Beta-Lactam Antibiotics: mechanism and resistance

• Antibacterial Pharmacology is covered in Phar506.

Objectives

• Learn the mechanisms of action (MOA) of beta-lactam, quinolone, macrolide, and other antimicrobials.
• Compare the spectrum of activities of beta-lactam, quinolone, and macrolides.
• Understand allergic reactions to antimicrobials and the process of desensitization.
• Review adverse side effects, including seizures and QT prolongation, associated with common antimicrobials.

Beta-Lactams

• Discovered over 75 years ago by Flemming in 1929.
• Belongs to the largest antimicrobial class.
• Includes penicillins, cephalosporins, carbapenems, and monobactams.
• Features a fused thiazolidine and beta-lactam ring structure, referred to as "house and garage".
• Includes compounds like penicillin, cephalosporin, imipenem, and clavulanate.
• The family tree includes penicillins (1940-), cephalosporins (1948-), cephamycins (1971-), cephabacins (1985-), clavulanic acid (1976-), carbapenems (1976-), nocardicins (1976-), and monobactams (1981-).

Pharmacology

• Mechanism of Action (MOA): Inhibits cell wall synthesis by binding to Penicillin Binding Proteins (PBPs), inhibiting transpeptidation (cross-linking).
• Generally bactericidal, except for enterococcus and when cells aren't actively growing.
• Has a faster kill rate compared to vancomycin for streptococcus.
• Efficacy is determined by the time above the minimum inhibitory concentration (MIC), which may require continuous infusion.
• Most are renally eliminated, except nafcillin, oxacillin, ceftriaxone, and cefoperazone; watch renal function.
• Most have poor oral absorption.
• Short half-life (t1/2) of less than 2 hours, except ceftriaxone.
• Poor CNS penetration, except ceftriaxone and cefotaxime.

Resistance

• Occurs through 4 general mechanisms:
  • Enzymatic inactivation of the antibiotic.
  • Modification of the target PBP.
  • Impaired penetration into the cell.
  • Efflux pumps.
• Beta-lactamase production is the most common mechanism of resistance; more than 100 types have been identified.
• Some beta-lactamases are specific to penicillin and not cephalosporins.
• Beta-lactamase inhibitors are added to beta-lactam antibiotics to prevent resistance.
• With enzymatic resistance microbes are paired with a beta-lactamase inhibitor.
• Overcomes resistance mediated by beta-lactamase.

Penicillin Classification

• Natural penicillins, such as penicillin G, benzathine, and VK*.
  • Active against staph/strep, but resistance rates.
• Antistaphylococcal penicillins, such as nafcillin, oxacillin, methicillin, dicloxacillin*.
• Aminopenicillins, such as ampicillin* and amoxicillin*.
• Carboxypenicillins, such as ticarcillin.
• Ureidopenicillins, such as piperacillin.
• Beta-lactamase inhibitor combinations, such as Amp/clav*, amp/sulb, ticar/clav, and pip/tazo.
• Those marked with * have oral formulations.

Spectrum of Activity

• Penicillins cover streptococci and T. pallidum.
• Antistaphylococcal penicillins: MSSA and strep.
• Aminopenicillins: strep, enterococcus, Listeria, Salmonella sp., Shigella sp., and "wimpy" GNB.
• Carboxy penicillins: more gram-negative including PSAE, E. coli, Proteus sp., Enterobacter sp., and less gram-positive.
• Ureidopenicillins: enhance GNB (PSAE), Serratia, streptococci, and less gram-positive.
• Beta-lactamase inhibitors: cover beta-lactamase producing strains of E.coli, Proteus sp., MSSA, H.flu, Neisseria, and Bacteroides sp.

Cephalosporins

• Introduced in the 1960s.
• Categorized into "generations," a classification based on spectrum of activity.
• More stable against beta-lactamases, thus having a broader spectrum of activity.
• Not active against most Extended-Spectrum beta-lactamase (ESBL's), enterococci, and Listeria.
• Cephalosporins are not indicated for enterococci, Listeria monocytogenes, and atypical respiratory pathogens (Legionella, Mycoplasma, Chlamydophila spp.).
• General structure consists of an Acyl Side Chain, Beta-Lactam Ring, and Dihydrothiazine Ring.

First Generation Cephalosporins

• Activity is narrow, mostly gram-positive cocci, mostly treats skin infections.
• Active against S. aureus (MSSA), streptococci, E. coli, and Klebsiella.
• Useful for skin and skin-structure infections, surgical prophylaxis, UTIs, and endocarditis.
• Includes cefazolin (Ancef®), cephalexin* (Keflex®), and cefadroxil* (Duricef®).
• Those marked with * have oral formulations.

