Unit 4 Pharm Flashcards
MIC
minimal inhibitory concentration
lowest concentration of antibiotic that prevents visible bacterial growth
low MIC is not necessarily best for bug, choose the most narrow spectrum first
MBC
minimal bactericidal concentration
derived from MIC testing
lowest concentration of the antibiotic that kills 99.9% or the original innoculum in a given time
must have less than 10 colonies for plate
used to determine whether certain drug is considered bactericidal or bacteriostatic against bacteria
Bactericidal: have MBC concentrations equal or above MIC
Bacteriostatic: antibiotics have MBC concentrations higher than MIC concentration
D test
- need to associate with cross resistance for 3 antibiotic families: macrolides, lincosamides, group B streptogrammins
- all bind same site on 23S rRNA of 50S
- erm resistance is constitutive (always expressed) or inducible
- when MLSb phenotype is due to constitutive erm gene on inducible type
- expression of respective erm gene requires induction by some of the drugs in the 3 families
- strains with inducible phenotype show resistance to inducing drugs
- are sensitive to non-inducing drugs
- treatment failures have happened in the last 10 years when clindamyacin was used fro MRSA infections caused by inducible erm resistance gene
- strains appear susceptible to clinda, but resistant to macrolides
- initially improve on clinda, then regress days/weeks into therapy
- isolated organisms are clinda resistant
- mutations change erm expression from inducible to constitutive
- occur spontaneously at high frequency
- clindamyacin treatment selects fro survival and growth of resistant subpopulations and treatment failure
- D test identifies isolates that have inducible iMLSb genotype
- Em disk is placed next to a clindamyacin disk, allows EM to diffuse out and induce erm expression in adjacent cells
- results in asymmetric zone of inhibition around clinda disk, smaller zone adjacent to Em and larger zone on distal side
- positive D test means its possible but not certain that its clindamyacin resistant
- may still be sensitive to clinda
bactericidal
cell membrane-homeostasis destroyed
DNA disruption
cell wall disruption
zone of hemolysis
- larger the zone of inhibited bacterial growth, the more susceptible the organism is to the antimicrobial
- size of zone varies depending on various factors
- size shows if resistant, intermediate, susceptible organisms
- zone size corresponds to MIC values below clinically attainable serum conc. are susceptible
- resistant is is MIC values above clinically attainable serum concentration of antimicrobial
- intermediate is isolates where zone size measurements are not clear.
cocci negative-neisseria
3rd gen cephalosporin (ceftriaxone)
gram + cocci-most
pen v/g
clinda
macro
doxy (comm. acquired)
gram + cocci-
s. pneumo
s. pyo
amox
gram + cocci- MSSA
1st ceph
amox+clav
clind
macro
gram + cocci-MSSA
doxy
tmr-smx
clinda
vanco
gram - rods-most ecoli
aminoglycosides amox amox+clav 1st ceph tmp-smx nitro
gram - rods-resistant ecoli
amino
cip-levo*
gram - rods-pseudomonas
amino
cip-levo
pip-taz
(3rd ceph)
anerobes-most
pip-taz
clind
penicillins
anerobes-c. diff
metro
vanco
anerobes- bacteroides
pip-taz
clinda
atypical-myco/chlamyd
doxy* (not preg/
cidal or static?
penicillins
cidal
cidal or static?
cephalosporins
cidal
cidal or static?
vanco
cidal
cidal or static?
carbapenems
cidal
cidal or static?
aminoglycosides
cidal
cidal or static?
streptogamins
cidal
cidal or static?
fluoroquinolones
cidal
cidal or static?
nitrofurantoin
cidal
cidal or static?
sulfonamides
cidal
cidal or static?
metronidazole
cidal
cidal or static?
macrolides
static
cidal or static?
tetracyclines
static
cidal or static?
clindamycin
static
cidal or static?
chloramphenicol
static
cidal or static?
oxazolidinones
static
routes of administration:
penicillin V
oral
routes of administration:
penicillin G
parenteral
routes of administration:
dicioxacillin
parenteral, oral
routes of administration:
amoxicillin
oral
routes of administration:
ampicillin
oral, parenteral
routes of administration:
piperacillin
parenteral
routes of administration:
ticaracillin
parenteral
routes of administration:
cefazolin
paraenteral
routes of administration:
cephalexin
oral
routes of administration:
cefuroxamine
oral, parenteral
routes of administration:
ceftriaxone
parenteral
routes of administration:
cefazidime
oral, parenteral
What is not renally eliminated?
