Erdman - PCN Flashcards
6 General Characteristics of β-Lactams
β-Lactams: PCN, Cephalosporins, Carbapenems, Monobactams)
1) Same MOA - inhibitors of a ___ synthesis
2) Same MOR - destruction by ___ enzymes, alteration of ___ , decreased permeability of outer cell membrane in gram ___ bacteria
3) Pharmacodynamic properties – Display ___ -dependent (T>MIC) bactericidal activity (except against ___ spp.)
4) ___ elimination half-life (< __ hours) – ___ dosing is needed to maintain serum concentrations above the MIC for an adequate amount of time (except ___ , ___ , ____ , and ___)
5) ___ elimination – Primarily eliminated unchanged by glomerular filtration and tubular secretion (except ___ , ___ , ___ , and ___ )
6) Cross-allergenicity – All except ___
1) cell wall
2) β-lactamase, PBPs, negative
3) time, Enterococcus
4) Short, 2, frequent, ceftriaxone, cefotetan, cefixime, ertapenem
5) renal, nafcillin, oxacillin, ceftriaxone, cefoperazone
6) aztreonam
PCN MOA
- Inhibition of ___ ➡ inhibit ___ synthesis ➡ exposes membrane ➡ decreased bacterial growth ➡ lysis and death
- Penicillins, like all B-lactam antibiotics, are ___ , except against ___ spp. where they display bacteriostatic activity
- PBP, peptidoglycan
- bacteriocidal, Enterococcus
Mechanisms of Resistance
Production of ___ enzymes
- Produced by one Gram-positive aerobe ( ___ ), many Gram-negative aerobes (H. influenzae, N. gonorrhoeae, M. catarrhalis, K. pneumoniae, E. coli, Proteus spp., P. aeruginosa, S. marcescens, etc.), some Gram-negative anaerobes (Bacteroides ___ )
- efficient MOR for gram ___ bacteria
- B-lactamase
- S. aureus
- B. fragilis
- negative
Mechanisms of Resistance
Alteration in the structure of the ___ leading to decreased binding affinity (e.g.)
- methicillin-resistant Staphylococcus aureus { ___ }
- penicillin-resistant Streptococcus pneumoniae { ___}
- PBPs
- MRSA
- PRSP
Mechanisms of Resistance
Altered ___ proteins
- Inability of the antibiotic to reach the PBP target due to poor penetration through the outer membrane of Gram- ___ bacteria
porin
negative
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Natural Penicillins (4)
- Aqueous Penicillin G
- Benzathine Penicillin
- Procaine Penicillin G
- Penicillin VK
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Natural Penicillins
Gram positive cocci and bacilli
- excellent activity against non - ___ -producing
- very little activity against ___ spp. due to penicillinase production (~ 5% susceptible)
Gram postitive ___
- Mouth anaerobes (Gram-positive cocci, “above the diaphragm”) – such as Peptococcus spp, Peptostreptococcus spp.
- ___ spp. (Gram-positive bacilli, “below the diaphragm”), with the exception of Clostridium difficile
Gram negative ___
- Neisseria meningitidis, non-B-lactamase-producing Neisseria
gonorrhoeae, Pasteurella multocida
Other
- ____ ___ , Actinomyces spp.
- B-lactamase
- Staphylococcus
- Anaerobes
- Clostridium
- COCCI
- Treponema pallidum
CLASSIFICATION AND SPECTRUM OF ACTIVITY
___ is still considered to be a potential DRUG OF CHOICE for the treatment of infections due to
- viridans and Group Streptococci
- Neisseria meningitidis
- Corynebacterium diphtheriae
- Bacillus anthracis (anthrax)
- Clostridium perfringens
- tetani, and Treponema pallidum (syphilis
Penicillin G
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Penicillinase-Resistant Penicillins (AKA Antistaphylococcal Penicillins)
- Developed to address the emergence of penicillinase-producing ___ that rendered the natural penicillins inactive
- These agents contain an ___ side chain that sterically inhibits the action of the penicillinase by preventing opening of the B-lactam ring
- Examples include (5)
- S. aureus
-
nafcillin, methicillin, oxacillin,
cloxacillin, and dicloxacillin
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Antistaphylococcal Penicillins
Gram-Positive
- Group and viridans streptococci (less activity than ___ )
- Methicillin Susceptible Staphylococcus aureus ( ___ ) - NOT ACTIVE AGAINST ___
- Not active against Enterococcus spp. or Streptococcus pneumoniae
Gram-Negative: NO activity
Anaerobes: limited to no activity
- Pen G
- MSSA, MRSA
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Aminopenicillins
- Developed to address the need for penicillins with extended activity against Gram- ___ ___ ___. Aminopenicillins were formulated by the addition of an amino group to the basic penicillin molecule.
