cell wall inhibitors

Question 1

what is the cell wall composed of?

Answer 1

peptidoglycan that
consists of glycan units joined to each other by peptide cross-links.

Question 2

✓ To be maximally effective, inhibitors of cell wall synthesis require
actively proliferating microorganisms. They have little or no effect on
bacteria that are not growing and dividing.

Question 3

what does the nature of the side chain determine in beta lactams

Answer 3

✓ 1. the antimicrobial spectrum,
✓ 2.stability to stomach acid,
✓ 3. cross hypersensitivity, and
✓ 4. susceptibility to bacterial degradative enzymes (β-lactamases).

Question 4

what is the MOA for penicillins

Answer 4

✓ Penicillins interfere with the last step of bacterial cell wall synthesis, which is the
cross-linking of adjacent peptidoglycan strands by a process known as
transpeptidation.
✓ Since penicillins structurally resemble the terminal portion of the peptidoglycan
strand, they compete for and bind to enzymes called penicillin-binding proteins
(PBPs), which catalyze transpeptidase and facilitate cross-linking of the cell wall

✓ The result is the formation of a weakened cell wall and ultimately cell death.
✓ Cell lysis can then occur, either through osmotic pressure or through the
activation of autolysins.
✓ These drugs are bactericidal and work in a time-dependent fashion.
✓ Penicillins are only effective against rapidly growing organisms that synthesize a
peptidoglycan cell wall.
✓ Consequently, they are inactive against organisms devoid of this structure, such
as mycobacteria, protozoa, fungi, and viruses.

Question 5

What is the effect of penicillin on PBPS

Answer 5

Penicillins inactivate numerous proteins on the bacterial cell
membrane. These penicillin-binding proteins (PBPs) are bacterial
enzymes involved in the synthesis of the cell wall and in the
maintenance of the morphologic features of the bacterium.
✓ Exposure to these antibiotics can therefore not only prevent cell wall
synthesis but also lead to morphologic changes or lysis of susceptible
bacteria.
✓ The number of PBPs varies with the type of organism.
✓ Alterations in some of these PBPs provide the organism with resistance
to the penicillins.
✓ [Note: Methicillin resistant Staphylococcus aureus (MRSA) arose
because of such an alteration.]

Question 6

what is the effect of penicillins on PBPs

Answer 6

Some PBPs catalyze formation of the cross-linkages between peptidoglycan
chains (Figure 29.3).
Penicillins inhibit this transpeptidase -catalyzed reaction, thus hindering the
formation of cross-links essential for cell wall integrity.

Question 7

what’s the effect of penicillins on autolysins

Answer 7

Many bacteria, particularly the g+ve cocci, produce degradative enzymes
(autolysins) that participate in the normal re-modeling of the bacterial cell
wall.
✓ In the presence of a penicillin, the degradative action of the autolysins
proceeds in the absence of cell wall synthesis.
✓ Thus, the antibacterial effect of a penicillin is the result of both inhibition of
cell wall synthesis and destruction of the existing cell wall by autolysins

Question 8

what is natural penicillin

Answer 8

Natural penicillins (penicillin G and penicillin V) are obtained from
fermentations of the fungus P. chrysogenum. ( acid labile)
Penicillin G (benzyl-penicillin) has activity against a variety of g+ve and g-ve
cocci, g+ve bacilli, and spirochetes (against gram + S. pneuomniae and P.pneuomniae, gram - neisseria and used in syphilis ).

✓ Most streptococci are very sensitive to penicillin G, but penicillin-resistant viridans
streptococci and Streptococcus pneumoniae isolates are emerging
✓ The vast majority of Staphylococcus aureus are now penicillinase producing and
therefore resistant to penicillin G
✓ Penicillins are susceptible to inactivation by β-lactamases (penicillinases) that
are produced by the resistant bacteria.
✓ Penicillin remains the drug of choice for the treatment of gas gangrene and
syphilis.

