Harrold 2 The Beta-Lactam Antibiotics

The base structure of all penicillins that is termed “penicillin” is known as _____

6-amino-penicillanic acid (6-APA)

6-amino-penicillanic acid (6-APA) comes from hydrolysis of _____

Penicillin G

6-amino-penicillanic acid (6-APA) is derived from which two amino acids?

L-Cys and L-Val

Acidity of penicillins

All are acidic

Some are amphoteric depending on the R group

The solubility and physiochemical properties of a penicillin depends on _____

The R group and the salt (inorganic vs. organic) that is used

Penicillins marketed as Na⁺ or K⁺ salts are known as _____

Inorganic salts

Advantages of inorganic salts of penicillins

Increased H₂O solubility

Increased dissolution

• Increased oral absorption

• Allows for a concentrated solution of a drug

  • IV, Ophthalmic

The R group of a penicillin determines its _____

Acid stability and oral absorption

Beta-lactamase resistance

Spectrum of activity

What are the two naturally occurring penicillins that are currently used in practice?

Penicillin G and Penicillin V

Route of administration for penicillin G

IV only

• Has been used PO in the past, but is no longer used due to poor oral bioavailability

Penicillin G exhibits poor oral bioavailability due to _____?

Acid lability

What does it mean if a penicillin is acid labile?

In an environment such as the stomach, the lone pair of electrons on the amide carbonyl attacks the beta-lactam ring, inactivating the penicillin

ALL penicillins have a _____ half-life due to _____

Short; Rapid tubular secretion

If a penicillin has a half life of less than one hour, why can it be dosed TID?

Irreversible inhibition of transpeptidase, so drug is working but not detected

Two mechanisms to increase the duration of penicillins

1. Form an organic salt with either procaine or benzathine

2. Administer the penicillin with probenecid

How does using an organic salt with procaine or benzathine increase the duration of penicillins?

These are organic bases that have decreased H₂O solubility

They are administered as an IM injection and create an IM depot

• Has a prolonged release from the injection site due to slower dissolution

Procaine and benzathine have a dual role when used in salts with penicillins because _____

They are local anesthetics which decrease pain at the injection site

Penicillin G Procaine has a drug interaction with _____ due to _____

Sulfonamides; release of PABA (para-amino benzoic acid), which directly competes with the sulfonamides and decreases their action (hydrolysis)

How does administering a penicillin with probenecid increase its duration of action?

Probenecid blocks the Organic Anion Transporters 1 and 3, which blocks the tubular secretion of organic acids

• Beneficial drug interaction

• Non-selective blockade → blocks secretion of penicillins and cephalosporins

Why is the use of penicillin G limited?

Poor oral absorption/acid labile

Susceptibility to beta-lactamase

Narrow spectrum of antibiotic action

How can the acid stability of a penicillin be increased?

Adding an electron withdrawing group at the alpha carbon

• Decreases availability of the lone pair of electrons to attack the beta-lactam ring

• Ex. Penicillin V

Increasing the acid stability of a penicillin improves its _____

Oral absorption

What structural changes make a penicillin beta-lactamase resistant?

Add steric hindrance around the beta-lactam ring by:

• Direct attachment of the carbonyl to the aromatic ring (no alpha carbon)

• Ortho substituents on the aromatic ring

• Ex. Methicillin

Is methicillin acid stable (with better bioavailability than penicillin G)?

No

• It has methoxy groups that are electron donating and make the lone pair of electrons more available

Why are oxacillin and dicloxacillin acid stable and orally active?

They have an isoxazole ring, which is an electron-withdrawing heterocycle

Why is nafcillin only used IM or IV?

It has poor oral activity due to its ring system having both electron donating and electron withdrawing properties

What structural modification allows for extended spectrum penicillins?

Hydrophilic R group

• Gram negative bacteria contain water soluble channels (such as porins), so increased hydrophilicity increases the ability of the antibiotic to penetrate into gram negative bacteria

Aminopenicillins have an NH₂ at the alpha carbon, which is _____

Ionized to NH₃⁺ in the stomach

• Electron withdrawing group

  • Orally active

Ampicillin is a zwitterion, so it experiences _____

Dissolution problems and low bioavailability

• Occurs with some but NOT ALL zwitterions

Why is excessive diarrhea associated with oral ampicillin?

A significant amount of the drug does not dissolve until it reaches the large intestine, so it disrupts normal GI flora and causes diarrhea

Compared to the structure of ampicillin, amoxicillin has a _____

para-hydroxyl group that is more H₂O soluble

• Increases dissolution and oral absorption

Carboxypenicillins such as _____ have a carboxylic acid at the alpha carbon

Carbenicillin and ticarcillin

How do carboxypenicillins compare to aminopenicillins?