- Examples include ___ and ___
- negative aerobicm bacilli
- ampicillin, amoxicillin
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Aminopenicillins
Gram-Positive: similar activity to the natural penicillins; also ineffective
against ____ because they are destroyed by penicillinase
- Better activity than natural penicillins against ___ spp.
- Excellent against ___ ___, a Gram-positive bacillus
Gram-Negative: better activity than natural penicillins
- Haemophilus influenzae (only B-lactamase negative strains ~70%)
- Escherichia coli (45 to 50% of strains are resistant)
- Proteus mirabilis
- Salmonella spp., Shigella spp.
Anaerobes: activity similar to ___
- S. aureus
- Enterococcus
- Listeria monocytogenes
- Pen G
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Aminopenicillins are DRUG OF CHOICE for infections due to ___ ___ and ___ spp
- Listeria monocytogenes
- Enterococcus
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Carboxypenicillins
- Developed to address the emergence of more resistant Gram- ___ bacteria and the increasing frequency of ___ ___as a nosocomial pathogen. These agents were formulated by adding a ___ group to the basic penicillin molecule
- Examples include carbenicillin and ___
- negative
- Pseudomonas aeruginosa
- carboxyl
- ticarcillin
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Carboxypenicillins
Gram-Positive: generally ___ activity
- Less active against Streptococcus spp.
- Not active against Enterococcus spp. or Staphylococcus spp.
Gram-Negative: ___ activity
- Same Gram-negative bacteria as aminopenicillins (including indole-
positive Proteus spp.)
- Enterobacter spp.
- Providencia spp.
- Morganella spp.
- ___ ___
** NOT active against ___ spp. or ___ spp**
- weak
- enhanced
- Pseudomonas aeruginosa
- Klebsiella, Serratia
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Ureidopenicillins:
- Developed to provide further activity against Gram- ___ bacteria. These agents were derived from the ___ molecule with acyl side chain adaptations that allow for greater cell wall penetration and increased PBP affinity
- The ureidopenicillins are the most ___ spectrum penicillins available without B-lactamase inhibitors
- Examples include mezlocillin, azlocillin, and ___
- negative
- ampicillin
- broad
- piperacillin
CLASSIFICATION AND SPECTRUM OF ACTIVITY
Ureidopenicillins
Gram-Positive
- Good activity against Group and viridans Streptococci
- Some activity against Enterococcus spp.
- No activity against Staphylococcus spp.
Gram-Negative: improved activity
- Display activity against most Enterobacterales
- Active against Serratia marcescens and some Klebsiella spp.
- ___ ___ ( ___ is the most active penicillin)
Anaerobes:
- Activity similar to Pen G against Clostridium and Peptostreptococcus
- Some activity against Bacteroides frag
- Pseudomonas aeruginosa
- piperacillin
CLASSIFICATION AND SPECTRUM OF ACTIVITY
B-lactamase Inhibitor Combinations
- The B-lactamase inhibitor irreversibly binds to the catalytic site of the B-lactamase enzyme, preventing the hydrolytic action on the penicillin
- These combination agents will retain the same activity of the ___ penicillin against non B-lactamase producing organisms, and will have ___ activity against some B-lactamase producing bacteria.
Examples
- ___ / Clavulanic Acid (Augmentin); administered ___
- ___ / Sulbactam (Unasyn) – administered ___
- ___ / Clavulanic Acid (Timentin) – administered ___
- Piperacillin / Tazobactam ( ___ ) – administered ___
- parent, enhanced
- amoxicillin, PO
- ampicillin, IV
- ticarcillin, IV
- Zosyn, IV
CLASSIFICATION AND SPECTRUM OF ACTIVITY
B-lactamase Inhibitor Combinations
Gram-Positive
- Provide activity against B-lactamase producing strains of Staphylococcus aureus (they have activity against ___ )
Gram-Negative
- Enhanced activity against some B lactamase producing strains of E. coli, Proteus spp., Klebsiella spp., H. influenzae, M. catarrhalis, and N. gonorrhoeae.
- Not very active against the inducible B lactamase enzymes produced by ___ ___, ___ , ___ -positive Proteus spp., ___ spp., and ___ spp. (SPiCE)
Anaerobes
- Enhanced activity against B-lactamase producing strains of ___ ___ and B. fragilis group ( ___ ) organism
- MSSA
- S. marcescens, P. aeruginosa, indole, Citrobacter, Enterobacter
- Bacteroides fragilis, DOT
PHARMACOLOGY
- Penicillins display ___-dependent bactericidal activity
- the pharmacodynamic parameter that correlates best with their clinical efficacy __ > ___
- Penicillins are ___ , but are only bacteriostatic against ___ spp.