Second Generation Cephalosporins

• Enhanced gram-negative and anaerobic activity while retaining gram-positve coverage.
• Active against H. influenza (penicillin resistant), M.catarralis, and Neisseria sp., Bacteroides sp. (including B. frag.).
• Used for colorectal, urogenital, and lower/upper respiratory tract infections.
• Includes cefotetan, cefoxitin, cefmetazole, and cefuroxime (Ceftin®*).
• Cefoxitin covers anaerobes below the waist.
• Used for polymicrobial infections such as intra-abdominal and gynecologic infections.
• Those marked with * have oral formulations.

Third Generation Cephalosporins

• Enhanced activity against Gram-negative organisms and less against Gram-positive and anaerobes.
• Variable activity to AMP-C hydrolysis (Serratia, Pseudomonas, Acinetobacter, Citrobacter, Enterobacter – "SPACE bugs").
• Effective against NGPR (now DOC), meningitis (PRP), gram-negative sepsis/UTI/RTI (HAP), and SSTI.
• Only ceftazidime has activity against PSAE (“Tasmanian Devil").
• Ceftriaxone and cefotaxime are used to treat meningitis since they have good CNS penetration.
• Primarily broad-spectrum against gram-negative.
• Ceftazidime (Fortaz®) has more stability against SPACE bugs.
• Third generation cephalosporins include ceftriaxone (Rocephin®), cefdinir (Omnicef®), cefixime (Suprax®), cefotaxime (Claforan®).
• • indicates oral formulation.

Fourth and Fifth Generation Cephalosporins

• Active against both gram-negative and gram-positive bacteria.
• Effective against MSSA, strep, Enterobacteriaceae, Citrobacter, and Enterobacter.
• Not effective against Stenotrophomonas and Burkholderia.
• Provide some stability against ESBL and Amp-C producers.
• Cefepime (Maxipime®) is a fourth-generation cephalosporin.
• Ceftaroline (Teflaro®) is a fifth-generation, similar to cefepime but is effective against MRSA.

Carbapenems

• Called "Bazooka" for having wide coverage.
• Has a broad spectrum - active against MSSA, strep, Enterobacteriaceae, Citrobacter sp., Enterobacter sp., Stenotrophomonas, Burkholderia sp., and ESBL producers.
• Include Imipenem (Primixim®), meropenem (Merrem®), ertapenem (Invanz®) doripenem (Doribax®).
• Imipenem and meropenem have similar spectrums (mero>PSAE, imi>enterococcus).
• Ertapenem covers Psedomonas aeruginosa (PSAE) or enterococcus.
• They are all the "drug of choice" for ESBL's and inducible Amp-C producers.
• Effective against Polymicrobial infections, HAP (not dori/erta), and meningitis (mero).

Monobactams

• Has a broad-spectrum, only active against gram-negative bacteria.
• Has similar gram-negative activity to ceftazidime.
• Reserved for penicillin allergic patients.
• "Garage" only structure.
• Aztreonam (Azactam®) – IV only.

Allergic Reactions - Antimicrobials

• Cross-reactivity % is the percentage likelihood that an allergy to one agent will also mean allergy to another agent.
• Drug surveillance data indicates that 2.2% of cutaneous drug reactions are due to amoxicillin, ampicillin, or Trimethoprim/sulfamethoxazole.
• Maculopapular rash is the most common reaction, occurring days to weeks (delayed) and appearing in minutes to hours (immediate).
• Risk is higher for those with immune dysfunctions.

Allergic Reactions – Beta-Lactams

• Crossreactivity was overestimated due to partial contamination from manufacturing practices.
  • This can overestimate accuracy if the patients reports it as an allergy.
  • Could be to do with impurities in manufacture.
• Cross-reactivity between different beta-Lactams appears to be between 1 and 10%.
• Cross-reactivity appears higher in those individuals w/ more serious reactions. This may cause:
• 10% in those with hives rash.
• 20% in those with Hives.
• 40 to 50% in those with anaphylaxis.
• Aztreonam is missing reactive “house portion", therefore it is reserved for those w/ serious allergy.
• Meropenem is safer than Imipenem.

Antimicrobial Desensitization

• A safe procedure that allows the administration of antibiotics (abx) to patients with severe allergic reactions (e.g., hives, anaphylaxis).
• Utilized for Type I, IgE mediated hypersensitivity.
  • Process converts hyperactive state to tolerant.
• Desensitization can be performed if the reaction is a type I IgE mediated hypersensitivity reaction.
• Abx dose started at 1/10,000 to 1/100,000 of the full dose.
• Abx and infusion concentrations increase over time.
• Slow degranulation produces low or undetectable levels of inflammatory mediators.