✓ Penicillin V has a similar spectrum to that of penicillin G, but it is not used for
treatment of severe infections (e.g. bacteremia) because of its poor oral
absorption.
✓ Available only in oral formulation and is more acid stable than penicillin G

Question 9

what are antistaphylococcal penicillins

Answer 9

✓ Methicillin, nafcillin, oxacillin, and dicloxacillin are β-lactamase (penicillinase)-
resistant penicillins.
✓ Because of its toxicity (interstitial nephritis),methicillin is not used clinically in the United
States except in laboratory tests to identify resistant strains of Staphylococcus aureus.
✓ Their use is restricted to the treatment of infections caused by penicillinase-
producing staphylococci, including methicillin sensitive Staphylococcus aureus
(MSSA).
✓ MRSA( methicillin resistant staphylococcus aureus) is currently a source of serious
community and nosocomial infections and is resistant to most commercially
available β-lactam antibiotics.
✓ The penicillinase-resistant penicillins have minimal to no activity against g-ve
infections.

Question 10

what are extended spectrum penicillins

Answer 10

Ampicillin and amoxicillin have an antibacterial spectrum similar to that
of penicillin G but are more effective against g-ve bacilli (more effective against gram + Enterococci and listeria and a wider gram - like E.coli,H. influanzae and S.typhi).
✓ These extended-spectrum agents are also widely used in the treatment
of respiratory infections, and amoxicillin is employed prophylactically by
dentists in high-risk patients for the prevention of bacterial
endocarditis.
✓ Resistance to these antibiotics is now a major clinical problem because
of inactivation by plasmid-mediated penicillinases.
✓ Formulation with a β-lactamase inhibitor, such as clavulanic acid or
sulbactam, protects amoxicillin or ampicillin, respectively, from
enzymatic hydrolysis and extends their antimicrobial spectra.
✓ For example, without the β-lactamase inhibitor, MSSA is resistant to
ampicillin and amoxicillin.

Question 11

what are antioseudomonal penicillins

Answer 11

piperacillin is called antipseudomonal penicillins because
of their activity against Pseudomonas aeruginosa .
✓ These agents are available in parenteral formulations ONLY.
✓ Piperacillin is the most potent of these antibiotics.
✓ They are effective against many g-ve bacilli, but not against Klebsiella
because of its constitutive penicillinase.
✓ Formulation of piperacillin and tazobactam,
extends the antimicrobial spectrum of these antibiotics to include
penicillinase-producing organisms (for example, most Enterobacteriaceae
and Bacteroides species).

Question 12

what are the MOA of resistance against penicillins

Answer 12

1. β-Lactamase activity:
   ✓ This family of enzymes hydrolyzes the cyclic amide bond of the β-lactam
   ring, which results in loss of bactericidal activity (Figure 29.2).
   ✓ They are the major cause of resistance to the penicillins and are an
   increasing problem.
2. Decreased permeability to the drug:
   ✓ Decreased penetration of the antibiotic through the outer cell membrane
   of the bacteria prevents the drug from reaching the target PBPs.
   ✓ Mainly in gram negative bacteria:
   ✓ (cell wall& porins?) p.aeruginosa
   ✓ Presence of an efflux pump: k.pneumonia
3. Altered PBPs:
   ✓ Modified PBPs have a lower affinity for β-lactam antibiotics. This explains
   MRSA resistance to most commercially available β-lactams.

