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Penicillins Flashcards

1
Q

Natural penicillins

A

Aqueous Penicillin G, Benzathine Penicillin, Procaine Penicillin G, Penicillin VK

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2
Q

Penicillinase-Resistant Penicillins

A

Nafcillin, Oxacillin, Dicloxacillin

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3
Q

Aminopenicillins

A

Ampicillin, Amoxicillin

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4
Q

Carboxypenicillins

A

Ticarcillin

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5
Q

Ureidopenicillins

A

Piperacillin

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6
Q

β-Lactamase Inhibitor Combinations

A

Ampicillin-Sulbactam (Unasyn), Amoxicillin-Clavulanic Acid (Augmentin), Ticarcillin-Clavulanic Acid (Timentin)), Piperacillin-Tazobactam (Zosyn)

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7
Q

B-LACTAMS

A

Penicillins, Cephalosporins, Carbapenems, Monobactams)

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8
Q

Six General Characteristics of B-Lactam Antibiotics

A

1) MOA-inhibitors of cell wall synthesis
2) MOR- destruction by β-lactamase enzymes; alteration in penicillin binding proteins (PBPs); decreased permeability of outer cell membrane in gram-negative bacteria
3) Pharmacodynamic properties – time-dependent bactericidal activity (except against Enterococcus spp.)
4) Short elimination half-life (< 2 hours) - repeated, frequent dosing is needed for most agents to maintain serum concentrations above the MIC of the infecting bacteria for an adequate amount of time (except ceftriaxone, cefoperazone, cefotetan, cefixime, ertapenem)
5) Renal elimination – primarily eliminated unchanged by glomerular filtration and tubular secretion (except nafcillin, oxacillin, ceftriaxone, cefoperazone)
6) ​Cross-allergenicity - all except aztreonam

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9
Q

Basic structure of penicillin

A

All penicillins share the basic structure of a 5-membered thiazolidine ring connected to a - lactam ring, with attached acyl side chains.

Manipulations of the side chain have led to agents with differing antibacterial spectrums, greater -lactamase stability, and pharmacokinetic properties.

Bacterial B-lactamase enzymes may hydrolytically attack the B-lactam ring and render the penicillin inactive.

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10
Q

Site of bacterial penicillinase action in a beta lactam ring of penicillin

A

A = thiazolidine ring, B = β-lactam ring, C = acyl side chain

hydrolysis of cyclic amide bond

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11
Q

Mechanism of action of penicillins

A

Penicillins interfere with bacterial cell wall synthesis by binding to and inhibiting enzymes called penicillin-binding proteins (PBPs) that are located in the cell wall of bacteria

PBPs are enzymes (transpeptidases, carboxypeptidases, and endopeptidases) that regulate the synthesis, assembly, and maintenance of peptidoglycan (cross-linking of the cell wall). The number, type, and location of PBPs vary between bacteria.

Inhibition of PBPs by B-lactam antibiotics leads to inhibition of the final transpeptidation step of peptidoglycan synthesis, exposing a less osmotically stable cell membrane that leads to decreased bacterial growth, bacterial cell lysis, and death.

Penicillins, like all B-lactam antibiotics, are bactericidal, except against Enterococcus spp. where they display bacteriostatic activity.

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12
Q

3 primary mechanisms of resistance to penicillin antibiotics

A

Production of B-lactamase enzymes

Alteration in the structure of the PBPs, which leads to decreased binding affinity of penicillins to the PBPs (e.g., methicillin-resistant Staphylococcus aureus, penicillinresistant Streptococcus pneumoniae).

Inability of the antibiotic to reach the PBP target due to poor penetration through the outer membrane of the bacteria (Gram-negative).

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13
Q

B-lactamase enzymes

A

Over 100 different -lactamase enzymes have been identified. -lactamase enzymes may be plasmid-mediated or chromosomally-mediated, constitutive or inducible.

