Quiz 2: Medicinal Chemistry (Duerfeldt)

What antibiotic classes are included in the β-lactam family?

penicillins, cephalosporins, carbapenems, and monobactams

MOA of β-lactam antibiotics?

bind PBPs → inhibit peptidoglycan cross-linking → incomplete cell wall → cell death

What structural feature is shared by all cephalosporins despite their different side chains?

β-lactam ring fused to a six-membered ring

General activity trend as cephalosporins progress through generations?

gram-negative activity generally increases, sometimes at the expense of gram-positive activity

Primary role of the R1 substituent at C7 in cephalosporins?

determines spectrum of activity and β-lactamase resistance

Primary role of the R2 substituent at C3 in cephalosporins?

modifies PK, including stability, solubility, metabolism, and excretion

How does the six-membered ring affect cephalosporin stability compared with penicillins?

makes the β-lactam less reactive and more acid-stable

Key characteristics of cefazolin and cephalexin?

Cefazolin: IM/IV

Cephalexin: oral, ~90% bioavailability, same side chain as ampicillin

Are cefazolin and cephalexin destroyed by general penicillinases?

No

How are first-generation cephalosporins generally eliminated?

renally with minimal metabolism; adjust doses in renal impairment

How do cephalexin and cefazolin differ in oral bioavailability and half-life?

cephalexin is ~90% orally bioavailable; cefazolin is IV/IM and has a slightly longer t½ (~1.9 h vs ~1 h)

Why is cefuroxime axetil orally bioavailable while cefuroxime is not?

axetil is a prodrug that masks the charged carboxylate, improving absorption

How does the oxime group of cefuroxime affect β-lactamase resistance?

Z-oxime sterically blocks β-lactamase cleavage

What structural feature gives cefotetan and cefoxitin greater β-lactamase resistance and anaerobic coverage?

C7 methoxy group; they are cephamycins

Disposition characteristics of second-generation cephalosporins?

primarily renal elimination with minimal metabolism; renal dose adjustment is needed

What is important about the disposition of cefuroxime axetil?

it has ~37-52% oral bioavailability; the active cefuroxime itself is not orally bioavailable

Why can cefotetan cause a disulfiram-like reaction with alcohol?

its side chain produces a metabolite that inhibits aldehyde dehydrogenase, causing acetaldehyde accumulation

Coagulation-related adverse effect associated with cefotetan?

hypoprothrombinemia

Important characteristics of cefdinir?

oral, ~20-25% bioavailability, can cause diarrhea, and chelates iron, reducing absorption

What is unique about ceftriaxone?

strong N. gonorrhoeae activity, ~8-h t½, IV/IM, and substantial biliary excretion

What is unique about ceftazidime?

strongest 3rd-gen activity against Pseudomonas aeruginosa but poor gram-positive activity

How are most third-generation cephalosporins eliminated?

primarily renally with minimal metabolism

How does ceftriaxone differ from most other cephalosporins in disposition?

partly metabolized/biliary eliminated and has an unusually long ~8-hour half-life

GI adverse effects associated with third-generation cephalosporins?

nausea, vomiting, diarrhea, and risk of C. difficile infection

Important adverse effect associated with ceftriaxone?

biliary sludge from calcium precipitation, especially in children

What causes the red stool associated with cefdinir?

chelation/complex formation with iron

Cephalosporins SOA

1st: mainly gram-positive;

2nd: more gram-negative, with cephamycins adding anaerobes

3rd: broader gram-negative, with ceftazidime covering Pseudomonas

Why do cefotetan and cefoxitin have anaerobic activity?

C7 methoxy group protects against anaerobic β-lactamases

Characteristics of cefepime?

4th gen, IV/IM with activity against Enterobacterales and A. baumannii

What is unique about cefiderocol?

4th gen, covers MDR gram-negative bacilli and is highly stable to ESBLs, AmpC, and carbapenemases

Important organisms covered by fourth-generation cefepime and cefiderocol?

broad gram-negatives including P. aeruginosa; cefiderocol also targets difficult MDR gram-negatives such as A. baumannii

Specific clinical uses for cefepime?

severe nosocomial infections, febrile neutropenia, nosocomial pneumonia

Specific clinical uses for cefiderocol?

complicated UTIs from MDR/carbapenem-resistant gram-negatives

What makes ceftaroline unique among the cephalosporins?

the only β-lactam active against MRSA

What are the approved uses and route of ceftaroline?

