Antibiotics Flashcards
Beta-Lactam Mechanism of activity
kills bacteria by interfering with the synthesis of the bacterial cell wall
Binds to penicillin binding proteins (PBPs)
activity is limited to cells that are actively producing cell walls
Beta-Lactam mechanism of resistance
1) enzymatic destruction through beta lactamases (penicillinases in S. areus penicillin resistance)
2) alteration of penicillin-binding proteins (low-affinity PBP in MRSA called PBP2a)
Name the two major categories under Beta-Lactams.
Penicillins and Cephalosporins
Name the penicillin subclasses. What is the cellular target for all of these subclasses? What are the toxicities? Any exceptions?
- Natural penicillins
- Anti-staphylococccal penicillins
- Aminopenicillins
- Anti-speudomonal penicillins
- Beta-lactam/Beta-lactam inhibitor combinations
Cellular target - Cell wall, inhibits cross-linking
Toxicities - rash, hypersensitivity, drug fever, antibiotic-associated diarrhea, C. difficile colitis, bone marrow suppression, seizures with high CNS levels, Coombs test, intersitital nephritis, anaphylaxis, allergic reactions
Natural penicillins
- primarily for gram-positive bacteria
- streptococcal infections (S. pyogenes, S. pneumoniae, enterococci)
- will also cover N. meningitidis, Syphilis, and Listeria
- will not cover most S. aureus because of penicillinase
ex. penicillin G (iv) and penicillin V (po)
Beta-Lactam, Penicillin
Anti-staphylococcal penicillins
- not hydrolyzed by penicillinases or other beta-lactamases produced by S. aureus
- used to treat MSSA
- do not cover enterococci
- note: workhorse for serious staphylococcal infections - endocarditis, osteomyelitis
ex. axacillin (iv), nofacillin (iv), dicloxacillin (po)
Beta-Lactam, Penicillin
Aminopenicillins
- inactivated by many beta-lactamases
- Gram-positive coverage similar to natural penicillins
- covers some gram-negative infections
- covers enterococci, L. monocytogenes, E. coli, Salmonella spp, and H. influenzae
- increased activity due to ability to penetrate gram-negative outer membranes
ex.amoxicillin (po), ampicillin (iv and po)
Beta-Lactam, Penicillin
Anti-pseudomonal penicillins
- Gram-positive coverage similar to natural penicillins, stronger gram-negative coverage
- nosocomial gram-negative infections, including Pseudomonas
- also covers many enterobacteriaceae
ex. piperacillin (iv), ticarcillin (iv)
Beta-Lactam, Penicillin
Beta-lactam/Beta-lactamase inhibitor combinations
- gram-positive coverage
- improved gram negative coverage and anaerobic activity due to the beta-lactamase inhibitor
- covers S. aureus (MSSA)
- covers gram-negatives including E. coli, K. pneumoniae, and Proteus mirabilis
ex. amoxicillin/clavulanate (po), ampicillin/sulbactam (iv), piperacillin/tazobactam (iv)
Beta-Lactam, Penicillin
Name the cephalosporin subclasses. What is the cellular target for all of these subclasses? What are the toxicities? Any exceptions?