D(Q) CRIMES
Doxycycline: non-renally eliminated tetracycline
Quinolones: Ciprofloxacin renal but CYP450 inhibitor
Clindamycin: non-renally eliminated
Rifampin: inducer of P450 - potential for hepatotoxicity
Isoniazid: genetic polymorphism - potential for hepatotoxicity
Metronidazole: drug-drug interaction with alcohol due to inhibition of aldehyde metabolism (Antabuse reaction)
Erythromycin-like: drug-drug interactions due to inhibition of P450 (Clar-Ery not Azi)
resistance: penicillins
- production of penicillinase via a plasmid (MSSA)
- modification of PBPs (MRSA)
- inability to penetrate (pseudomonas)
resistance: cephalosporins
- MRSA
- Pseudo
- B fragillis
resistance: vanco
modification of terminal peptidoglycan motif (S. aureus and enterococcus)
resistance: macrolides
- methylation of 50S ribosomes via MDR gene (S pneumo and flu)
- multidrug efflux via MDR
resistance: tetracyclines
- changes in transport in and out of cells
- proteins that block tetracycline binding (MDR)
resistance: clindamycin, aminoglycosides
- anerobes require O2
- chemical modification of drug to block action (may be plasmid mediated in gram neg)
resistance: fluoroquinolones
- point mutations on DNA gyrase
- impermeable cells
- Qnr proteins that protect gyros
- acetyltransferase can modify drug
resistance: nitrofurantoin
-pseudomonas
resistance: metranidazole
nitromidazole reductase
resistance: trimethoprim-sulfamethoxazole
- escape mechanisms via methionine, purines, thymine
- acquired via increases in PABA or altered DHPS or DHFR
intrinsic resistance
-occurs just because of natural properties of bacteria
acquired resistance
- develops via genetic mutation or by acquisition of new genes
- new genetic material mediating antibiotic resistance is spread from cell to cell by mobile genetic elements (plasmids, transposons, bacteriophages)
major mechanisms of resistance
- inactivate/modify the drug
- alter antibacterial target
- reduce ability of drug to get to the target
reducing antibiotic success
-specific growth states (e.g.: growth in a biofilm, aerobic conditions, stationary phase) can negatively impact susceptibility
porins
- outer membrane gram negative bacteria
- form channels to allow selective uptake of nutrients/compounds
- changes in configuration adversely affect uptake
efflux pumps
- eliminate substrates from cytoplasm
- originate as mechanisms to get rid of toxic substances
- can be present in + or -
- can be specific or general (multi-drug resistance)
peptidoglycan as resistance mechanism
- backbone of 2 sugars with cross linking peptide bridge
- formed by precursors and 5 attached aa
- cross link, driven by cleavage of peptide aa
- things that cross link are PBPs (penicillin binding proteins)
- altered PBPs are a moving target
beta lactam resistance
- peptidoglycans are made by PBPs (perform transpeptidase, transglycoslyase reaction)
- involved in sythesis and growth
- beta lactam antibiotics bind and inactivate the TRANSPEPTIDASE reaction of PBPs. inhibit CROSS LINKING and synthesis.
- resistance comes from:
1. modifying drug-destroy with beta lactamase
2. modify target-alter PBPs
3. prevent interaction with target-porin channel mutation, efflux mechanism
beta lactamases
- enzymes that inactivate beta lactam antibiotics
- split amide bond of beta lactam ring
- encoded by chromosomal or transferrable genes
- found in + and -
- broad spectrum beta lactamases are found in gram - bacteria
narrow spectrum beta lactamase
- hydrolize penicillin antibiotics
- not much activity against cephalosporins, carbapenems
- found in + and -
- occur frequently or less commonly
ESBLs (extended spectrum beta lactamases)
- arose 1980s
- mutants of TEM1, 2 and SHV1. 1-4 aa substitutions
- ability to attach cephalosporins
- found on plasmids, mobile, can disseminate
- found almost exclusively in gram negative rods, prevalence is low
ampC-encoded beta lactamase
- ampC is a chromosomally located gene in gram neg organisms
- encodes for beta lactamase that is capable of hydrolyzing penicillins, 1-3 cephs
- not inhibited by beta lactamase inhibitors
- found in some gram neg rods: enterobacter, pseudomonas
- is inducible or constitutive
- normal conditions, is expressed in small amounts, can be induced in some beta lactams
- some mutations can lead to constitutive expression
enterobacter in inducible state
ampicillin–R
cefazolin–R
bug is resistant since both induce amp C
enterobacter with mutation to express ampC
ampicillin--R cefazolin--R ceftriaxone--R ceftazidime--R piper/taz--R ertapenem--S now all third gens are degraded by ampC since expressed all the time
what does mutation of ampC mean clinically
mutational events lead to permanent expression of ampC during therapy.