Produced by many gram-negative (H. influenzae, N. gonorrhoeae, M. catarrhalis, K. pneumoniae, E. coli, Proteus spp., P. aeruginosa, S. marcescens, etc.), some gram-positive (Staphylococcus aureus), and some anaerobic (Bacteroides fragilis) bacteria. B-lactamase enzymes produced by gram-negative bacteria reside in the periplasmic space (very efficient).

B-lactamase inhibitors have been developed and combined with some penicillin agents to prevent the -lactamase enzymes of some bacteria from hydrolyzing the penicillin.

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14
Q

Natural Penicillins

A

The first agents in the penicillin class to be used clinically. Examples of natural penicillins include aqueous penicillin G, benzathine penicillin G, procaine penicillin G, penicillin VK.

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15
Q

Natural Penicillins effect on Gram-positive bacteria

A

xcellent activity against non-B-lactamase-producing grampositive cocci and bacilli

  • Group Streptococci (groups A, B, C, F, G)
  • Viridans streptococci
  • Some Enterococcus spp.
  • Some Streptococcus pneumoniae (high level resistance ~ 15 to 20%)
  • Very little activity against Staphylococcus spp.- due to penicillinase production
  • Bacillus spp. (including B. anthracis)
  • Corynebacterium spp
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16
Q

Natural penicllins and gram negative bacteria

A

only against some gram-negative cocci

  • Neisseria meningitidis
  • non-B-lactamase-producing Neisseriagonorrhoeae
  • Pasteurella multocida
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17
Q

Natural penicllins and anaerobes

A

good activity against gram-positive anaerobes

  • Mouth anaerobes (gram-positive cocci, “above the diaphragm”) – such as Peptococcus spp, Peptostreptococcus spp., Actinomyces spp.
  • Clostridium spp. (gram-positive bacilli, “below the diaphragm”), with the exception of C. difficile
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18
Q

Natural penicillins and other bacteria

A

works against Treponema pallidum

Penicillin G is still considered to be a DRUG OF CHOICE for the treatment of infections due to Treponema pallidum (syphilis), Neisseria meningitidis, Corynebacterium diphtheriae, Bacillus anthracis (anthrax), Clostridium perfringens and tetani, viridans and Group Streptococci.

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19
Q

Penicillinase-Resistant Penicillins

A

Developed to address the emergence of penicillinase-producing staphylococci that rendered the natural penicillins inactive. They contain an acyl side chain that sterically inhibits the action of penicillinase by preventing opening of the B-lactam ring. Examples include nafcillin, methicillin (no longer available in US), oxacillin, and dicloxacillin.

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20
Q

Penicillinase-Resistant Penicillins and gram positive bacteria

A

Methicillin Susceptible Staphylococcus aureus (MSSA) - NOT ACTIVE AGAINST MRSA

Viridans and Group streptococci (less activity than Pen G)

No activity against Enterococcus spp. or S. pneumoniae

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21
Q

Penicillinase-Resistant Penicillins and gram negative bacteria

A

No activity

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22
Q

Penicillinase-Resistant Penicillins and anaerobes

A

limited activity

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23
Q

Aminopenicillins

A

Developed to address the need for penicillins with extended activity against gram-negative aerobic bacilli. Aminopenicillins were formulated by the addition of an amino group to the basic penicillin molecule. Examples include ampicillin and amoxicillin.

24
Q

Aminopenicillins and gram positive bacteria

A

similar activity to the natural penicillins (also ineffective against Staphylococcus aureus because destroyed by penicillinase)

Better activity than natural penicillin against Enterococcus spp

Excellent against Listeria monocytogenes, a gram-positive bacillus

25
Q

Aminopenicillins and gram negative bacteria

A

better activity than natural penicillins

H. influenzae (only B-lactamase negative strains about 70%)

E.coli (45 to 50% of strains are resistant)

Proteus mirabilis

Salmonella spp., Shigella spp.

