need high concentrations
Ceftriaxone hepatic excretion (diarrhea)
3rd Gen. Cephalospporins (Anti-pseudomonals)
Ceftazidime, Cefoperazone
Coverage: strep, poor staph, H Flu, M Cat, PEK, SPACE
Cefoperazone has NMTT group (alcohol & bleeding)
Cefoperazone is hepatc excretion (diarrhea)
Community acquired Pneumonia
4th Gen. Cephalosporins
Cefapime
Coverage: strep, staph, H Flu, M Cat, PEK, SPACE
nosocomial acquired pneumonia
5th Gen. Cephalosporins
Ceftaroline
Coverage: strep, staph (including MRSA), H Flu, M Cat, PEK, SCE
Carbapenems (General)
Binds PBP induces cidal effect
Covers most of our general classes
Save for life threatening or multiple organism infections and/or ESBL producing organisms
Imipenem
extensive renal metabolism by dehydropeptidase-1 (cilistatin inhibits this enzyme)
seizures - increased risk especially if history; must adjust for renal function
Meropenem
Does not cause seizures s can be used for meningitis
Ertapenem
No enterococcus or SPACE coverage
Once a day dosing (higher compliance?)
Doripenem
Newest carbapenem
Aztreonam
Coverage: Gram negs including SPACE
Used when anaphalaxis to penicillin
adverse hematological effects
Save for extreme situations
Aminoglycosides
Binds outer membrane of gram - and rearranges LPS and crosses into cell binding 30s and 50s ribosomal subunit decreasing protein synthesis and causing misread RNA
Coverage: Gram- including SPACE
poorly absorbed in GI, excreted in urine almost unchanged
Ototoxicity, Nephrotoxicity, Neuromuscular blockade (rare)
Gent & Tobra want trough under 2
Neomycin - gut decontamination for surgery
Streptomycin - reserved for TB
Hartford Nomogram
Vancomycin
inhibits synthesis peptidoglycan polymers by binding D-alanyl-D-alanine precursor
Coverage: gram+ (MRSA & penicillin allergy)
poorly absorbed in GI, renal excretion, usually IV except in C Diff
Red Man Syndrome, ototoxic, nephrotoxic
Can be used for endocarditis prophylaxis
Quinupristin/Dalfopristin
Irreversibly binds 50s subunit
Quinupristin - inhibit chain formation (early termination)
Dalfopristin - interferes with peptidyl transferase
individual = static Combo = cidal
MRSA, VRE (faecium), PCN resistant strep pneumo, anaerobes, and some gram-
IV (PICC or central line) because toxic to veins
Linezolid
Bind 23s of 50s ribosomal subunit inhibiting protein synthesis
MSRA, PCN resistant strep pneumo, VRE, Vanc intermedia staph aureus
100% bioavailable by IV and PO
thrombocytopenia, superinfection, mitochondrial toxic over long courses
MAO inhibition (SSRIs and cytokine storm)
mupirocin
Topical ointment that eliminates MRSA in nares (bactroban)
Colistin - Polymixin E
Coverage: Pan-resistant gram negs, such as carbapenem resistant enterobactericae, SPACE and resistant PEK
nephrotoxic and neurotoxic
reserved for last ditch effort
Fosfomycin
single dose for MDR UTIs
Tigecycline
Coverage: resistant gram- and gram+ and anaerobes, but not pseudomonas or bacteremias
Higher mortality rate, low serum because goes to tissue
Bacteriostatic
Daptomycin
Coverage: Gram+ including MRSA and VRE
skin and soft tissue infections, staph aureus bactermia, and endocarditis right side
Rhabdomylysis, requires CPK monitoring Eosinophilic pneumonia (rare)
Televancin
Skin and soft tissue gram+
Red Man Syndrome, QT prolongation, nephrotoxicity
Sulfonamides
Structure similar to PABA, compete for Dihydropteroate synthetase depriving cell of folic acid for DNA synthesis; does not affect host cell
Coverage: Gram+, Gram- piddly and PEK and CE
excreted via glomerular filtration (used for UTI)
Steven Johnson’s Syndrome,
Nephrotoxicity - increased with IV make sure pt. is hydrated, crystalluria
Kernicterus - elevated levels of unconjugated bilirubin in fetal blood if given to female in third trimester
Treats acute uncomplicated UTIs, Toxoplasmosis, Pneumocystis carinii, nocardosis, malaria if chloroquine resistant
Trimethoprim
Inhibits Dihydrofolate reductase, prevents formation of tetrahydrofolic acid, does affect human enzyme