- time
- T, MIC
- bacteriocidal, Enterococcus
PHARMACOLOGY
Absorption
- Many penicillins are degraded by gastric acid and are unsuitable for oral administration, so they must be administered ___
- oral penicillins should only be used for mild to moderate infections. ___ typically delays the rate and/or extent of absorption
- parenterally
- food
PHARMACOLOGY
Special Absorption Considerations
- Natural penicillins – Oral pen G is poorly absorbed so that phenoxymethyl penicillin (pen ___ ) is used orally; IM benzathine and IM procaine penicillin G are formulated to delay absorption
resulting in prolonged low serum and tissue concentrations
- Aminopenicillins – Amoxicillin displays ___ bioavailability than ampicillin; food delays ___ absorption
- Penicillinase-Resistant Penicillins – Oral ___ displays the best bioavailability
- Extended Spectrum Penicillins - Carbenicillin available orally but with low bioavailability (30-40%) and used only for ___
- VK
- higher, ampicillin
- dicloxacillin
- UTIs
PHARMACOLOGY
Distribution
- distribute everywhere except the prostate and eye
- Adequate concentrations of penicillins (but NOT the β-lactamase inhibitors) in the ___ are attainable only in the presence of ___ meninges when high, maximal doses of ___ penicillins are used
- Penicillin binding is variable, ranging from 15% for the ___ to 97% for ___
- CSF, inflamed, parenteral
- aminopenicillins, dicloxacillin
PHARMACOLOGY
Elimination
- Most penicillins are eliminated primarily by the kidneys unchanged via glomerular filtration and tubular secretion, and require dosage adjustment in the presence of renal insufficiency. Exceptions include ___ and ___ , which are eliminated primarily by the liver, and ___ which undergoes dual elimination
- ___ blocks the tubular secretion of renally-eliminated penicillins and can increase their serum concentrations
- Most penicillins are removed during hemodialysis or peritoneal dialysis, and may require supplemental dosing after a hemodialysis procedure: the exceptions are ___ and ___
- ALL penicillins have relatively ___ elimination half-lives (< 2 hours) and require repeated daily dosing (4 to 6 times daily) or continuous infusion to maintain therapeutic serum concentrations
- nafcillin, ozacillin, piperacillin
- probenecid
- nafcillin, oxacillin
- short
Sodium Load
Several parenterally-administered penicillins (especially the ___ and ___ penicillins) contain sodium in their parenteral preparations, which must be considered in patients with ___ or ___ dysfunction
- Aqueous Sodium Penicillin __ contains 2.0 mEq per 1 million units
- ___ contains 2.9 mEq per gram
- ___ contains 4.7 mEq per gram
- ___ contains 5.2 mEq per gram (also in Timentin)
- ___ contains 1.85 mEq per gram (also in ___ )
- carboxy, ureido
- CHF, renal
- G
- nafcillin
- carbenicillin
- ticarcillin
- piperacillin
Which 3 PCNs do not require renal adjustment?
- Piperacillin
- nafcillin
- oxacillin
CLINICAL USES - Natural Penicillins
potential DOC for
- Streptococcus pneumoniae (IV or IM for penicillin-susceptible or penicillin intermediate strains)
- Other Streptococci, including S. pyogenes (IM benzathine or IV aqueous penicillin) or viridans streptococci pharyngitis (PO or IM), bacteremia (IV), endocarditis (IV with an aminoglycoside), meningitis (IV)
- Neisseria meningitidis - meningitis, meningococcemia (IV aqueous pen)
- ___ ___ – ___ (IM benzathine pen or IV aqueous pen)
- Clostridium perfringens or tetani
- Actinomycosis
- Treponema pallidum, syphilis
CLINICAL USES - Antistaphylococcal Penicillins
- Because of enhanced activity against Staphylococcus aureus, these agents are
useful for the treatment of infections due to ___ such as skin and soft tissue infections, septic arthritis, osteomyelitis, bacteremia, endocarditis, etc. - Parenteral therapy should be used for moderate to severe infections
- Oral dicloxacillin is useful for the treatment of mild to moderate skin and soft tissue infections, and as follow-up therapy after parenteral therapy for the treatment of more serious infections such as osteomyelitis or septic arthritis
- MSSA
CLINICAL USES - Aminopenicillins
- Because of activity against respiratory tract pathogens, oral ampicillin and amoxicillin are useful for the treatment of mild to moderate pharyngitis, sinusitis, bronchitis, and otitis media
- Oral ampicillin or amoxicillin are useful for uncomplicated urinary tract infections due to susceptible organisms
- Parenteral ampicillin is used for the treatment of ___ infections (with an aminoglycoside for endocarditis) and ___ ___ meningitis.