- 1st generation
- 2nd generation
- 3rd generation
- 4th generation
Cellular target - cell wall, inhibits cell-wall cross-linking
Toxicities - rash, hypersensitivity (5-10% cross-reactivity with penicillins), antibiotic associated diarrhea, C. difficile colitis, neurotoxicity/seizures
- cefepime notorious for neurotoxicity
- ceftriazone assocciated with gallbladder sludge (caldium-ceftriazone salt percipitate)
1st generation
- good activity against gram-positive organisms, including methicillin-susceptible S. aureus
- most active cephalosporins against GPC, including MSSA (not enterococci)
- covers gram-negatives such as E. coli, K. pneumoniae, and Proteus mirabilis
ex. cefazolin (iv), cephalexin (po)
note: cefazolin is common agent for surgical prophylaxis given skin coverage and some gram-negative
Beta-lactams, Cephalosporin
2nd generation
- More gram-negative and less gram-positive activity
- some in this group are active against anaerobes (cephamycins)
ex. cefuroxime (iv and po)
Beta-lactams, Cephalosporin
3rd generation
- very active against most streptococci (except enterococci) and MSSA
- good gram-negative coverage vs. Enterobacteriaceae but not Pseudomonas (except for ceftazidime)
ex. ceftriaxone (iv), cefixime (po), ceftazidime (iv)
note: ceftazidime is active against Pseudomonas and many nosocomial gram-negatives, but has no action against gram-positive or anaerobic activity
Beta-lactams, Cephalosporin
4th generation
- maintains gram-positive coverage of all earlier generations
- enhanced gram-negative and anti-pseudomonal coverage
- remains active against many beta-lactamases produced by gram-negative organisms because of the zwitter-ion structure
- very active against most streptococci (except enterococci) and MSSA
ex. cefepime (iv) and ceftaroline (iv)
note: ceftaroline is the only beta-lactam with activity against MRSA and some activity against Enterobacteriaceae
Beta-lactams, Cephalosporin
Monobactams
- no gram-positive or anaerobic activity
- active against Pseudomonas
ex. aztreonam
note: can be used in patients with allergy to penicillins/carbapenems
Toxicity: rash, hypersensitivity, antibiotic-associated diarrhea, C. difficile colitis, seizures with high CNS levels
Beta-lactam
Carbapenems
- very broad gram-positive activity (including MSSA and enterococci)
- anaerobic and gram-negative activity for Enterobacteriaceae, Pseudomonas, Acinetobacter
ex. imipenem (iv), meropenem (iv), doripenem (iv), ertapenem (iv)
note 1: ertapenem is not active against Pseudomonas
note 2: most reliable agents for Enterobacteriaceae with extended spectrum beta-lactamases
Toxicity: rash, hypersensitivity, antibiotic-associated diarrhea, C. difficile colitis, seizures with high CNS levels
Beta-lactams
Glycopeptides - Vancomycin mechanism of activity
inhibits bacterial cell wall synthesis, but at a different point than the beta-lactams
Glycopeptides - Vancomycin mechanisms of resistance
change in peptidoglycan with reduced binding to vancomycin - terminus altered to D-ala-D-lactate or D-ala-D-serine
production of thick cell wall with increased or false targets for vancomycin
Glycopeptides - Vancomycin spectrum of activity and toxicity
- Gram-positive coverage only - aerobic and anaerobic
- includes methicillin-resistant S. epidermidis, MRSA, and enterococci (not VRE)
- intravenous vancomycin commonly used for serious infections of gram-positive organisms
- oral vancomycin is not absorbed systmically, only used for infections within the intestinal lumen, primarily C. difficile
- almost all gram-negatives are resistant
Toxicity: Red Man’s Syndrome/infusion reaction - not an allergy, nephrotoxicity, ototoxicity, bone marrow suppression
Lincosamides - Clindamycin mechanism of activity
inhibits proteins ynthesis by binding to the 50S subunit of the ribosome
blocks peptide bond formation, binding site is close to the site for erythromycin, shared resistance