26
Q

aminopenicillins and aneorobes

A

Activity similar to Pen G

27
Q

Carboxypenicillins

A

Developed to address the emergence of more resistant gram-negative bacteria and the increasing frequency of Pseudomonas aeruginosa as a nosocomial pathogen. These agents were formulated by adding a carboxyl group to the basic penicillin molecule. Ticarcillin was the only available carboxypenicillin (discontinued 2004)

28
Q

Carboxy penicillins and gram positive bacteria

A

generally weak activity

Less active against Streptococcus spp

Not active against. Enterococcus or Staphylococcus spp

29
Q

carboxy penicillins and gram negative bacteria

A

enhanced activity

Same gram-negative bacteria as aminopenicillins (including indole-positive Proteus mirabilis)

Enterobacter spp.

Providencia spp.

Morganella spp.

Pseudomonas aeruginosa

NOT active against Klebsiella spp., Serratia spp., or Actinobacter spp

30
Q

Ureidopenicillins

A

Developed to further enhance activity against gram-negative bacteria. These agents are derived from the ampicillin molecule with acyl side chain adaptations that allow for greater cell wall penetration and increased PBP affinity. The ureidopenicillins are the broadest-spectrum penicillins available without -lactamase inhibitors. Piperacillin was the only available ureidopenicillin (discontinued 2011)

31
Q

Ureidopenicillins and gram-positive bacteria

A

Good activity against viridans and Group Streptococci

Some activity against Enterococcus spp

No activity against Staphylococcus spp

32
Q

Ureidopenicillins and gram-negative bacteria

A

improved activity

Displays activity against most Enterobacteriaceae

Active against Klebsiella spp. and Serratia marcescens

Pseudomonas aeruginosa (piperacillin is the most active penicillin)

33
Q

Ureidopenicillins and anaerobes

A

Activity similar to Pen G against Clostridium and Peptostreptococcus

34
Q

B-Lactamase inhibitor combinations

A

Available as a combination product containing a penicillin and a B-lactamase inhibitor. The -lactamase inhibitor irreversibly binds to the catalytic site of the -lactamase enzyme, preventing the hydrolytic action on the penicillin. The B-lactamase inhibitors enhance the antibacterial activity of their companion penicillin in situations where the resistance is primarily the result of B-lactamase production.

Amoxicillin / Clavulanate (Augmentin) – PO Ampicillin / Sulbactam (Unasyn) – IV Ticarcillin / Clavulanate (Timentin) – IV (discontinued 2014) Piperacillin / Tazobactam (Zosyn) – IV

These combination agents will retain the same activity of the parent penicillin against non B-lactamase producing organisms, and will have enhanced activity against B-lactamase producing bacteria.

35
Q

B-lactamase Inhibitor Combinations anf bram-positive bacteria

A

Provide activity against B-lactamase producing strains of Staphylococcus aureus (they have activity against MSSA).

36
Q

B-lactamase Inhibitor Combinations and gram-negative bacteria

A

Enhanced activity against B-lactamase producing strains of E. coli, Proteus spp., Klebsiella spp., H. influenzae, M. catarrhalis, and N. gonorrhoeae.

Not very active against the inducible -lactamase enzymes produced by Serratia marcescens, P. aeruginosa, indole-positive Proteus spp., Citrobacter spp., and Enterobacter spp. (SPICE bacteria).

Ticarcillin/clavulanate is active against Stenotrophomonas maltophilia

37
Q

B-lactamase Inhibitor Combinations and anaerobes

A

Enhanced activity against B-lactamase producing strains of B. fragilis and B. fragilis group (DOT) organisms.

38
Q

Pharmacodynamic principles of dosing for penicillins

A

Penicillins display time-dependent bactericidal activity.

