Antimicrobials: Cell Wall Synthesis Inhibitors: All but penicillins

Question 1

Moving on to the next class of cell wall synthesis inhibitors are the cephalosporins. All cephalosporins are considered inactive against what bacteria?

Answer 1

Enterococci
Listeria 
Legionella 
Chlamydia 
Mycoplasma 
Acinetobacter

Question 2

Cephalosporins are divided into generations. There are five generations. Starting with first generation cephalosporins are Cefazolin and Cephalexin, what are some features of these drugs?

Answer 2

Cefazolin (IV)
Cephalexin (oral)
–both active against gram + cocci (including staph and strep) (many strains of E.coli, P. mirabilis, and Klebsiella are sensitive)
Good penicillin G substitutes
Used for tx of infections due to sensitive bacteria
Rarely the drug of choice for any infections but oral drugs may be used for tx of UTIs or staph/strep skin infections

Question 3

The major use of cefazolin (1st generation) is for what?

Answer 3

Surgical Prophylaxis (due to the long half life)

Question 4

Moving on to the second generation cephalosporins. They include Cefaclor, Cefoxitin, Cefotetan and Cefamandole. What are some features?

Answer 4

Less active against gram + cocci but more active against gram - bacilli.
Clinical use: sinus, ear, and resp infections caused by H. influenzae and M. catarrhalis (cefamandole and cefaclor) and infections caused by the anaerobe bacteroides fragilis (Cefotetan and Cefoxitin)
Combo activity against aerobic and facultative gram negative bacilli plus bacteroides has led to the use of these drugs (cefotetan and cefoxitin) in the prophylaxis and therapy of infections in the abdominal and pelvic cavities.

Question 5

The third generation cephalosporins are next. They include cefoperazone, cefotaxime, ceftazidime, ceftriaxone and cefixime. What are some features of these drugs?

Answer 5

Increased activity against gram - organisms
Resistant to other beta lactam drugs
Ability to penetrate the BBB
Active against: Enterobacteriacae (e.coli and p.mirabilis), neisseria and H.influenzae.
Less active against most gram + organisms than the first generation drugs and are inactive against enterococci, listeria, MRSA and Acinetobacter

Question 6

Ceftriaxone is the drug of choice for the therapy of what?

Answer 6

Penicillin-resistant gonorrhea and meningitis due to ampicillin-resistant H. influenzae in children
Tx of lyme disease involving CNS, joints
Prophylaxis of meningitis in exposed individuals (including prego women)

Question 7

Cefoperazone and Ceftazidime have activity against what?

Answer 7

P. aeruginosa

Question 8

Drugs in third generation are usually reserved for what?

Answer 8

Tx of serious infections resistant to other drugs
Exceptions: tx of gonorrhea and in acute otitis media when a single injection of ceftriaxone is effective as a 10 day course of amoxicillin

Question 9

Next are the fourth generation cephalosporins. Include: Cefepime. What are some features?

Answer 9

IV only
More resistant to beta lactamases produced by gram negative organisms including enterobacter, haemophilis, neisseria and some penicillin resistant pneumococci
Combines the activity of first generation agents with the wider gram negative spectrum of third generation drugs

Question 10

Finally is the fifth generation cephalosporin: Ceftaroline. What are some features?

Answer 10

IV only
Binds to PBP2a (a penicillin binding protein encoded by methicillin resistant S. Aureus)
Inactive against P. aeruginosa, acinetobacter and B. fragilis
Useful in skin and soft tissue infections due to MRSA, particularly if gram - organisms are coinfecting
Tx of community acquired pneumonia when first line agents are not successful

Question 11

Moving on to the pharmacokinetics, what is the administration of cephalosporins?

Answer 11

Most administered IV due to poor oral absorption

oral includes: cephalexin, cefaclor, and cefixime

Question 12

What is the distribution of cephalosporins?

Answer 12

Most 1st and 2nd generation drugs do not enter the CSF even when the meninges are inflamed
Ceftriaxone is well distributed and crosses the BBB easily.

Question 13

What is the excretion of cephalosporins?

Answer 13

Major route is renal

Cefoperazone and Ceftriaxone: bile (so you can give to a person in renal failure)

Question 14

Moving on to adverse effects of cephalosporins, what is hypersensitivity?

Answer 14

Complete cross hypersensitivity between different cephalosporins should be assumed
–however if a patient has a mild penicillin allergy a cephalosporin should still be given

Question 15

What are some other adverse effects of cephalosporins?

Answer 15

Pain at IM injection site
Drugs containing a methylthiotetrazole group may cause hypoprothrombinemia and disulfiram-like reactions
Ceftriaxone should not be used in pregnancy as it can cross the BBB and displaces bilirubin from binding sites leading to kernicterus

Question 16

The next group of cell wall synthesis inhibitors are the Carbapenems (IV). what are some features of these drugs?

Answer 16

Imipenem and Meropenem
–low susceptibility to beta lactamases
Very broad spectrum of activity against Gram + cocci, Gram - rods, aerobes and anaerobes
Affective against pseudomonas

Question 17

What infections are carbapenems used for?

Answer 17

Infections caused by organisms resistant to other antibiotics.
–not effective against MRSA
To reduce the risk of resistance their use is usually restricted to these types of multi-drug resistant infections

Question 18

Carbapenems are the drug of choice for what?

Answer 18

For enterobacter infections and extended spectrum beta lactamase producing gram -
Used for surgical infection prophylaxis
Current Concern: resistant to the carbapenems by producing carbapenemases (ex. carbapenem-resistant enterobacteriaceae and carbapenem-resistant klebsiella)

Question 19

What are the pharmacokinetics and adverse effects for Imipenem?