IV for complicated skin/soft-tissue infections and community-acquired pneumonia

Major mechanism of bacterial resistance to β-lactam antibiotics?

β-lactamases, which hydrolyze/open the β-lactam ring and inactivate the antibiotic

Why are β-lactamases especially effective in gram-negative bacteria?

they are concentrated in the periplasmic space; can destroy β-lactams before they reach PBPs

Why are β-lactamases generally less effective in gram-positive bacteria?

secreted outside the cell and usually diffuse away, lowering their concentration; abscess-forming bacteria are an exception

How is the initial acylation step similar for PBPs and serine β-lactamases?

activated Ser-OH attacks the β-lactam, opening the ring and forming a covalent acyl-enzyme complex

Key difference that allows β-lactamases to destroy β-lactams instead of remaining inhibited like PBPs?

β-lactamases deacylate/hydrolyze the covalent complex; release inactive drug regenerating the enzyme

TEM-1

prototypical class A serine β-lactamase

What catalytic residues are important in TEM-1 β-lactamase activity?

Ser70, Lys73, and Glu166; serine acts as the major nucleophile

What antibiotics can TEM-type β-lactamases cleave?

all penicillins and 1st-generation cephalosporins

Which β-lactamase classes are serine-mediated versus metallo-mediated?

A, C, D = serine β-lactamases

B = Zn-dependent metallo-β-lactamases

Two major strategies for overcoming β-lactamase resistance?

1. Modify the β-lactam so it is not a good β-lactamase substrate (ex. dicloxacillin)

2. Combine the antibiotic with a β-lactamase inhibitor (BLI)

What is clavulanate?

potent β-lactamase inhibitor; no antibacterial activity because it does not effectively bind PBPs

What happens when clavulanate is combined with a β-lactam such as amoxicillin?

inhibits β-lactamases and restores/potentiates amoxicillin activity

How does clavulanate inhibit serine β-lactamases?

active-site serine attacks clavulanate, forms covalent intermediate that can rearrange into a stable enzyme-inhibitor complex

Why are first-generation BLIs like clavulanate generally poor antibiotics themselves?

they lack the important side chain needed for strong PBP binding

Which β-lactamases does clavulanate inhibit best?

primarily class A, including TEM-1 and many ESBLs; activity against other classes is limited, especially class B

How does adding clavulanate change amoxicillin's spectrum?

restores activity against many β-lactamase-producing gram-negatives and adds useful anaerobic coverage

ex. H. influenzae, M. catarrhalis, some Enterobacterales, anaerobes

Why is matched PK important for amoxicillin and clavulanate?

they must remain present together so clavulanate can protect amoxicillin from β-lactamases

Major PK characteristics of amoxicillin/clavulanate?

short ~1-hour half-lives and substantial renal elimination; clavulanate is potent, so a much smaller dose is needed

First-generation β-lactam/BLI combinations

amoxicillin + clavulanate (Augmentin), ampicillin + sulbactam (Unasyn), and piperacillin + tazobactam (Zosyn)

What is unique about sulbactam compared with most β-lactamase inhibitors?

sulbactam itself has antibacterial activity against A. baumannii, although it is susceptible to β-lactamase degradation

Major limitation of first-generation BLIs?

incomplete coverage of classes A, C, and D and do not cover class B

Mmajor second-generation DBO β-lactamase inhibitors?

avibactam, relebactam, and durlobactam

Advantages of DBO BLIs over first-generation BLIs?

broader inhibition of serine β-lactamases, including ESBLs and some carbapenemases, and they do not induce β-lactamase production

What β-lactams are paired with the major DBO BLIs?

Avibactam + ceftazidime = Avycaz

Relebactam + imipenem/cilastatin = Recarbrio

Durlobactam + sulbactam = Xacduro

What is particularly important about durlobactam + sulbactam (Xacduro)?

specifically used for MDR/XDR A. baumannii

Which classes are well covered by DBO β-lactamase inhibitors?

classes A, C, and D, the serine-mediated β-lactamases

How do DBOs inhibit serine β-lactamases?

they form a covalent carbamate adduct with the active-site serine

Major mechanistic advantage DBOs have over clavulanate?

inhibition is reversible; the intact DBO can reform and inhibit another enzyme instead of being consumed

Structural features important for DBO β-lactamase inhibitors?