carbapenems and carbapenemases
- beta lactam antibiotics
- broad spectrum against gram neg rods, used in hospitalized patients with resistant infections
- plasmid mediated, found in gram negative rods like Klebsiella, ecoli, enterobacter
- some gram negative organisms can become resistant to carbapenems without a carbapenemase
altered penicillin binding proteins (PBPs)
- produce a PBP that has reduced affinity for beta lactamase drug
- mutation of existing genes, but acquisition of new PBP genes or new pieces of PBP genes is more important
- has mecA, mosaic
- generally change slowly over time, so resistance slowly proceeds
mecA PBPs
- seen in staph
- encodes for low affinity PBP called PBP2a
- resistance to all beta lactam agents
- makes MRSA
mosaic PBPs
- in strep and neisseria
- pick up pieces genetic material
- genes encoding can become mosaics over time
- encode then for markedly reduced beta lactam antibiotic affinity
vanco resistance
-stage 2 synthesis
-vanco targets precursor molecule, binds d-ala region
resistance comes from:
1. modifying target (entero does this though plasmid acquisition), unrecognizable precursor
2. preventing drug target interaction: binds free vance in existing peptide wall (mostly in S. aureus)
enterococcus resistance to vanco
- genes encoded on plasmids
- change the d-ala to d-lactate
staph resistance to vanco
- moderate reduction in susceptibility
- don’t have genes that mediate vance resistance, they have perturbations in cell wall synth
- thicker peptidoglycan layers
- less cross linking
- vanco gets bound up in the wall, and there is less free to bind the precursor molecules
- develop in prolonged vanco therapy
quinolone resistance
-quinolones target bacterial enzymes DNA gyros and topoisomerase4
resistance comes from:
1. modifying drug (rare)
2. modifying target through aa changes (DNA mutations) (majority of cases)
-mutations result in aa substitutions in quinolone resistance determining region (QRDR)
-make enzyme less sensitive to inhibition, reduce affinity
-mutations are easy to select for during therapy
3. prevent drug target interaction via efflux and porin mutations (less common)
resistance to macrolides
- macrolides inhibit bacterial protein synthesis by binding 50S subbing of bacterial ribosome
- prevents chain elongation
- resistance comes from
1. modify drug (rare)
2. modify target (common) prevents macrolide binding to ribosome. mediated by term gene. found on plasmids/transposons - dimethylation by term
- erm regulation induced by macrolides only (not by clindamycin)
- constituent expression tests resistant to macrolides and cloned
- inducible test sensitive then become constitive
3. prevent drug-target interaction (common), efflux pumps
aminoglycoside resistance
-not used much anymore due to toxicity
resistance due to:
1. modifying drug (classic mechanism).