Lincosamides - Clindamycin mechanism of resistance
methylation of the 50S subunit prevents clindamycin attachment
cross resistance with macrolides
Lincosamides - Clindamycin spectrum of activity and toxicity
- good gram-positive and anaerobic activity
- no gram-negative activity
- active against most, but not all, MSSA and MRSA
- good choice for empiric treatment of skin and soft tissue infections because of coverage for both streptocci and staphylococci
- good oral bioavailability so may be used for outpatient therapy
toxicity: rash, antibiotic-associated diarrhea, C. difficile colits, esophagitis, hepatitis
Folate Antagonists - Trimethoprim-Sulfamethoxazole mechanism of action
blocks sequential steps in folate metabolism, synergistic combination
sulfonamides - compete with PABA for dihydropteroate synthas
trimethoprim - inhibits dihydrofolate reductase
Folate Antagonists - Trimethoprim-Sulfamethoxazole mechanisms of resistance
increased PABA concentration
enzymes with reduced affinity
loss of permeability
Folate Antagonists - Trimethoprim-Sulfamethoxazole spectrum of activity and toxicity
- Gram-positive activity
- S.aureus, including MRSA
- some streptococci, but not reliable for causes of cellulitis
- Listeria monocytogenes
- Some Gram-negative activity
- enterobacteriaceae - acquired resistance in E. coli and others now limits use as first line for urinary tract infection
Toxicity: rash, hypersensitivity, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, aseptic meningitis, hepatitis, bone marrow suppression, hyperkalemia, elevated creatinine
Oxazolidinones - Linezolid mechanism of activity
inhibits protein synthesis by binding to 23S portion of 50S subunit
prevents formation of ribosomal complex that initiates protein synthesis
Oxazolidinones - Linezolid mechanism of resistance
enterococci and staphylococci resistance due to point mutations in 23S rRNA
requires mutations in two or more copies
Oxazolidinones - Linezolid spectrum of coverage and toxicity
- good gram-positive activity
- active against streptocci and staphylococci
- MRSA and VRE are susceptible
- no gram-negative activity
- no anaerobic activity
- covers Mycobacterium tuberculosis and others
Toxicity: bone marrow suppression, peripheral neuropathy, serotonin syndrome (do not take with SSRIs), thrombocytopenia
Lipopetide - Daptomycin mechanism of activity
binds to cell membrane
causes depolarization due to K+ efflux
depolarization disrupts cellular processes and leads to cell death
no resistance mentioned
Lipopetide - Daptomycin spectrum of activity and toxicity
- only gram-positive activity
- active against streptococci and staphylococci
- active against MRSA and VRE
- cannot use in pulmonary infections due to being inactivated by pulmonary surfactant
Toxicity: muscle toxicity (myopathy, rhabdomyolysis), eosinophilic pneumonia
Streptogrammins - quinupristin-dalfopristin
mechanism
- binds to 50S ribosomal subunit and blocks peptide chain elongation
spectrum
- bacteriostatic against E. faecium
- bactericidal against S. aureus (including MRSA)
- not active against E. faecalis
toxicity
- phlebitis, arthralgias, myalgias, GI upset, elevated bilirubin
note: may have a role in treatment failure of first line agents vs. MRSA or VRE, not commonly used
Rifamycin - Rifampin
mechanism
- inhibits DNA-dependent RNA-polymerase, preventing chain initiation
spectrum
- S. aureus, including MRSA
- used in combination for Mycobacterium tuberculosis
toxicity
- hepatitis, reddish discoloration of body fluids, rash, numerous drug-drug interactions
note: penetration into biofilms makes this useful for prosthetic material infections due to S. aureus
Tetracyclines
mechanism
- binds to 30S ribosomal subunit and blocks binding of aminoacyl RNA
spectrum
- S. aureus, including MRSA
- Chlamydia, Mycoplasma, Lyme disease, Tularemia, Brucella, Rickettsiae