- Endocarditis prophylaxis in patients with valvular heart disease
- Treatment of Salmonella (amoxicillin) and Shigella (ampicillin)
- Enterococcal
- Listeria monocytogenes
CLINICAL USES - Carboxypenicillins and Ureidopenicillins
- Due to enhanced activity against Gram-negative bacteria, these agents are useful for the treatment of serious infections such as bacteremia, pneumonia, complicated urinary tract infection, peritonitis, intraabdominal infections, skin and soft tissue infections, bone and joint infections, and meningitis caused by Gram-negative bacteria (especially ___ -acquired infections). ___ is the most active penicillin against Pseudomonas aeruginosa.
- May be used as ___ therapy in immunocompromised patients.
- hospital, piperacillin
- empiric
β-Lactamase Inhibitor Combination Products
- Amoxicillin-clavulanate (Augmentin - __ ) is useful for the treatment of otitis media, sinusitis, bronchitis, lower ___ tract infections, and human or animal ___
- Due to expanded activity against Gram-positive and Gram-negative bacteria (including anaerobes), the parenteral combination agents are often utilized in the treatment of ___ infections such as ___ infections, ___ infections, diabetic ___ infections, infected sacral decubitus ulcers, etc
“Dogmentin”
- PO
- respiratory, bites
- polymicrobial, intraabdominal, gynecological, foot
β-Lactamase Inhibitor Combination Products
- ___ -sulbactam (Unasyn – IV) is useful for the treatment of mixed aerobic/anaerobic infections (but has limited Gram- ___ coverage)
- ___ -tazobactam (Zosyn – IV) is useful for the treatment of ___ infections and other infections involving Gram-negative bacteria (including ___ ___ ) such as ___ -acquired pneumonia, bacteremia, complicated urinary tract infections, complicated skin and soft tissue infections, intraabdominal infections, empiric therapy for hospitalized patients and in patients with febrile neutropenia
- ampicillin, negative
- piperacillin, Pseudomonas aeruginosa, hospital
ADVERSE EFFECTS
___ – most frequently occurring side effect (3 to 10%)
- Anaphylaxis is rare, occurring in 0.004-0.015% of patients
- Mediated by antibodies produced against penicillin degradation products that become haptens when bound to tissue proteins
hypersensitivity
ADVERSE EFFECTS
Cross-allergenicity is observed among natural and semisynthetic penicillins
due to their common nucleus
T or F: patients allergic to one penicillin should be considered allergic to ALL other members of the penicillin family, and
caution should be used with some other B-lactams
T
ADVERSE EFFECTS
Neurologic
- Direct toxic effect observed primarily in patients who receive large intravenous doses of renally-eliminated penicillins in the presence of renal dysfunction.
- Irritability, jerking, myoclonus, confusion, generalized ___
seizures
ADVERSE EFFECTS
Hematologic
β-lactam-specific cytotoxic IgG or IgM antibodies are developed that bind to
circulating RBCs, WBCs, or platelets.
- In the case of RBCs, intravascular hemolysis (Coomb’s positive hemolytic anemia) rarely occurs when the antigen (penicillin) is encountered; anemia may also develop when the cells are removed by the reticuloendothelial system.
- In the case of WBCs and platelets, cell lysis may occur through activation of the complement system when the antigen (penicillin) is encountered leading to ___ , ___ or ___ . Occurs primarily in patients receiving long-term (> 2 weeks) therapy;
reversible upon discontinuation.
- leukopenia
- neutropenia
- thrombocytopenia
ADVERSE EFFECTS
Gastrointestinal
- Transient increases in liver enzymes – especially oxacillin, nafcillin, piperacillin, and carbenicillin
- Nausea, vomiting
- Diarrhea – especially with amoxicillin- ___
- Pseudomembranous colitis (Clostridium difficile diarrhea)
- clavulanate
ADVERSE EFFECTS
Interstitial Nephritis
- Immune-mediated damage to renal tubules (cell-mediated immunity or antigen- antibody reactions) where the penicillin acts as a hapten when bound to renal tubular cells ➡ most commonly associated with ___ , but can occur
with ___ and other penicillins
- May progress to renal failure
- initial manifestations may be fever, eosinophilia, pyuria, ___ , and an abrupt increase in ___
- methicillin
- nafcillin
- eosinophiluria, SCr
- Other adverse effects include ___ (nafcillin)
- pain and induration with IM injection (benzathine penicillin, ampicillin)
- ___ (carbenicillin and ticarcillin because they act as nonreabsorbable anions resulting in increased excretion of potassium)
- ___ overload and fluid retention ( ___ , ___ )
- phlebitis
- hypokalemia
- Na, ticarcillin, piperacillin