Question 13

what are the PK of penicillins

Answer 13

1. Administration:
   ✓ The route of administration of a β-lactam antibiotic is determined by
   the stability of the drug to gastric acid and by the severity of the
   infection.
   a. Routes of administration:
   ✓ The combination of ampicillin with sulbactam, ticarcillin with clavulanic
   acid, and piperacillin with tazobactam, and the antistaphylococcal
   penicillins nafcillin and oxacillin must be administered IV or IM.
   ✓ PenicillinV, amoxicillin , and dicloxacillin are available ONLY as oral
   preparations. Figure 29.6
   ✓ Others are effective by the oral, IV, or IM routes (Figure 38.6).
   b. Depot forms:
   ✓ Procaine penicillin G and benzathine penicillin G are administered IM
   and serve as depot forms
2. Absorption:
   ✓ Most of the penicillins are incompletely absorbed after oral
   administration.
   ✓ Food ↓ the absorption of all the penicillinase-resistant penicillins
   because as gastric emptying time ↑, the drugs are destroyed by
   stomach acid→they should be taken on an empty stomach.
3. Distribution:
   ✓ The β-lactam antibiotics distribute well throughout the body. All the
   penicillins cross the placental barrier, but none have been shown to
   have teratogenic effects.
   ✓ Penetration into bone or cerebrospinal fluid (CSF) is insufficient for
   therapy unless these sites are inflamed (Figures 29.7 and 29.8).
   ✓ Penicillin levels in the prostate are insufficient to be effective against
   infections.
4. Metabolism:
   ✓ Host metabolism of the β-lactam antibiotics is usually insignificant, but
   some metabolism of penicillin G may occur in patients with impaired
   renal function.
5. Excretion:
   ✓ The primary route of excretion is through the organic acid (tubular)
   secretory system of the kidney as well as by glomerular filtration.
   ✓ Patients with impaired renal function must have dosage regimens
   adjusted.
   ✓ Nafcillin and oxacillin are exceptions to the rule. They are primarily
   metabolized in the liver and do not require dose adjustment for renal
   insufficiency.
   ✓ Probenecid ↓the secretion of penicillins by competing for active tubular
   secretion via the organic acid transporter→↑blood levels.
   ✓ The penicillins are also excreted in breast milk.

Question 14

what are the side effects of penicillins

Answer 14

1. Hypersensitivity:
   ✓ Approximately 5-10 %percent of patients have some kind of reaction,
   ranging from rashes to angioedema?? and anaphylaxis??.
   ✓ Cross-allergic reactions occur among the β-lactam antibiotics.
2. Diarrhea:
   ✓ Diarrhea is a common problem that is caused by a disruption of the
   normal balance of intestinal microorganisms.
   ✓ Occurs to a greater extent with those agents that are incompletely
   absorbed and have an extended antibacterial spectrum??
3. Nephritis:
   ✓ Penicillins, particularly methicillin, have the potential to cause acute
   interstitial nephritis.
   ✓ Methicillin is no longer used clinically.
4. Neurotoxicity:
   ✓ The penicillins are irritating to neuronal tissue, and they can provoke
   seizures :
   ✓ if injected intrathecally or if very high blood levels are reached.
   ✓ Epileptic patients are particularly at risk due to the ability of penicillins
   to cause GABAergic inhibition. Assignment
5. Hematologic toxicities:
   ✓ Decreased coagulation may be observed with high doses of piperacillin,
   ticarcillin, and nafcillin (and, to some extent, with penicillin G).
   ✓ Cytopenias have been associated with therapy of greater than 2 weeks,
   and therefore, blood counts should be monitored weekly for such
   patients.