2. modify target (common). methylate 16s rRNA. plasmids
-modifying enzymes do N-acetylation, O-nucleotidylation, O-phosphorylation
3. prevent drug target interaction. uptake depends on sufficient electrochemical gradient. aerobic bacteria (with no aerobic respiratory chain) don’t have gradient necessary, so they are resistant to aminoglycosides
Cell Wall Synthesis Inhibitors
Penicillins:
Narrow Penicillin V, Penicillin G
β-lactamase resistant Dicloxacillin
Extended spectrum Amoxicillin-(clavulanate), Ampicillin
Antipseudomonal Piperacillin-(tazobactam)
Cephalosporins:
*1st Cephalexin, Cefazolin
3rd Ceftriaxone
Vancomycin
Protein Synthesis Inhibitors
Macrolides:
Azithromycin
Clarithromycin
Erythromycin
Tetracyclines:
Doxycycline
Tetracycline
Clindamycin
*Aminoglycosides:
Tobramycin
Gentamicin
Inhibitors of DNA Function
Fluoroquinolones:
Ciprofloxacin
Levofloxacin
Moxifloxacin
Nitrofurantoin
Metronidazole
Inhibitors of Intermediary Metabolism
Sulfonamides Sulfamethoxazole
Trimethoprim
Trimethoprim-Sulfamethoxazole
Bactericidal agents
Preferred in severe infections
Act more quickly, often irreversible with sustained effect
Can compensate for patients with an impaired host defense
Required for treatment of infections in located in immune sanctuaries (CNS-endocarditis infections)
Bactericidal mechanisms
Inhibition of cell wall synthesis
Disruption of cell membrane function
Interference with DNA function or synthesis
bacteriostatic mechanisms
Inhibition of protein synthesis (except AGs -cidal)
Inhibition of intermediary metabolic pathways
Narrow spectrum
effect against either gram + or gram –
Most effective on susceptible organism
Less disturbance of host flora
Extended spectrum
effect against gram + and gram –
Broad spectrum
effective against gram + and gram – and atypical
Sacrifice efficacy for greater scope of activity for initial empiric treatment
More likely to cause superinfections
Tetracyclines - Adverse Reactions
Yeast (candidal) overgrowth: Disturbance of normal gut flora can lead to thrush and vaginitis
Liver / kidney toxicities: If pre-existing conditions
Drug Interactions
Antacids / Iron Supplements (metal ions): Decrease bioavailability by forming insoluble salts
Phenytoin / Barbiturates / Carbamazepine: Increased metabolism of doxycycline
Oral Anticoagulants: Increased anticoagulant effect
Nitrofurantoin - Mechanism
Most commonly used urinary tract antiseptic
Not used for systemic infections - effective Cp cannot be obtained with safe doses
Since it concentrates in renal tubules, can be given orally to treat urinary tract infections (i.e., non-systemic)
Mechanism of Action
Reduced by bacterial enzymes to intermediates that damage bacterial DNA
Concentration dependent effect – generally bactericidal
Selectively toxic because mammalian enzymes don’t reduce nitrofurantoin as rapidly
Selective Distribution (accumulation) Beneficial
Selective Distribution (accumulation)
Beneficial:
Clindamycin into bone (osteomyelitis)
Macrolides into pulmonary cells (URIs-pneumonia)
Tetracyclines into gingival crevicular fluid and sebum (periodontitis and acne)
Nitrofurantoin rapid excretion into urine (UTIs)
Selective Distribution (accumulation) Potential for toxicity
Aminoglycosides bind cells of the inner ear and renal brush border ototoxicity and nephrotoxicity
Tetracyclines bind Ca++ in developing bone and teeth abnormal bone growth and tooth discoloration
CNS distribution
Antibiotics vary substantially in ability to cross BBB
CNS penetration necessary to treating CNS infections effectively
3rd generation cephalosporins excellent - ceftriaxone
Fetus distribution
Adverse effects if antibiotics cross the placental “barrier”
Rule of thumb: Oral antibiotics for systemic infections can also cross the placenta and have potential to harm the fetus
Aminoglycosides - Mechanism of Action
Bind irreversibly to 30S ribosome altering interaction of mRNA with subunit
Produces inhibition of protein synthesis initiation
Breakup of polysomes
Misreading the code (? producing lethal proteins)
Bactericidal at clinically utilized concentrations
Actively transported into bacteria; requires O2 - thus NOT effective against anaerobic organisms
Aminoglycosides - Adverse Reactions
Renal Toxicity (usually reversible when drug D/C’d)
25% of patients show mild impairment
Manifested by rising BUN and creatinine levels, proteinuria, oliguria, acute tubular necrosis
Followed by reduced glomerular filtration resulting in further accumulation
Eighth nerve damage (often irreversible) - involves sensory receptors of the nerve - affects Ca++ fluxes
Auditory (0.5-12%): Tinnitus and high frequency hearing loss (outside normal speech)
Vestibular (1-3%): Dizziness, nausea / vomiting, vertigo
Sulfonamides Spectrum Clinical Uses
Gram positive cocci
Staph. aureus (community-acquired MRSA skin / skin structure infections [TMP/SMX]
Staph aureus conjunctivitis [Sulfacetamide]
Gram-negative rods
E. coli, Klebsiella, Proteus, Enterobacter uncomplicated urinary tract infections [TMP/SMX]
Atypical organisms [TMP/SMX]
Chlamydia trachoma, community-acquired pneumonia, urethitis
Cephalosporins - Adverse Reactions
Generally well tolerated due to high selective toxicity
Allergy / Hypersensitivity
Anaphylaxis, skin rashes, nephritis, hemolytic anemia - not as severe as with penicillins
Cross-reactivity with penicillins
Cephalosporins
Mechanisms of action and resistance - similar to penicillins
Relative to penicillins (G and V), cephalosporins have:
Broader spectrum of action vs gram-negative bacteria
Less susceptibility to β-lactamases (penicillinases) but ESBLs are emerging
Less cross-reactivity in penicillin sensitive patients (1% or less)
what should NEVER be given to patients with penicillin allergies?