Quinolones

• Derivatives of nalidixic acid and cinoxacin.
• Original compounds are fluorinated to improve activity.
• Inhibit Topoisomerase (gram -) and DNA gyrase (gram +).
• All have high PO bioavailability if the patients have a functioning gut.
• Activity covers both gram (-) and gram (+) newer agents.
• Bactericidal against susceptible bugs.
• List of drugs goes of the market:
  • Temafloxacin – gone (G)
  • Grepafloxacin – gone (C)
  • Sparfloxacin – gone (P/C)
  • Trovafloxacin (Trovan®) – gone (H)
  • Lomefloxacin – gone (P)
  • Clinafloxacin – gone (P)
  • Gatilfoxacin is also gone.

Quinolone Spectrum

• All cover Enterobacteriaceae, Neisseria sp., Moraxella sp., and Haemophilus sp..
• Good against Gram Negative bugs.
• MSSA, pneumococci covered by levofloxacin, moxi, gemiflox(S. pneumonia not Cipro)
• Moxi+Gemifloxacin does not cover PEudomonas
• Cipro is only effective against Levofloxacin
• Moxifloxacin – Good anaerobes
• Covers Atypicals
• Cipro does NOT cover strep pneumo

Quinolone Indications

• Used in:
• CAP- Levo, Moxi, Gemi
• Hap/VAP- Levo and cipro
• NO MOXI or GEMI
• Intraabdominal Moxifloxacin only
• STI- Levo and Moxi
• UTI Cipro Levo
• Now Gonorrhea second line
• Mycobacterium

Precautions

• Arthropathy/tendonopathy that is seen only in juvenile subjects
• Increased risk in failure, renal transplant over 50 steroid use
• Achillies tendon is what usually snaps in this Rx.
• It takes 1–2 months rest for healing.
• QT Prolong
• Glucose Homeostasis
• CNS affects you by hearing, HA and Dizzyness.
• Phototoxicity in over 1% of the agents.
• Binds with divalent cations and decreases effectiveness requires doze separation

Macrolides

• Includes erythromycin, clarithromycin, azithromycin and telithromycin.
  • Erythromycin is the initial Rx from this class.
• Most common Rx ends in “-mycin”
  • Erythromycin (initial macrolide)
    • Acid liable
    • GI intolerance
• Narrow Spectrum
• Low doze use as prokenetic agent. - Can be long lasting esp. azithro, Penatrates pulmonary tissue.
• Macrolides (erythromycin/clarithromycin) and moxifloxacin appear at highest risk for arrhythmia.

Macrolides and ketolides Spectrum

• Gram (+)
• Gram (-) No active activity against “gut bugs.” Has excellent atypicals. M.Avium

Macrolides Use Cases

• Use in respiratory infections
• Sinusitis/Cap and pharyngitis.
• Mycobacterium Avuim
• Skin and Skin Structure
• STD's
• Anti inflammatory.

Macrolide Monitoring Parameters

• Drug interactions only with azithro
• GI Intolerannce
• Ototoxicity but usually heard with high doze of erythro
• Monitor for:
• QT prolongation
• Erythro more clatirth more telith and azith,
• Hepatic functions.

QTC Prolongation

Seen with macrolides, quinolones, azole Most information comes from after market surveillance Difficult to define a QTC Change is there. Many cases are due to multiple RX 65% due to the Female Sex, 53% with heart Disease. Zelter due to noncardiac reports. Macrolides are 77% of a market share. Concurrent RX and old age can all cause issues.

Seizures

RX can cause these due ti GABA

• The Rx attack the GABA Symptoms Proconvulsant cause for Seizures
• PCN
• Cephalosporin’s
• Carbapenems
• Quinlones Side effects Kidney cause because the kidney are removing the RX. Those under the age of 7 months do have a greater time

Risks of Seizures

Those over 60s. History of CNS disorder. Cardiopulmonary. To reduce the chances

• Lower the dose, space the RX
• Add Benzo’s to reduce the issues
• Remember risk factors with your patient and adjust RX

Newer Gram RX’s

• New - Vancomycin - Azolid. Also know as “Vitimin L)
• These are for those with MRSA VRE VISA and GISO -Dalbivanchin- Once a weak RX for MRSA
• The newer Gram - (Negative) are used with “turn back time.” - Cefepime or Avibactam

Review of Rx’s

• PCN rx and why
• Those that are used for specific types of ailments.
• Always Check kidney functions. – Renal is extremely important - Cross reactivity

Explore the mechanism of action of beta-lactam antibiotics, their effectiveness, and bacterial resistance. Learn about the role of beta-lactamase inhibitors and factors influencing bacterial sensitivity. Includes discussion of safe alternatives for patients with penicillin allergies.