Question 15

what are the spectrums for the cephalosporins

Answer 15

1. First generation:
   ✓ The first-generation cephalosporins act as penicillin G substitutes.
   ✓ Proteus mirabilis, E. coli, and K. pneumonia (modest activity)
2. Second generation:
   ✓ The second-generation cephalosporins display greater activity against
   additional g-ve organisms(Proteus mirabilis, E. coli, K. pneumonia, H.
   influenzae and Moraxella ctarrhalis)
   ✓ whereas activity against g+ve organisms is weaker
   ✓ Antimicrobial coverage of the cephamycins (cefotetan and cefoxitin) also
   includes anaerobes. ( Bacteroid.fragilis)
   ✓ They are the only cephalosporins commercially available with appreciable
   activity against g-ve anaerobic bacteria.
   ✓ However, neither drug is first line because of the increasing prevalence of
   resistance to both agents.
3. Third generation: important role in the treatment of infectious diseases
   ✓ The third-generation cephalosporins have enhanced activity against g-ve
   bacilli, as well as most other enteric organisms.
   ✓(Proteus mirabilis, E. coli, and K. pneumoniae H. influenzae, Enterobacter
   aerogenes, and some Neisseria gonorrhea, And Serratia)
   ✓ Ceftriaxone & cefotaxime have become agents of choice in the treatment of
   meningitis.
   ✓ Ceftazidime has activity against P. aeruginosa; resistance is ↑ & use should be
   evaluated on a case-by-case basis.
   ✓ Third-generation cephalosporins must be used with caution, why?
   ✓ as they are associated with significant “collateral damage,” essentially
   meaning the induction and spread of antimicrobial resistance & development
   Pseudomembranous colitis??
   ✓ [Note: Fluoroquinolone use is also associated with collateral damage.]
4. Fourth generation:
   ✓ Cefepime is administered parenterally.
   ✓ Cefepime has a wide antibacterial spectrum:
   ✓ G+ve cocci ( only MSSA)
   ✓ also effective against aerobic g-ve organisms and Pseudomonas
   aeruginosa,
5. Advanced generation:
   ✓ Ceftaroline is a broad spectrum, that is administered IV as a prodrug,
   ceftaroline fosamil.
   ✓ It is the only commercially available β-lactam in the US with activity
   against MRSA and is indicated for the treatment of complicated skin
   and skin structure infections and community-acquired pneumonia.

✓ The unique structure allows ceftaroline to bind to PBP2a found with
MRSA and PBP2x found with penicillin-resistant Streptococcus
pneumoniae.
✓ In addition to its broad g+ve activity, it also has similar g-ve activity to the
third-generation cephalosporin ceftriaxone.
✓ Important gaps in coverage include:
✓ P. aeruginosa, extended-spectrum β-lactamase (ESBL)-producing
Enterobacteriaceae, and Acinetobacter baumannii
✓ The twice-daily dosing regimen also limits use outside of an institutional
setting.

Question 16

cephaolo has the same resistance as penicellins

Question 17

what are the PK of cephalosporins

Answer 17

1. Administration:
   ✓ Many of the cephalosporins must be administered IV or IM (Figure
   29.11) because of their poor oral absorption.
   ✓ Exceptions are noted in Figure 29.13.
   Page 37
2. Distribution:
   ✓ All cephalosporins distribute very well into body fluids.
   ✓ Adequate therapeutic levels in the CSF, regardless of inflammation, are
   achieved with only a few cephalosporins.
   ✓ For example, ceftriaxone and cefotaxime are effective in the treatment
   of neonatal and childhood meningitis caused by H. influenzae.
   ✓ Cefazolin is commonly used as a single prophylaxis dose prior to surgery
   because of its 1.8-hour half-life and its activity against penicillinase-
   producing S. aureus.
   ✓ Cefazolin is effective for most surgical procedures, including orthopedic
   surgery because of its ability to penetrate bone.
   ✓ All cephalosporins cross the placenta.
3. Elimination:
   ✓ Cephalosporins are eliminated through tubular secretion and/or
   glomerular filtration (Figure 2.11).
   ✓ Therefore, doses must be adjusted in cases of renal dysfunction to
   guard against accumulation and toxicity.
   ✓ One exception is ceftriaxone, which is excreted through the bile into the
   feces and, therefore, is frequently employed in patients with renal
   insufficiency.

Question 18

what are the side effects of cephalo

Answer 18

✓ Like the penicillins, the cephalosporins are generally well tolerated.
✓ However, allergic reactions are a concern.
✓ Patients who have had an anaphylactic response, Stevens-Johnson
syndrome, or toxic epidermal necrolysis to penicillins should not receive
cephalosporins.
✓ Cephalosporins should be avoided or used with caution in individuals
with penicillin allergy.
✓ Current data suggest that the cross-reactivity between penicillin and
cephalosporins is around 3% to 5% and is determined by the similarity
in the side chain, not the β-lactam structure.
✓ The highest rate of allergic cross-sensitivity is between penicillin and
first-generation cephalosporins.