Answer 19

Pharmacokinetics:
–rapidly inactivated by renal dehydropeptidase I to form a potentially nephrotoxic metabolite
–it is always administered in a fixed combo with cilastatin (an inhibitor enzyme)
–cilastatin increases the plasma half life of imipenem and inhibits formation of this metabolite
Adverse Effects:
–GI distress and at very high levels it can cause CNS toxicity

Question 20

What are the pharmacokinetics and adverse effects for Meropenem?

Answer 20

Pharmacokinetics:
–not metabolized by renal dehydropeptidases and does not have to be given with cilastatin
Adverse effects:
—is similar to imipenem apart from that it is less likely to cause seizures
Note the carbapenems have partial cross allergenicity with penicillins

Question 21

Moving on to the next set of cell wall synthesis inhibitors are the Monobactams. What are some features?

Answer 21

Aztreonam
–monocyclic beta lactam ring
Limited activity to aerobic gram - rods (pseudomonas)
Do not have activity against gram + bacteria or anaerobes
Resistant to the action of most beta lactamases

Question 22

What is the main use of Aztreonam (monobactam)?

Answer 22

Tx of UTIs, LRTs, septicemia, skin/structure infections, intra-abdominal infections and gynecological infections caused by susceptible gram negative bacilli

Question 23

What are the pharmacokinetics for Aztreonam?

Answer 23

Administered either IM or iV and penetrates well into the CSF when inflamed
–can also be given by inhalation to improve resp symptoms in cystic fibrosis with P. aeruginosa
Eliminated via renal tubular secretion thus its half life is prolonged in renal failure

Question 24

What are the adverse effects for Aztreonam?

Answer 24

Non-toxic and penicillin-allergic patients tolerate it without reaction
–occasional skin rashes and elevation of serum aminotransferases, along with thrombophlebitis and pain at the injection

Question 25

Next in the cell wall synthesis drugs is Vancomycin, what is the MOA and resistance?

Answer 25

Inhibits cell wall synthesis (At :d-ALA-d-ALA)
–inhibits the transglycosylase, preventing further elongation of peptidoglycan and cross linking
–both peptidoglycan and polymerization and cell wall synthesis are inhibited so lysis of cell
Resistance:
Enterococci resistance due to modification of the d-ALA-d-ALA binding site
–ALA is replaced by D-lactate resulting in vancomycin being unable to bind to its target.

Question 26

What is the spectrum of activity and clinical applications of vancomycin?

Answer 26

Bactericidial: against Gram positive bacteria only
Needs to be given with aminoglycosides against enterococcus faecium and enterococcus faecalis strains that do not inhibit high levels of aminoglycogside resistance.
—this combo is first line choice for the treatment of enterococcal endocarditis

Question 27

What are the main uses of Vancomycin?

Answer 27

Tx of serious infections caused by beta lactam resistant gram + organisms
Tx of infections caused by gram + organisms in individuals who have serious allergies to beta lactam agents

Question 28

Vancomycin can be administered orally for the treatment of what?

Answer 28

Staphylococcal Enterocolitis

Antibiotic Associated pseudomembranous colitis

Question 29

How is vancomycin administered?

Answer 29

Poorly absorbed from the GI tract so give IV
IV infusions must be given slowly (60-90min) to reduce infusion related adverse effects
–adequate penetration to the CSF only occurs when the meninges are inflamed
Drug excreted via kidneys so be careful in renal insufficiency this drug will accumulate

Question 30

What are the adverse effects of vancomycin?

Answer 30

Minor
-most common phlebitis at site of injection with fever and chills
Red man or red neck syndrome: infusion related flushing of the face and upper torso caused by release of histamine (prevented by prolonging infusion time)
Ototoxicity and nephrotoxicity are rare: occurs when vancomycin is allowed to accumulate
If given with aminoglycoside the risk for ototoxic or nephrotoxic effects increases.

Question 31

Moving on to the next cell wall synthesis inhibitor, Daptomycin. What is the MOA and resistance?

Answer 31

MOA:

• -developed to meet the need for drugs active against resistant organisms.
• -bind to the cell wall membrane of sensitive bacteria via calcium dependent insertion of its lipid tail —-depolarization of the cell wall membrane with potassium efflux and rapid cell death

Question 32

What is the spectrum of activity of Daptomycin?

Answer 32

It is active against vancomycin-resistant strains of enterococci and S. aureus
Inactive against gram - bacteria
Pulmonary surfactant antagonizes daptomycin and it should not be used for pneumonia

Question 33

What is Daptomycin used for?

Answer 33

Tx of complicated skin and skin structure infections caused by susceptible aerobic gram + organisms, S. aureus bacteremia, including right sided native valve infective endocarditis caused by MSSA or MRSA
Tx: severe infections caused by MRSA or VRE

Question 34

What are the pharmacokinetics and adverse effects for daptomycin?

Answer 34

Pharmacokinetics:
—IV and can accumulate in patients with renal insufficiency
AE:
—constipation, myopathy and creatine phosphokinase levels should be monitored

Question 35

The next cell wall synthesis bacteria is bacitracin, what are some feature?

Answer 35

Peptide abx: gram + microorganisms
Inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall
–no cross resistance between bacitracin and other drugs
Very nephrotoxic when given systemically so only used for topical tx of mixed bacterial infections of the skin, wounds or mucus membranes

Question 36

The last cell wall inhibitor is Fosfomycin what are some features?

Answer 36

Active against gram + and gram - organisms
Inhibits cytoplasmic enzyme enolpyruvate transferase (important in early stages of cell wall synthesis)
Given orally
Tx: of uncomplicated lower UTIs