toxicity
- GI upset, diarrhea, photosensitivity, vestibular symptoms, increased skin pigmentation, tooth discoloration in children
- ex. doxycycline (iv and po) and minocycline (po)*
factors that influence whether the antibiotic is right
speed
IV vs. oral
breadth of empiric therapy
antibiotic resistance of pathogen
MIC of the effective antibiotic for the pathogen(s)
steps take for patients in septic shock or severe sepsis
1) aggressive fluid resuscitation wtihin the first six hours
2) cultures and imaging studies, at least 2 sets of blood cultures
3) within the first hour after sepsis is identified, adminsiter broad, effective antimicrobials that has Gram positive and Gram negative coverage
SIRS criteria
Systemic Inflammatory Response Sydrome
2 or more of the following:
- Temp >38 or < 36
- heart rate > 90
- respiratory rate > 20 or PaCO2 < 32mmHg
- WBC > 12,000/mm3 or <4000/mm3
sepsis
SIRS + source of infection present or suspected
severe sepsis
sepsis with organ dysfunction, hypoperfusion, hypotension, and/or lactic acidosis
septic shock
severe sepsis with hypotension despite adequate fluid resuscitation
sequestered vs. non-sequestered site of infection
non-sequestered - site that has no anatomic or physiologic barriers to the antibiotic such as well perfused skin, kineys, lungs
sequestered - prostate, brain, bone, large abscess, poorly perfused site (severe trauma)
broad spectrum antibiotic combination for penicillin-allergic patients
vancomycin + aztreonam + metronidazole
Fluoroquinolones mechanism of action
inhibits DNA gyrase in Gram-negative organisms
inhibits Topoisomerase IV in Gram-positive organisms
Fluoroquinolones mechanism of resistance
1) a single point mutation in the bacterial chromosome can result in resistance by altering affinity of the antibiotic to bind to the target enzyme, most common mechanism of resistance
2) plasmids can code for efflux pumps
Fluoroquinolones spectrum of activity and toxicity
- all have Gram-negative activity
- activity against intracellular organisms such as Chlamydophila pneumoniae, Legionella spp., and Mycoplasma pneumoniae
- S. pneumoniae activity
- MSSA, though resistance may develop on therapy
- good activity against Enterobacteriaceae and Pseudomonas
Toxicity
- tendonitis/tendon rupture, antibiotic-associated diarrhea, C. difficile colitis, CNS toxicity, QTc prolongation
note 1: ciprofloxacin is very useful against genitourinary infections, bu tresistance is common due to overuse
note 2: respiratory fluoroquinolones can be used as a single agent for community acquired pneumonia (active against typical and atypical organisms)
ex. ciprofloxacin (iv and po), levofloxacin (iv and po), and moxifloxacin (iv and po)
Aminoglycosides mechanism of action
binds irreversibly to the 30S ribosome within the cytoplasm and inhibit protein synthesis by preventing the translocation of peptidyl-t-RNA
bacterial cell death depends on high concentrations of the drug reaching the site of infection, and oxygen is necessary
postantibiotic effect - after the serum concentration ahs fallen, residual intracellular drug remains bacteriocidal
Aminoglycosides mechanism of resistance
1) drug inactivation, plasmid that encodes for an enzyme that alters the drug
2) rare mutations that alter the structure of the ribosomes so that binding is impaired
natureal resistance:
1) bacteria is an anaerobe and growing in an anaerobic enviroment, drug can’t cross the cytoplasmic membrane
2) ribosome has low affinity for the drug
Aminoglycosides spectrum of activity and toxicity
- targets aerobic Gram-negatives
- active against Pseudomonas
- used as a second agent for serious staphylococcal or enterococcal infections
- works against S. aureus
Toxicity: nephrotoxicity, ototoxicity, neuromuscular blockade
ex. gentamicin (iv), tobramycin (iv), amikacin (iv) - know these!
