B-lactam antibiotics and penicillins

Question 1

Natural penicillins

Answer 1

Aqueous Pen G, benzathine penicillin, procaine pen G, pen VK

Question 2

penicillinase-resistant penicillins

Answer 2

nafcillin, oxacillin, methicillin, dicloxacillin

Question 3

aminopenicillins

Answer 3

ampicillin, amoxicillin

Question 4

carboxypenicillins

Answer 4

ticarcillin

Question 5

ureidopenicillins

Answer 5

piperacillin

Question 6

B-lactamase inhibitor comcinations

Answer 6

ampicillin-sulbactam, amoxicillin-clavulanate, ticarcillin-clavulanate, piperacillin-tazobactam

Question 7

six general characteristics of B-lactam antibiotics**

Answer 7

B-lactams: penicillins, cephalosporins, carbapenems, monobactams

1) same MOA - inhibitors of cell wall synthesis
2) same mechanism of resistance (MOR) - destruction by B-lactamase enzymes, alteration in PBPs, decreased permeability of outer cell membrane in gram-neg bacteria
3) pharmacodynamic properties - display time dependent (T>MIC) bactericidal activity (except against enterococcus spp.)
4) short elimination half-life (under 2 hours) - repeated, frequent dosing is needed to maintain serum conc above the MIC of the infecting bacteria for an adequate amount of time (except ceftriaxone, cefotetan, cefixime, ertapenem)
5) renal elimination - primarily eliminated unchanged by glomerular filtration and tubular secretion (except nafcillin, oxacillin, ceftriaxone, cefoperazone)
6) cross-allerginicity - all except aztreonam

Question 8

chemistry of penicillins

Answer 8

All penicillins share the same basic structure of a 5-membered thiazolidine ring connected to a β-lactam ring - “house w a garage”
The side chains differ among the groups of penicillins, providing different antibacterial spectrums and pharmacokinetic properties, as well as greater β-lactamase stability.
Bacterial β-lactamase enzymes may hydrolytically attack the β-lactam ring and render the penicillin inactive.

Question 9

penicillin MOA**

Answer 9

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 and are primarily expressed during cell division.
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 among bacteria.
Inhibition of PBPs by β-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 β-lactam antibiotics, are bactericidal**, except against Enterococcus spp. where they display bacteriostatic activity.

Question 10

Penicillins MOR

Answer 10

production of B-lactamase enzymes:
-The most important and most common mechanism of bacterial resistance where the bacteria produces a β-lactamase enzyme that hydrolyzes the cyclic amide bond of the β-lactam ring, inactivating the antibiotic.
-Over 850 different β-lactamase enzymes have been identified. β-lactamase enzymes may be plasmid-mediated or chromosomally-mediated, constitutive or inducible.
-Produced by some Gram-positive aerobes (Staphylococcus aureus), many Gram-negative aerobes (H. influenzae, N. gonorrhoeae, M. catarrhalis, K. pneumoniae, E. coli, Proteus spp., P. aeruginosa, S. marcescens, etc.), and some Gram-negative anaerobes (Bacteroides fragilis). - β-lactamase enzymes produced by Gram-negative bacteria reside in the periplasmic space, making this a very efficient mechanism of resistance.
-β-lactamase inhibitors have been developed and combined with some penicillins to prevent the β-lactamase enzymes of some bacteria from hydrolyzing the penicillin.
Alteration in the structure of the PBPs, which leads to decreased binding affinity of the penicillins to the PBPs (e.g., methicillin-resistant Staphylococcus aureus {MRSA}, penicillin-resistant Streptococcus pneumoniae {PRSP}).
Inability of the antibiotic to reach the PBP target due to poor penetration through the outer membrane of Gram-negative bacteria (altered porin proteins).

Question 11

Natural penicillins

Answer 11

First group of penicillins to be discovered and used clinically; other groups of penicillins are semi-synthetically derived from natural penicillin. Examples of natural penicillins include aqueous penicillin G (IV), benzathine penicillin G (IM), procaine penicillin G (IM), penicillin VK (PO).
**Penicillin G 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 and tetani, and Treponema pallidum (syphilis).