DBO ring is essential, a negative charge is required, and substituent changes modify β-lactamase inhibition and PK

General physicochemical properties of marketed DBOs?

very polar, which strongly affects their PK and contributes to poor oral absorption

What important activity does avibactam add to ceftazidime?

estores strong activity against ESBL-producing Enterobacterales

Important uses of ceftazidime/avibactam (Avycaz)?

complicated intra-abdominal/urinary infections, hospital/ventilator-associated pneumonia, and resistant gram-negative infections

Key spectrum and clinical use of durlobactam/sulbactam (Xacduro)?

A. baumannii coverage; used for hospital- or ventilator-associated bacterial pneumonia caused by susceptible A. baumannii-calcoaceticus complex

BLI Combinations SOA

coverage generally broadens, especially against resistant gram-negative organisms

BLI combinations that provide activity against P. aeruginosa?

iperacillin/tazobactam, ceftolozane/tazobactam, and ceftazidime/avibactam

Major drug-disposition characteristics of DBO β-lactamase inhibitors?

not orally bioavailable, minimal metabolism, primarily renal elimination, so renal impairment requires dose adjustment

How do DBO half-lives compare with first-generation BLIs?

avibactam (~2.7 h) and durlobactam (~2.5 h) have longer half-lives than first-generation BLIs such as tazobactam (~1 h)

How do carbapenems kill bacteria?

inactivate PBPs, especially PBP1/PBP2, disrupting peptidoglycan cross-linking

Why do carbapenems kill more rapidly than penicillins or cephalosporins?

they inhibit PBPs more broadly

Why are carbapenems resistant to many β-lactamases?

hydroxyethyl group displaces the water needed for β-lactam hydrolysis

What is DHP-1 and where is it found?

zinc-dependent renal dehydropeptidase on the proximal tubule brush border

Why is DHP-1 problematic for imipenem?

hydrolyzes imipenem, causing rapid drug clearance

How is imipenem protected from DHP-1 metabolism?

co-administer cilastatin, a DHP-1 inhibitor

How do meropenem and ertapenem avoid DHP-1 metabolism?

1β-methyl group blocks DHP-1 binding/metabolism

What structural feature improves Gram-negative activity of meropenem and ertapenem?

pyrrolidine side chain that improves penetration and reduces efflux

What is unique about tebipenem pivoxil?

orally bioavailable carbapenem prodrug; its capped carboxylate improves absorption

How do imipenem, meropenem, and ertapenem differ in spectrum?

Imipenem: best Gram+ activity

Meropenem/Ertapenem: better Gram− activity

What is important about meropenem?

good Pseudomonas aeruginosa activity

What is important about ertapenem?

poor Pseudomonas/A. baumannii activity, high protein binding, and useful once-daily dosing

How are the commonly used carbapenems administered?

IV, IM

Why can ertapenem's narrower spectrum be beneficial?

better antimicrobial stewardship by avoiding unnecessary pressure on Pseudomonas/A. baumannii

What are important specific carbapenem uses?

ESBL Enterobacterales: all carbapenems

Ertapenem: outpatient parenteral therapy

Meropenem: Burkholderia cepacia

How are carbapenems generally eliminated?

primarily renal, with minimal metabolism; dose-adjust in renal impairment

Why does ertapenem have a longer half-life?

very high plasma protein binding (~95%)

Main adverse effects of carbapenems?

GI upset, rare hypersensitivity, hematologic effects, and seizures

When is seizure risk greatest with carbapenems?

with high drug levels, especially in renal impairment; imipenem has the highest risk

Major carbapenemases causing carbapenem resistance?

KPC most common; also NDM and OXA-48

What is the most common source of carbapenem-resistant Enterobacterales (CRE) isolates?

urine (>90%)

How susceptible are CRE to most older β-lactams?

very poorly susceptible, generally only a few percent

β-lactam/BLI combination with high CRE activity?

ceftazidime-avibactam (~97.5%).

What is vaborbactam?

boronate β-lactamase inhibitor paired with meropenem

Which β-lactamases does vaborbactam inhibit?

ESBLs and KPC carbapenemases, not metallo-β-lactamases

Other advantage does vaborbactam have?

does not induce β-lactamases such as AmpC

Vaborbactam MOA?

forms a reversible covalent adduct with the active-site serine and mimics the tetrahedral intermediate to inhibit serine β-lactamase

Key activity gained by adding vaborbactam to meropenem?

restored activity against KPC-producing CRE