Question 19

what are carbapenems

Answer 19

Carbapenems are synthetic β-lactam antibiotics that differ in structure from
the penicillins in that the sulfur atom of the thiazolidine ring (Figure 38.2)
has been externalized and replaced by a carbon atom (Figure 38.13).
✓ Imipenem, meropenem, doripenem, and ertapenem are the drugs of this
group currently available.
✓ Imipenem is compounded with cilastatin to protect it from metabolism by
renal dehydropeptidase.

1. Antibacterial spectrum
   Imipenem resists hydrolysis by most β-lactamases,
   This drug plays a role in empiric therapy because it is active against β-
   lactamase–producing gram-positive and gram-negative organisms, anaerobes,
   and P. aeruginosa
   Meropenem and doripenem have antibacterial activity similar to that of
   imipenem.
2. Pharmacokinetics
   Imipenem, meropenem, and doripenem are administered IV and penetrate well into
   body tissues and fluids, including CSF

Question 20

what are monobactams

Answer 20

✓ The monobactams, which also disrupt bacterial cell wall synthesis, are
unique because the β-lactam ring is not fused to another ring (Figure
38.13).
✓ Aztreonam, which is the only commercially available monobactam,
✓ has antimicrobial activity directed primarily against g-ve pathogens,
including the Enterobacteriaceae and P. aeruginosa.
✓ It lacks activity against g+ve organisms and anaerobes.
✓ Aztreonam is resistant to the action of most β-lactamases, with the
exception of the ESBLs.
✓ It is administered either IV or IM and can accumulate in patients with
renal failure.
✓ Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash and,
occasionally, abnormal liver function tests.
✓ This drug has a low immunogenic potential, and it shows little cross-
reactivity with antibodies induced by other β-lactams.
✓ Thus, this drug may offer a safe alternative for treating patients who are
allergic to other penicillins, cephalosporins, or carbapenems.

Question 21

what are b-lactamase inhibitors

Answer 21

✓ Hydrolysis of the β-lactam ring, either by enzymatic cleavage with a β-
lactamase or by acid, destroys the antimicrobial activity of a β-lactam
antibiotic.
✓ β-Lactamase inhibitors, such as clavulanic acid, sulbactam, and
tazobactam, contain a β-lactam ring but, by themselves, do not have
significant antibacterial activity or cause any significant adverse effects.
✓ Instead, they bind to and inactivate β-lactamases, thereby protecting
the antibiotics that are normally substrates for these enzymes.
✓ The β-lactamase inhibitors are therefore formulated in combination
with β-lactamase–sensitive antibiotics.

Question 22

VI. Vancomycin
VII. Daptomycin
VIII. Telavancin
All are glycopeptides,
inhibit cell wall synthesis
Active against gram positive bacteria

Answer 22

they are all conc dependant bactericidal

vancomycin is used against C.difficile(oral), infused iv with 6-10hr half life through renal. has a side effect with releasing histamine while being infused. used against MRSA

dapto and TELA are a VRE

Question 23

what are fosfomycin and polymyxins?

Answer 23

IX. Fosfomycin:
a bactericidal synthetic derivative of phosphonic acid.
It blocks cell wall synthesis by inhibiting a key step in peptidoglycan
synthesis.
Used for UTI caused by E.coli or E. faecalis
X. Polymyxins
The polymyxins are cation polypeptides that bind to phospholipids on the bacterial
cell membrane of gram-negative bacteria.
They have a detergent-like effect that disrupts cell membrane integrity, leading to
leakage of cellular components and cell death
The use of these drugs has been limited due to the increased risk of nephrotoxicity
and neurotoxicity