The pharmacodynamic parameter that correlates with clinical efficacy of the penicillins is Time above the MIC

Penicillins are bactericidal, but only display bacteriostatic activity against Enterococcus spp. Bactericidal activity (synergy) can be achieved against Enterococcus spp. by adding an aminoglycoside (gentamicin or streptomycin), which is used in the treatment of Enterococcal endocarditis

39
Q

Absorption of penicillins

A

Many penicillins are degraded by gastric acid and are unsuitable for oral administration, so they must be administered parenterally

Orally-available penicillins are variably absorbed from the gastrointestinal tract. Concentrations achieved with oral dosing are lower than those achieved with parenteral dosing, so oral therapy should only be used for mild to moderate infections. Food typically delays the rate and/or extent of absorption.

Natural penicillins – oral pen G is poorly absorbed so that phenoxymethyl penicillin is used orally (pen VK); IM benzathine and procaine penicillin G are formulated to delay absorption resulting in prolonged serum and tissue concentrations

Aminopenicillins – amoxicillin displays higher bioavailability than ampicillin; food delays ampicillin absorption

Penicillinase-Resistant Penicillins – oral dicloxacillin displays the best bioavailability

40
Q

Distribution of penicillins

A

Penicillins are widely distributed into body tissues and fluids including pleural fluid, synovial fluid, bone, bile, placenta, and pericardial fluid, but do NOT penetrate the eye or prostate. The variation in distribution of various penicillins depends on their molecular configuration and protein binding.

Adequate concentrations of penicillins in the cerebrospinal fluid (CSF) are attainable only in the presence of inflamed meninges when high doses of parenteral penicillins are used.

Penicillin binding to serum proteins is variable, ranging from 15% for the aminopenicillins to 97% for dicloxacillin.

41
Q

Elimination of penicillins

A

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.

Probenecid blocks the tubular secretion of renally-eliminated penicillins and can increase their serum concentrations.

Most penicillins are removed during hemodialysis or peritoneal dialysis, and require supplemental dosing after a hemodialysis procedure – the exceptions are nafcillin and oxacillin.

ALL penicillins have relatively short elimination half-lives (< 2 hours) and require repeated daily dosing (4 to 6 times daily) or continuous infusion to maintain therapeutic serum concentrations.

42
Q

Which penicillins are not eliminated by the kidney?

A

Exceptions include nafcillin and oxacillin, which are eliminated primarily by the liver, and piperacillin which undergoes dual elimination

43
Q

Sodium load and penicillins

A

Sodium Load – several parenterally-administered penicillins (especially the carboxy- and ureidopenicillins) contain sodium in their parenteral preparations, which must be considered in patients with cardiac or renal dysfunction

Aqueous Sodium Penicillin G contains 2.0 mEq per 1 million units

Ticarcillin contains 5.2 mEq per gram (also in Timentin)

Piperacillin contains 1.85 mEq per gram (also in Zosyn)

44
Q

Penicillinase-Resistant Penicillins (Antistaphylococcal Penicillins)

A

Because of enhanced activity against S. aureus, these agents are useful for the treatment of infections due to methicillin-susceptible Staphylococcus aureus (MSSA) 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.

45
Q

Clinical Uses of natural penicillins

A

drug of choice for infections due to:

S. pneumoniae (IV or IM – for penicillin-susceptible or penicillin-intermediate strains)

Other Streptococci, including S. pyogenes (benzathine pen or aqueous pen), viridans streptococci pharyngitis (PO or IM); bacteremia, endocarditis (with an aminoglycoside), meningitis (IV)

Neisseria meningitidis - meningitis, meningococcemia (IV)

Treponema pallidum – syphilis (benzathine pen or IV pen)

Clostridium perfringens or tetani

Actinomycosis

Endocarditis prophylaxis in patients with valvular heart disease undergoing dental procedures at high risk for inducing bacteremia

Prevention of rheumatic fever

46
Q

Clinical uses of Penicillinase-Resistant Penicillins (Antistaphylococcal Penicillins)

A

Because of enhanced activity against S. aureus, these agents are useful for the treatment of infections due to methicillin-susceptible Staphylococcus aureus (MSSA) 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.