The alpha-COOH group increases water solubility and provides an extended spectrum compared to ampicillin and amoxicillin

Similar to ampicillin and amoxicillin, these drugs are susceptible to beta-lactamase

Unlike ampicillin and amoxicillin, they are not orally active

Why are carboxypenicillins not orally active?

Acid catalyzed decarboxylation in the stomach

What is the only commercially available ureidopenicillin?

Piperacillin

How does the structure of piperacillin differ from that of ampicillin?

The basic alpha NH₂ is replaced with a substituted urea

• No longer basic → not ionized → not electron withdrawing → not orally active

Characteristics of piperacillin

Extended spectrum

• Active against Pseudomonas and Klebsiella

Not orally active

Susceptible to beta-lactamase

Most common adverse drug reaction associated with penicllins

Hypersensitivity reactions

Types of penicillin allergies

Immediate (Occurring within 1 hour or less)

• Antibody mediated

Accelerated (Occurring within 1-72 hours)

• Antibody mediated

Delayed (Occurring after more than 72 hours)

• NOT antibody related

• Cross-sensitivity with cephalosporins is very low

The basic nucleus of cephalosporins is known as _____

7-aminocephalosporanic acid (7-ACA)

7-aminocephalosporanic acid (7-ACA) comes from hydrolysis of _____

Cephalosporin C

General characteristics of cephalosporins

All are acidic, some may be amphoteric based on their side chains

Undergo rapid tubular secretion like penicillins

• In comparison, have longer duration of action and can be dosed less frequently than penicillins

Mechanism of action, reactivity of the beta-lactam ring to acidic and basic hydrolysis, and formation of an antigenic protein are all identical to penicillins

Like penicillins, main side effect is hypersensitivity reactions

Unlike penicillins, cephalosporins have _____ sites of structural variability

Two

The R₁ group of cephalosporins determines _____

Beta-lactamase resistance

The R₂ group of cephalosporins determines _____

Metabolism and pharmacokinetic parameters

The spectrum of action of all cephalosporins is _____

Broader than penicillin G

Oral activity of cephalosporins depends on what three factors?

1. Stability of the beta-lactam ring to acid hydrolysis

2. Acid stability of the R₂ group

3. Overall lipid solubility

What structural feature imparts stability to the beta-lactam ring of a cephalosporin?

If R₁ contains an electron withdrawing group or an alpha amino group

Adding a para-hydroxyl group to a cephalosporin with an alpha amino group at R₁ (such as cephalexin) provides _____

Increased oral absorption

• Ex. Cefadroxil

What effect does an acetoxymethyl group at R₂ have on a cephalosporin?

Causes the cephalosporin to be orally inactive, even if it has an alpha amino group

• The group hydrolyzes and cyclizes in an acidic environment

• Ex. Cephaloglycin

What happens to a cephalosporin with a 3-acetoxymethyl group at physiological pH?

Undergoes hydrolysis to its active hydroxyl metabolite, but lactonization/cyclization does NOT occur

How can a cephalosporin with a 3-acetoxymethyl group be modified to produce an acid stable structure?

Isosteric modification of the 3-acetoxymethyl group to a 3-carbamate (-CH₃ → -NH₂)

What modifications can make a cephalosporin beta-lactamase resistant?

Addition of structural features that provide steric hindrance to prevent beta-lactamase from binding

• 7-OCH₃ group (Ex. Cefoxitin)

• Alkoxyimino group (C=N-OR) at the R₁ position (Ex. Cefotaxime)

The thiazole ring is a common R₁ group found in many _____ cephalosporins

Third generation

Some beta-lactamase resistant cephalosporins may be used with beta-lactamase inhibitors for _____

Resistant organisms that have not responded to other therapy

If a cephalosporin contains a quaternary nitrogen, it is _____

Not orally active

Enhanced lipid solubility of cephalosporins via lipid soluble prodrugs allows for _____

Oral absorption

• These prodrugs are known as tripartite prodrugs (Drug-Linker-Carrier)

Lipid soluble prodrugs of cephalosporins are not used for IV administration because _____

You want increased H₂O solubility

• Ex. Cefuroxime axetil → oral

•        Cefuroxime → parenteral

Orally active third generation cephalosporins contain _____

An acid stable, lipid soluble vinyl group and/or a second carboxylic acid that is NOT directly attached to the alpha carbon

• If the carboxylic acid is attached directly to the alpha carbon → acid catalyzed decarboxylation

Also contain an alkyoxyimino group (or analog) at the R₁ position that provides beta-lactamase resistance

Requirements for a cephalosporin to be orally active

R₂ group must be acid stable (cannot be an acetoxymethyl group)

Cannot contain a quaternary nitrogen group

Must contain at least ONE of the following:

• Alpha amino group

• Lipid soluble ester prodrug

• Vinyl group at the R₂ position

• Carboxylic acid present as part of the R₁ substituent (not directly attached to the alpha carbon)