Question 12

natural penicillins vs gram positive

Answer 12

excellent activity against non-β-lactamase-producing Gram-positive cocci and bacilli
Group Streptococci (Groups A, B, C, F, G)
Viridans streptococci
Some Streptococcus pneumoniae (high level resistance ~15 to 20%)
Most Enterococcus spp.
Very little activity against Staphylococcus spp. due to penicillinase production*** (cannot be used for S. aureus)
Bacillus spp. (including B. anthracis)
Corynebacterium spp.

Question 13

natural penicillins vs “other”

Answer 13

Treponema pallidum, Actinomyces spp. (syphilis*)

Question 14

penicillinase-resistant penicillins

Answer 14

AKA antistaphylococcal penicillins
Developed to address the emergence of penicillinase-producing Staphylococcus aureus that rendered the natural penicillins inactive. These agents contain an acyl side chain that sterically inhibits the action of the penicillinase by preventing opening of the β-lactam ring. Examples include nafcillin, methicillin, oxacillin, cloxacillin, and dicloxacillin*.

Question 15

penicillinase-resistant penicillins

Answer 15

AKA antistaphylococcal penicillins
Developed to address the emergence of penicillinase-producing Staphylococcus aureus that rendered the natural penicillins inactive. These agents contain an acyl side chain that sterically inhibits the action of the penicillinase by preventing opening of the β-lactam ring. Examples include nafcillin (IV), methicillin (IV), oxacillin (IV), cloxacillin (PO), and dicloxacillin (PO)*.

Question 16

penicillinase-resistant penicillins vs gram positives

Answer 16

Group and viridans streptococci (less activity than Pen G)
Methicillin Susceptible Staphylococcus aureus (MSSA) - NOT ACTIVE AGAINST MRSA***
Not active against Enterococcus spp. or Streptococcus pneumoniae

Question 17

penicillinase-resistant penicillins vs gram negatives

Answer 17

no activity

Question 18

penicillinase-resistant penicillins vs anaerobes

Answer 18

limited to no activity

Question 19

aminopenicillins

Answer 19

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 (-NH2-R) to the basic penicillin molecule. Examples include ampicillin* and amoxicillin*.

Question 20

aminopenicillins

Answer 20

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 (-NH2-R) to the basic penicillin molecule. Examples include ampicillin* and amoxicillin.
**DRUG OF CHOICE for infections due to Listeria monocytogenes and Enterococcus spp.

Question 21

aminopenicillins vs gram negative

Answer 21

better activity than natural penicillins
SHEP
Haemophilus influenzae (only β-lactamase negative strains ∼ 70%)
Escherichia coli (45 to 50% of strains are resistant)
Proteus mirabilis
Salmonella spp., Shigella spp.

Question 22

aminopenicillins vs anaerobes

Answer 22

activity similar to Pen G

“above the diaphragm” and clostridium spp (except C. diff)

Question 23

carboxypenicillins

Answer 23

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. Examples include carbenicillin and ticarcillin (IV)*.

Question 24

carboxypenicillins vs gram positive

Answer 24

generally weak activity
Less active against Streptococcus spp.
Not active against Enterococcus spp. or Staphylococcus spp.

Question 25

carboxypenicillins vs gram negative

Answer 25

enhanced activity
SHEPMEPP
Haemophilus influenzae (only β-lactamase negative strains)
Escherichia coli (45 to 50% of strains are resistant)
Proteus mirabilis
Salmonella spp., Shigella spp.
Enterobacter spp.
Providencia spp.
Morganella spp.
Pseudomonas aeruginosa**

** NOT active against Klebsiella spp. or Serratia spp **

Question 26

ureidopenicillins

Answer 26

Developed to provide further activity against Gram-negative bacteria. These agents were 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 most broad-spectrum penicillins available without β-lactamase inhibitors. Examples include mezlocillin, azlocillin, and piperacillin**.

Question 27

ureidopenicillins vs gram positives

Answer 27

Good activity against Group and viridans Streptococci
Some activity against Enterococcus spp.
No activity against Staphylococcus spp.