47
Q

Clinical uses of Aminopenicillins

A

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 Enterococcal infections (with an aminoglycoside for endocarditis) and Listeria monocytogenes meningitis.

Endocarditis prophylaxis in patients with valvular heart disease

Treatment of Salmonella and Shigella.

48
Q

Clinical uses of Carboxypenicillins and Ureidopenicillins

A

Due to enhanced activity against gram-negative bacteria, these agents are (were) 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 (hospital-acquired infections). Piperacillin is the most active penicillin for infections due to Pseudomonas aeruginosa.

49
Q

Clinical uses of β-Lactamase Inhibitor Combination Products

A

Amoxicillin-clavulanate (Augmentin® - PO) is useful for the treatment of otitis media, sinusitis, bronchitis, lower respiratory tract infections, and human or animal bites

Due to expanded activity against gram-positive and gram-negative bacteria (including anaerobes), the parenteral combination agents are often utilized in the treatment of polymicrobial infections such as intraabdominal infections, gynecological infections, diabetic foot infections, etc.

  • Ampicillin-sulbactam (Unasyn® – IV) is useful for the treatment of mixed aerobic/anaerobic infections (limited gram-negative coverage).
  • Ticarcillin-clavulanate (Timentin® –IV) is (was) used as second line for treatment of infections caused by Stenotrophomonas maltophilia. It has similarly broad coverage to piperacillin-tazobactam but the latter is preferred due to tolerability (i.e., sodium load).
  • Piperacillin-tazobactam (Zosyn® – IV) is useful for the treatment of polymicrobial infections or other infections involving gram-negative bacteria including hospitalacquired pneumonia, bacteremia, complicated urinary tract infections, complicated skin and soft tissue infections, intraabdominal infections, and empiric therapy for febrile neutropenia.
50
Q

Penicillin hypersensitivity

A

most frequently occurring side effect (3 to 10%)

Less frequent with oral administration, somewhat higher when administered intravenously.

Reactions include pruritus, rash (maculopapular, erythematous, or morbilloform), urticaria, angioedema, hypotension, vasodilation, shock, and anaphylaxis.

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.

enicillin skin testing – occasionally used to predict hypersensitivity reactions when a history of a hypersensitivity reaction is unclear.

Desensitization is possible (oral or parenteral) in some patients

Other allergic reactions include drug fever, serum sickness, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and exfoliative dermatitis

51
Q

Nuerologic effects of penicillin

A

Direct toxic effect observed primarily in patients who receive large intravenous doses of some penicillins in the presence of concomitant renal dysfunction.

Irritability, jerking, confusion, generalized seizures

52
Q

Hematologic effects of penicillins

A

β-lactam-specific cytotoxic IgG or IgM antibodies are developed that bind to circulating WBC or platelets; cause cell lysis when antigen (penicillin) encountered by activation of the complement system

Leukopenia, neutropenia or thrombocytopenia - especially in patients receiving longterm (> 2 weeks) therapy

53
Q

Gastrointestinal effects of penicillins

A

Transient increases in liver enzymes – especially oxacillin and nafcillin

Nausea, vomiting

Diarrhea – especially with amoxicillin-clavulanic acid

Pseudomembranous colitis (Clostridium difficile diarrhea)

54
Q

Interstitial Nephritis

A

Immune-mediated damage to renal tubules (cell-mediated immunity or antigenantibody reactions) where the penicillin acts as a hapten when bound to renal tubular cells - most commonly associated with methicillin, but can occur with nafcillin and other penicillin

Initial manifestations may be fever, eosinophilia, pyuria, eosinophiluria, and an abrupt increase in serum creatinine.

55
Q

Adverse affects of penicillins

A

Other adverse effects include phlebitis (nafcillin); pain and induration with IM injection (benzathine penicillin, penicillin G, ampicillin); hypokalemia (ticarcillin because it acts as nonreabsorbable anions resulting in increased excretion of potassium); sodium overload and fluid retention (ticarcillin, piperacillin)

56
Q
A

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