Indications of ceftaroline fosamil

Treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) caused by susceptible organisms

Ceftaroline fosamil is the first cephalosporin to be active against _____

Resistant gram positive pathogens including:

• Methicillin resistant S. aureus (MRSA)

• Vancomycin resistant S. aureus (VRSA)

• Vancomycin insensitive S. aureus (VISA)

• Hetero-resistant vancomycin insensitive S. aureus (hVISA)

Notable structural features of cetaroline fosamil

Phosphorylated prodrug to enhance water solubility

Quaternary nitrogen → not orally absorbed

Indications of cefiderocol

Treatment of patients 18 years or older with limited or no alternative treatment options for complicated urinary tract infections (cUTI), including pyelonephritis caused by susceptible gram negative microorganisms

Key structural features of cefiderocol

Alkoxyimino group → beta-lactamase resistant

Quaternary ammonium group → not orally active

Catechol ring → acts as a siderophore

• Transports iron into bacterial cells

• Provides entry into bacteria and overcomes efflux pumps

• “Trojan horse”

Common adverse effects associated with cephalosporins

Hypersensitivity reactions

Diarrhea

Pseudomembranous colitis

• Occurs with cephalosporins and other broad/extended spectrum antibiotics

• Alteration of normal flora of the colon permits overgrowth of Clostridia species

• A toxin produced by C. difficile is the primary cause of antibiotic-associated colitis

Potential for nephrotoxicity with some

Adverse effects traced to a functional group

• Ex. Methyl-tetrazole-thiomethyl (MTT)

Adverse effects traced to a Methyl-tetrazole-thiomethyl (MTT) group on a cephalosporin

Intolerance to alcohol (disulfuram-like reaction)

Serious bleeding related to hypoprothrombinemia 

Ex. Cefotetan

• These reactions are also seen with cefazolin, which has a similar ring system

Common drug interactions with penicillins and cephalosporins

Probenecid → increases duration and plasma concentrations

Warfarin → may increase INR → increases risk for bleeding

• Occurs with many antibiotics

May decrease efficacy of oral contraceptives

• Occurs with all antibiotics

Characteristics of carbapenems (or thienamycin)

Not orally active

Broad spectrum

• Ertapenem has a narrower spectrum of activity than the others (no activity against Pseudomonas aeruginosa or Acinetobacter)

Mechanism of carbapenems

Inhibits transpeptidase

Very stable to most, but not all, beta-lactamases

• Imipenem and meropenem have combination products with beta-lactamase inhibitors

Imipenem is metabolized in the kidneys by the enzyme _____ and must be used in combination with _____

Dehydropeptidase I; cilastatin sodium

Mechanism of cilastatin

NOT an antibiotic

Inhibits dehydropeptidase I, preventing the renal metabolism of imipenem

Also blocks the tubular secretion of imipenem → decreases possible renal toxicity and causes slow elimination → increased duration and decreased concentration in the kidney

Why is cilastatin not required for carbapenems other than imipenem?

Addition of a methyl group provides steric hindrance to dehydropeptidase I

Common adverse effects associated with carbapenems

Injection site reactions

Seizures

• Imipenem is the most eleptogenic

Role of probencid in combination with sulopenem etzadroxil

Prevents tubular secretion and increases duration of action

Chemically, beta-lactamase inhibitors are _____

Beta-lactams that possess weak antibacterial activity

The clinical utility of beta-lactamase inhibitors comes from _____

Irreversible inhibition of beta-lactamase → allows them to prevent the destruction of beta-lactamase susceptible antibiotics

How does clavulanic acid act as a beta-lactamase inhibitor?

Hydrolyzed by beta-lactamase → forms an acyl-enzyme complex

• This complex is normally quickly hydrolyzed when the substrate is a penicillin

• Clavulanic acid is a poor substrate, so the intermediate lingers and eventually causes irreversible inhibition

Beta-lactamase inhibitors are also known as _____ due to their ability to undergo enzymatic transformation to a reactive covalent intermediate

“Suicide-substrate” inhibitors

• Enzyme catalyzes its own irreversible inhibition

Role of durlobactam in combination with sulbactam

Protects sulbactam from degradation by certain serine-beta-lactamases

• Sulbactam has bactericidal activity against Acinetobacter baumannii-calcoaceticus complex (ABC) penicillin binding proteins PBP1 and PBP3

• No antibacterial activity against ABC isolates when used alone

Unlike clavulanic acid, sulbactam, and tazobactam, durlobactam and avibactam are _____

Bicyclic ring systems NOT beta-lactams

How does avibactam cause pseudo-irreversible inhibition of beta-lactamase?

Forms a carbamate

• No rearrangements

• Slowly hydrolyzed