CEPHALOSPORIN
Cephalosporins - Classifications general
Five generations - originally based on activity against gram negative organisms
Now also consider resistance to cephalosporinases (4th) and activity against MRSA (5th)
Cephalosporins - Classifications
First Gen
First - Cephalexin (po), Cefazolin (IV)
Spectrum like amoxicillin - gram + and gram but rarely drugs of first choice
More stable than penicillins to many beta-lactamases
Cephalosporins - Classifications
Second Gen
Second - Cefaclor (po), Cefuroxime (po, IV)
Gram + activity
Cephalosporins - Classifications
3rd gen
Third - Cefdinir (po), Ceftriaxone (IV-IM)
Excellent activity against some gram + (S. Pneumoniae)
Expanded gram vs 2nd gen (enteric gram bacilli)
Moderate antipseudomonal activity (ceftazidime)
Clindamycin - Adverse Reactions
Pseudomembranous colitis
Toxigenic Clostridium difficile selected out during treatment (superinfection, 0.1-10%)
Probably no worse than some broader spectrum agents (amoxicillin-ampicillin, 2nd-3rd gen cephalosporins, FQs)
Common: Nausea, diarrhea (severe 2-20%), skin rashes
Rarely: Impaired liver function, neutropenia
Clindamycin - Pharmacokinetics
Absorption
90% of oral dose absorbed - not affected by food
Distribution
Penetrates most tissues well - especially bone - but not well into CSF
Elimination
Metabolized by liver, then primarily biliary excretion
No dosage adjustment required in renal failure
Excreted in breast milk
Tetracyclines - Adverse Reactions
Teeth and bone
Temporary depression of bone growth - permanent discoloration of teeth if given during development
Chelates to Ca++ in developing bone and teeth
Avoid use during latter half of pregnancy and in children under 8 years old (Pregnancy Risk Factor D)
GI disturbance: Nausea, vomiting, diarrhea common
Photosensitivity: Abnormal sunburn reaction
Yeast (candidal) overgrowth: Disturbance of normal gut flora can lead to thrush and vaginitis
Liver / kidney toxicities: If pre-existing conditions
Drug Interactions
Antacids / Iron Supplements (metal ions): Decrease bioavailability by forming insoluble salts
Phenytoin / Barbiturates / Carbamazepine: Increased metabolism of doxycycline
Oral Anticoagulants: Increased anticoagulant effect
Fluoroquinolones - Mechanism
Target: Bacterial DNA gyrase and topoisomerase IV
DNA gyrase facilitates unwinding of DNA strands
Required for normal DNA replication - transcription and some aspects of DNA repair and recombination
Inhibition by quinolones is rapidly bactericidal (99.9% lethal within 2 hr)
Fluoroquinolones - Adverse Reactions
Overall very well tolerated
GI (5-10%): N/V, diarrhea (C. difficile associated)
CNS: Dizziness, headache, insomnia, rarely seizures
Black Box Warning
3-4-fold ↑ risk of tendon rupture, but still rare, 1:10,000
Potential for arthropathies limits use in pregnancy and children
Penicillins - Pharmacokinetics
absorption
Oral absorption varies depending on acid stability
Penicillin G poor and unreliable
Penicillin V and Amoxicillin excellent
Piperacillin and Ticarcillin and IV only
IM absorption dependent on salt form
Rapid from aqueous solutions
Delayed from suspensions (procaine - benzathine)
Use against organisms susceptible to low but sustained levels of Pen G (syphilis- endocarditis)
Penicillins - Pharmacokinetics
distribution
Distribute throughout body water - penetrate into cells and tissues poorly (ionized at physiological pH)
Can enter inflamed tissues or membranes (CSF, joint, eye)
Penicillins - Pharmacokinetics
elimination
Most excreted as active drug via the kidney (t1/2
Classes of Penicillins