Question 28

ureidopenicillins vs gram negative

Answer 28

improved activity
SHEPMEPP+KS
Display activity against most Enterobacteriaceae
Active against Serratia marcescens and some Klebsiella spp.
Pseudomonas aeruginosa (piperacillin is the most active penicillin) ***

Question 29

ureidopenicillins vs anaerobes

Answer 29

Activity similar to Pen G against Clostridium and Peptostreptococcus
Some activity against Bacteroides fragilis

Question 30

B-lactamase Inhibitor combinations

Answer 30

Combination antibiotics containing a penicillin and a β-lactamase inhibitor. The β-lactamase inhibitor irreversibly binds to the catalytic site of the β-lactamase enzyme, preventing the hydrolytic action on the penicillin. The β-lactamase inhibitors enhance the antibacterial activity of their companion penicillin against bacteria where the resistance is primarily mediated by β-lactamase production.
Amoxicillin / Clavulanic Acid** – PO
Ampicillin / Sulbactam** – IV
Ticarcillin / Clavulanic Acid – IV
Piperacillin / Tazobactam** – IV
These combination agents will retain the same activity of the parent penicillin against non β-lactamase producing organisms, and will have enhanced activity against some β-lactamase producing bacteria***.

Question 31

B-lactamase inhibitor combinations vs gram-positive

Answer 31

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

Question 32

B-lactamase inhibitor combinations vs gram negative

Answer 32

Enhanced activity against some β-lactamase producing strains of E. coli, Proteus spp., Klebsiella spp., H. influenzae, M. catarrhalis, and N. gonorrhoeae.
Not very active against the inducible β-lactamase enzymes produced by Serratia marcescens, P. aeruginosa, indole-positive Proteus spp., Citrobacter spp., and Enterobacter spp. (SPICE bacteria).

Question 33

B-lactamase inhibitor combinations vs anaerobes

Answer 33

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

Question 34

pharmacodynamic principles of penicillins

Answer 34

Penicillins display time-dependent* bactericidal activity - the pharmacodynamic parameter that correlates best with their clinical efficacy is Time above the MIC (T>MIC)**.
Penicillins are bactericidal, but are only bacteriostatic* against Enterococcus spp.
Clinically-useful synergy has been demonstrated:
-Viridans streptococcus - ampicillin or penicillin with gentamicin
-Enterococcus - ampicillin or penicillin with gentamicin or streptomycin (combination often used in the treatment of Enterococcal endocarditis)
-Staphylococcus aureus - nafcillin with gentamicin
-Pseudomonas aeruginosa and other Gram-negative aerobes - piperacillin with gentamicin, tobramycin or amikacin
PAE for Gram-positive bacteria; no significant PAE for Gram-negatives.

Question 35

absorption of penicillins

Answer 35

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 gastro-intestinal tract (see PK charts). Concentrations achieved with oral dosing of penicillins are lower than those achieved with parenteral dosing → oral penicillins should only be used for mild to moderate infections. Food typically delays the rate and/or extent of absorption.
Special Absorption Considerations
-natural penicillins* – Oral pen G is poorly absorbed so that phenoxymethyl penicillin (pen VK) 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 higher bioavailability than ampicillin; food delays ampicillin absorption
-Penicillinase-Resistant Penicillins* – Oral dicloxacillin displays the best bioavailability
-Extended Spectrum Penicillins* – Carbenicillin available orally but with low bioavailability (30-40%) and used only for UTIs

Question 36

penicillins distribution

Answer 36

Penicillins are widely distributed into body tissues and fluids including pleural fluid, synovial fluid, bone, bile, placenta, and pericardial fluid; do NOT penetrate the eye or prostate. Distribution pattern 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, maximal doses of parenteral penicillins are used.
Penicillin binding is variable, ranging from 15% for the aminopenicillins to 97%* for dicloxacillin.