Coverage: Gram+, Gram- piddly, PEK, and CE; Pneumocystis carinii if used with Dapsone
Renal excretion: most glomerular filtration some secretion
Caution in patients with folate deficiency (pregnant or alcoholic)
Treats acute uncomplicated UTIs or recurrent UTI prophylaxis
Bactram
Sulfamethoxazole/trimethoprim
Synergy combined mechanisms - cidal -reduce resistance
UTIs, respiratory tract infections, GI, STDs, travellers diarrhea
combined adverse effects
Drug of choice for strenotrophomonas maltophilia
Warfarin interaction: one of the worst potentiators
Methotrexate interaction: increase free concentraion
Nitrofurantoin
May interfere with early bacterial carb metabolism, inhibiting acetyl CoA
Gram positive resistant (MRSA), some Gram- but not Pseudomonas
Excretion is linear and related to creatinine clearance, impaired GFR = increased toxicity
Pulmonary reactions (sually reversible)
Used almost exclusivley for UTIs, do not use in males because of prostate tissue
Methenamine
hydrolyzed to formaldehyde at urine pH, denatures proteins
avoid in hepatic insufficiency (ammonia byproduct) and renal insufficiency (acidosis)
Only used as UTI prophylaxis, increased urine output decreases effects by voiding formaldehyde decreasing exposure time
Macrolides (General)
Binds reversibly to 50s ribosomal subunit decreasing protein synthesis - Bacteriostatic
Gram positives and atypicals
Distributes to tissues longer than blood
Very high concentration in alveolar macrophages and leukocytes
Use in Penicillin allergy, Mycoplasma pneumonia, C. trachomatis (no estolate form if pregnant), Legionnaires disease
Erythromycin
Estolate form not effected by hepatic metabolism
More severe GI symptoms (cramps), Large IV dose may cause QT prolongation, ototoxicity, and thrombophlebitis Cholestatic Hepatitis (rare) - DO NOT USE ESTOLATE in PREGNANT WOMEN
Motilin stimulation, P-450 enzymes: decreased metabolism of Theophylline, Warfarin, Carbemazepine, cyclosporine
Clarithromycin
Picks up H Flu, M Cat, and H Pylori
GI symptoms less severe, Headache, Dizziness, Allergy
P-450 enzymes: decreased metabolism of Theophylline, Warfarin, Carbemazepine, cyclosporine
Azithromycin
Picks up H Flu, M Cat, and H Pylori (possibly)
Slow release allows 5 day therapy, but lasts 10 days
GI symptoms less severe, Headache, Dizziness, Allergy
Does not inactivate P-450 enzymes, less worry of drug interactions
Clindamycin
Binds 50s ribosomal subunit leading to decrease in protein synthesis
Gram+, anaerobes
90% bioavailability, liver metabolism
Principally associated with diarrhea and C. Diff
Chloramphenicol
Binds 50s ribosomal subunit reversibly
Gram+ and -, anaerobes, chlamydia, rickettsia
aplastic anemia (idiosyncratic), grey baby syndrome (babies lack conjugation system so drug builds up)
great for meningitis but not first line
Quinolones (General)
Inhibit DNA gyrase reducing supercoiling leading to DNA cleavage
Oral dose excellent bioavailability, do not take with Mg, Al, Ca beacuse chelation,
Musculoskeletal tendon rupture, no use
Ciprofloxacin
SPACE, atypicals (watch Chlamydia resistance)
most potent against Gram- (pseudomonas)
Levofloxacin
SPACE, atypicals, Gram+
Moxifloxacin
SACE, atypicals, Gram+, anaerobes, (no UTIs)
Complicated intrabdominal infections
Gemifloxicin
Gram+
Tetracyclines (General)
Binds 30s reversibly to decrease protein synthesis - static
Gram+ (staph/strep), Gram- (H Flu, Neisseria), atypicals, rickettsia
Photosensitivity
Can replace bone and dentin (don’t use in children under 8)
Fanconi-Like Syndrome (if drug outdated) - lethargy, polydipsia, polyuria, proteinuria, acidosis
Di/trivalent cations decrease absorption
Warfarin - enhances anticoag
Doxycycline
hepatobiliary secretion
Minocycline
hepatobiliary secretion
Dizziness, ataxia, vertigo
Tetracycline
renal excretion
Oxytetracycline
renal excretion
Demeclocycline
renal excretion
used to treat SIADH