Prototype Penicillins - narrow antimicrobial spectrum
Penicillin G - Prototypical penicillin
Powerful and inexpensive
BUT, hydrolyzed by acid and penicillinase enzyme
Used IV for hospitalized patients with serious infections
Penicillin V - Acid resistant penicillin
Better absorbed than penicillin G, but still incomplete
Preferred for oral therapy - higher reliability of absorption
Efficacy
Classes of Penicillins
Penicillinase-Resistant Penicillins
Less potent against Pen G-sensitive organisms
Not substitutes for Pen G, except for PCNase-producers
Emergence of MRSA has greatly limited current clinical use
Methicillin is prototype, but no longer available - Nafcillin
NOTE: Acid resistance varies: Oxacillin and dicloxacillin good oral absorption
Relatively narrow spectrum agents: gram +/ cocci
NOTE: All other penicillin drugs are susceptible to penicillinase
Classes of Penicillins
Extended Spectrum Penicillins
Increased hydrophilicity [due to NH2 or COOH] penetration through porins of gram-negative organisms
NOT penicillinase-resistant given w/β-lactamase inhibitors
Amoxicillin and Ampicillin
Acid resistant, good oral absorption
Amoxicillin absorbed better less frequent dosing-diarrhea
Piperacillin and Ticarcillin - anti-pseudomonal penicillins
Must be given parenterally
Useful in anaerobic infections caused by B. fragilis
Effective against Pseudomonas and enterococci (+ AG)
gram positive vs gram negative with penicillins
gram positive: pen V/G
gram neg: amox-amp
Vancomycin - Pharmacokinetics
Poor oral absorption, administered IV, except for GI tract indications (e.g., Clostridium difficile)
Excretion mainly through kidneys – requires dosage adjustment if renal impairment
Macrolides - Spectrum Clinical Uses (Azithromycin – Clarithromycin – Erythromycin)
Gram positive cocci (increasing resistance):
Streptococci (increasing resistance) pneumonia, pharyngitis [All]
Staphylococci (MSSA)
Atypical organisms:
Chlamydia trachoma, CA pneumonia, urethitis [Azi]
Mycoplasma pneumoniae CA pneumonia [All]
Macrolides - Adverse Reactions
GI Disturbances
Nausea, vomiting, diarrhea, anorexia
Direct stimulation of gut motility by erythromycin - less with azithromycin and clarithromycin
Hepatotoxicity: Reversible acute cholestatic hepatitis (estolate salt)
Prolongs QT interval ventricular arrhythmias - use caution with other QT prolonging drugs
Drug Interactions: Clarithromycin - erythromycin metabolites can inhibit CYP450 enzymes [NOT azithromycin]
Macrolides - Mechanism of Action
Binds 50S ribosomal subunit blocks translocation of peptidyl tRNA from acceptor to donor site on ribosome prevents peptide elongation - bacteriostatic (BUT)
Not actively transported - enters by passive diffusion
Weak base that is more active at alkaline pH
Selectively toxic - no binding to human 60S ribosome
Resistance
Altered target - methylation of 50S ribosome prevents macrolide binding
Increasing for S. pneumonia and H. influenzae
Substrates for multi-drug efflux transporter (MDR gene)
Inactivation of drug not significant
Metronidazole - Adverse Reactions
Most common: nausea, headache, dry mouth, metallic taste
Occasionally: vomiting, diarrhea, abdominal distress
Exacerbation of candidiasis furry tongue, glossitis
Inhibits aldehyde dehydrogenase
Antabuse®-like effect (GI upset, vomiting, headache) if alcohol consumed within 3 days of metronidazole
Risk of severe reaction is low
Category B in pregnancy - but weigh benefit-risk
Conflicting evidence regarding teratogenicity in animals
Taken at all stages of pregnancy without adverse effects, but use during 1st trimester is not advised