Question 37

penicillin elimination

Answer 37

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 nafcillin and oxacillin, which are eliminated primarily by the liver, and piperacillin which undergoes dual elimination.
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 may require supplemental dosing after a hemodialysis procedure - the exceptions are nafcillin and oxacillin.
ALL penicillins have relatively short elimination half-lives (under 2 hours) and require repeated daily dosing (4 to 6 times daily) or continuous infusion to maintain therapeutic serum concentrations.

Question 38

other pharmacologic considerations

Answer 38

**Sodium Load – Several parenterally-administered penicillins (especially the carboxy- and ureidopenicillins) contain sodium in their parenteral preparations, which must be considered in patients with congestive heart failure or renal dysfunction.
Aqueous Sodium Penicillin G contains 2.0* mEq per 1 million units
Nafcillin* contains 2.9* mEq per gram
Carbenicillin contains 4.7* mEq per gram
Ticarcillin contains 5.2* mEq per gram (also in Timentin®)
Piperacillin contains 1.85* mEq per gram (also in Zosyn®)

Question 39

clinical uses of natural penicillins

Answer 39

Intravenous aqueous penicillin G is used for serious infections in hospitalized patients due to its rapid effect and high serum concentrations. Lower serum concentrations are achieved with oral penicillin VK, so its use is limited to the treatment of mild to moderate infections such as pharyngitis or prophylaxis in some circumstances.
Considered to be a potential drug of choice* for infections due to:
-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)
-Treponema pallidum – syphilis** (IM benzathine pen or IV aqueous pen)
-Clostridium perfringens or tetani
-Actinomycosis
Other Uses:
-Endocarditis prophylaxis in patients with valvular heart disease undergoing dental procedures at high risk for inducing bacteremia
-Prevention of rheumatic fever

Question 40

clinical uses of penicillinase-resistant penicillins

Answer 40

Because of enhanced activity against Staphylococcus 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.

Question 41

clinical uses of aminopenicillins

Answer 41

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 (amoxicillin) and Shigella (ampicillin).

Question 42

clinical uses of carboypenicllins and ureidopenicillins

Answer 42

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 hospital-acquired infections). Piperacillin is the most active penicillin against Pseudomonas aeruginosa.
May be used as empiric therapy in immunocompromised patients.

Question 43

clinical uses of B-lactamse inhibitor combination products

Answer 43

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, infected sacral decubitus ulcers, etc.
-Ampicillin-sulbactam (Unasyn® – IV) is useful for the treatment of mixed aerobic/anaerobic infections (but has limited Gram-negative coverage).
-Piperacillin-tazobactam (Zosyn® – IV) is useful for the treatment of polymicrobial infections* and other infections involving Gram-negative bacteria (including Pseudomonas aeruginosa) such as hospital-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.

Question 44

adverse effects of penicillins

Answer 44

hypersensitivity, neurologic, hematologic, GI, interstitial nephritis

Question 45

hypersensitivity to penicillins

Answer 45

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), hives, urticaria, angioedema, laryngeal edema, 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.
-Penicillin 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.
Cross-allergenicity is observed among natural and semisynthetic penicillins due to their common nucleus → 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 β-lactams.
Other allergic reactions include drug fever, serum sickness, Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis, and exfoliative dermatitis

Question 46

neurologic AEs to penicillins

Answer 46

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*

Question 47

hematologic AEs to penicillins

Answer 47

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 leukopenia, neutropenia or thrombocytopenia. Occurs primarily in patients receiving long-term (over 2 weeks) therapy; reversible upon discontinuation.

Question 48

GI AEs of penicillin

Answer 48

Transient increases in liver enzymes – especially oxacillin, nafcillin, piperacillin, and carbenicillin
Nausea, vomiting
Diarrhea – especially with amoxicillin-clavulanate
Pseudomembranous colitis (Clostridium difficile diarrhea)

Question 49

interstitial nephritis w penicillins*

Answer 49

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 methicillin*, but can occur with nafcillin and other penicillins. May progress to renal failure.
Initial manifestations may be fever, eosinophilia, pyuria, *eosinophiluria, and an abrupt increase in serum creatinine.**

Question 50

other AEs with penicillins

Answer 50

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