Nitroimidazoles - Metronidazole mechanism of action and toxicity
intracellularly generates short-live reactive intermediates that damage DNA by electron transfer system
Nitroimidazoles - Metronidazole spectrum of activity
- active against anaerobic bacteria
- Bacterioides, C. difficile, Trichomonas, Giardia, E. histolytica
Toxicity: headaches, nausea, metallic taste, disulfuram-like reaction, neuropathy with prolonged use
Macrolides mechanism of action
binds to the 50S ribosomal subunit and blocks peptide bond formation
Macrolides spectrum of coverage and toxicity
- Gram positive - S. pneumoniae
- Gram-negative - H. influenzae, Neisseria spp., B. pertussis, Campylobacter
- Atypical - Mycoplasma, Legionella, Chlamydia
Toxicity: GI upset, diarrhea, QTc prolongation leading to rosades des pointes, ventricular tachycardia and sudden death
ex. erythromycin (po), azithromycin (iv and po), clarithromycin (po)
Type I Antibiotic Allergy
Immediate
Mechanism
- IgE mediated
- binds to mast cells and basophils
- histamine, leukotrienes, and prostaglandins released
Symptoms
- urticaria, angioedema, anaphylaxis
- onset is rapid
Management
- epinephrine, antihistamines, H2-blocekrs, glucocorticoids
Type II Antibiotic Allergy
Cytotoxic
Mechanism
- Antibody mediated (usually IgG)
- leads to tissue destruction
Symptoms
- immune hemolytic anemia
- thrombocytopenia
Type III Antibiotic Allergy
Immune complex
Mechanism
- Immune complex disease
- soluble immune complex (IgG boudn to drug)
- deposition and complement activation
Symptoms
- serum sickness
- drug fever
- vasculitis
Type IV Antibiotic Allergy
Delayed
Mechanism
- T cell mediated
- sensitized lymphocytes
Symptoms
- Maculopaopular exanthem (outward from central location)
- contact dermatitis
- fixed drug eruption
- Stevens-Johnson Syndrome
- Toxic Epidermal Necrolysis
SJS and TEN
Stevens Johnson Syndrome and Toxic Epidermal Necrolysis
severe idiosyncratic reactions characterized by fever, mucocutaneous lesions, and sloughing of the epidermis
both are generally triggered by medications, antibiotics being the most likely
Streptogrammins - quinupristin-dalfopristin (iv) mechanism of action
binds to 50S ribosomal subunit, blocks peptide chain elongation
Streptogrammins - quinupristin-dalfopristin (iv) spectrum of activity and toxicity
- bacteriostatic against E. faecium (including VRE)
- bactericidal vs. S. aureus (including MRSA)
- not active against E. faecalis
Toxicity: phlebitis, arthralgias, myalgias, GI upset, elevated bilirubin
note: may have role in treatment failure of first line agents vs. MRSA or VRE, not commonly used
Chloramphenicol - chloramphenicol (iv and po) mechanism of action
binds to 50S ribosomal subunit and blocks aminoacyl tRNA attachment
Chloramphenicol - chloramphenicol (iv and po) spectrum of activity and toxcitiy
- Streptococci
- H. influenzae, Neisseria spp.
- Salmonella typi, Brucella spp., Bordetella pertusis
- most anaerobes
- Rickettsiae
Toxicity:
- reversible bone marrow toxicity, aplastic anemia, Gray baby syndrome
note: very infrequently used int he US
Glycyclcyline - tigecycline (iv) mechanism, spectrum of action, and toxicity
Tetracycline subclass
mechanism
- binds to 30S ribosomal subunit, blocks binding of aminoacyl tRNA
Spectrum
- MSSA, MRSA, VRE
- active against many gram-negatives, including some MDR Acinebacter and carbapenem-resistant Enterobacteriaceae (CRE)
not active against Pseudomonas
Toxicity: nausea and vomiting, photosensitivity, pancreatitis
note: bacteriostatic and does not achieve high serum levels, so despite its very broad activity, it is less useful for serious infections
Urinary antiseptics - nitrofurantoin (po) mechanism of action
inhibits bacterial acetyl-coenzyme A, interfering with the organism’s carbohydrate metabolism
Urinary antiseptics - nitrofurantoin (po) spectrum of activity and toxicity
- Enterococci, including VRE
- S. sapprophyticus
- gram negatives, including E. coli
Toxicity: interstitial pneumonia wiht fibrosis, hepatitis, rash, polyneuropathy
note: useful first line agent for UTI, except in elderly or others with reduced CrCl
Polymixins mechanism of action
disrupts the cell membrane permeability by charge alteration
Polymixins spectrum of activity and toxicity
- Gram-negative activity, including Enterobacteriaceae and Pseudomonas
Toxicity: nephrotoxicity, neuromuscular blockade
note: used in combination against very resistant organisms - MDR Pseudomonas, MDR Acinetobacter, carbapenem-resistant Enterobacteriaceae (CRE)
ex. colistin (iv) and polymixin B (iv)
antibiotics with time-dependent activity
Beta-lactams
Carbapenems
Vancomycin
Clindamycin
Linezolid
antibiotics with concentration-dependent activity
aminoglycosides
fluoroquinolones
metronidazole
