number 29

Done by Nadia S. Sweis

Corrected by Jaleel G. Sweis

Doctor Malik

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Lecture 29

Fifth Generation of Cephalosporins

- They are considered new drugs that differ from all previous generations

of cephalosporins.

- The two most important examples on 5th generation cephalosporins are

ceftaroline and ceftobiprole. Only ceftaroline will be discussed in this

lecture.

Ceftaroline

- Ceftaroline was FDA approved in 2012 and was newly introduced to the

Jordanian market.

- This drug takes us away from the general atmosphere of cephalosporins,

introduces us to what was never mentioned in a drug before, and leads

us to vancomycin.

- Cephalosporins of the 1st, 2nd, 3rd, and 4th generations are generally

active against Gram-positive and Gram-negative bacteria.

But certain bacteria of great importance were not mentioned when

these generations were discussed, such as the methicillin-resistant

Staphylococcus aureus (MRSA), and enterococci.

- As mentioned before, the 5th generation drugs of cephalosporins are

completely different than those of preceding generations; for their

activity extends to include what was excluded in previous generations:

MRSA and enterococci.

- Their activity on Gram-negative bacteria, however, is not really great.

They do cover Gram-negative bacteria, but generally speaking, the

problem of extended-spectrum beta-lactamases (ESBLs) serves to act

against them.

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- Indication of such a drug is quite complicated since it hasn’t been truly

tested on patients. So, the indication and clinical uses of a drug like

ceftaroline haven’t been clearly specified.

- Its usage, in fact, is restricted. This drug is kept “hidden”; since there are

drugs that act against MRSA and enterococci already. Ceftaroline,

therefore, is only indicated in cases of resistance to vancomycin, for

example, which will be discussed later.

- Example: if a patient who has MRSA is prescribed vancomycin or

teicoplanin, and shows no response, we’d use a 5th generation

cephalosporin (ceftaroline). Otherwise, its usage is prohibited since it’s a

new drug and should be kept ‘alive’.

Slide 61:

•Active against, g +vecocci especially MRSA (BINDS TO & INHIBITS ‘PBP-

2A’* (type produced by MRSA)

•penicillin resistant S. pneumoniae

•and enterococci

•Gram negative???? ESBL

*PBP-2A: Penicillin Binding Protein 2A

- So the spectrum of these drugs is quite wide, but there’s a big question

mark over their usage for Gram-negativity. Therefore, when using 5th

generation cephalosporins, we keep to using them for cases of

enterococci (recall that all other generations of cephalosporins are NOT

active against enterococci)

- Example: In cases of enterococci, we usually use ampicillin; the drug of

choice in endocarditis. If the patient has bacterial resistance to

ampicillin, we’d use vancomycin - to be explained later. If the patient

also has bacteria with vancomycin resistance; VRE (vancomycin-resistant

enterococci), we’d then use ceftaroline.

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- So they are mostly active against Gram-positives, specifically MRSA, and

enterococci, in addition to penicillin-resistant Streptococcus pneumonia.

- In conclusion, 5th generation cephalosporins are remarkably unique in

their spectrum of activity, and are quite the opposite of all previous

generations in terms of activity against MRSA and enterococci.

- The second drug of the 5th generation has a similar spectrum of activity

as the first, with the exception of it having more activity over Gram-

negatives.

- The only problem concerning these drugs lies in the fact that we need a

real clinical use when it comes to Pseudomonas and Enterobacter. Keep

in mind that these drugs are not actually in use yet.

Cephalosporins Adverse Effects

- Once again, we’re talking about drugs that don’t bind to receptors in

humans; they bind to receptors in bacteria (cell wall inhibitors).

Consequently, they are generally free from side-effects, other than the

diarrhea that has also occurred in the case of penicillins.

- Hypersensitivity may exist, and according to Lippincott, and many other

text books:

Hypersensitivity patient who has an anaphylactic response to penicillin

should avoid cephalosporins (Slide 63)

- The previous statement, however, is false. The percentage of people

who have cephalosporin allergy does not exceed 1% of the population as

a whole. But doctors, and medical workers in general, assume that

allergy to penicillin is always accompanied by cephalosporin allergy,

which is far from true.

In fact, 10% of the population is allergic to penicillins, and 10% of those

allergic to penicillins are also allergic to cephalosporins (1% of the

population).

Therefore, we shouldn’t jump to conclusions as the text books have.

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- Based on the above, the only criterion by which we decide whether the

patient is allergic or not is a skin test. Skin tests for cephalosporins are

available these days, but generally speaking, hypersensitivity to

cephalosporins occurs much less than that to penicillins.

- Some cephalosporins are more common to cause hypersensitivity than

others, which is a dilemma we’ll not get into.

And some types of cephalosporins, which are no longer in the market,

used to cause allergy slightly more commonly (up to 3 or 4% of the

population are affected).

- Of all previous drugs we studied, cefotetan, unlike the rest, can cause a

bizarre side effect.

(Have in mind that of 2nd gen cephalosporins, we use cefoxitin more than

cefotetan for treatment of Bacteroides, especially in Jordan).

The aforementioned side effect occurs with SOME compounds of

cephalosporins; not all of them, which are:

•N-methyl-thiotetrazole-containing cephalosporins

•cefamandole, cefotetan, cefditoren, cefoperazone, and only

(Slide 63)

- Recall that cefoperazone is a substitute for ceftazidime

- Cefotetan is most important of all since it’s still in use.

- These drugs induce a phenomenon called the disulfiram-like effect.

- Disulfiram is a medication used for treatment of alcohol addiction

(On a side note: alcohol addiction is the hardest to get over, since

drinking is associated with social events. 10% of Americans are alcohol

addicts).

- Disulfiram is an inhibitor for aldehyde dehydrogenase. Alcohol turns to

an aldehyde during its metabolism, and the aldehyde is metabolized by

aldehyde dehydrogenase and excreted from the body. Inhibition of

aldehyde dehydrogenase raises the concentration of aldehyde in the

body. Aldehyde then enters the CNS and causes feelings of nausea and

vomiting, and an overall aversion to alcohol.

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- Cefamandole, cefotetan, cefditoren, cefoperazone have a structure that

enables them to bind to aldehyde dehydrogenase as well.

1) A disulfiram-like effect: happened when some cephalosporins is

indigested with alcohol, because of the blockade to the alcohol

metabolism, which result in accumulation of acetaldehyde.

(Slide 63)

USMLE sample question: a patient who drinks has an intra-abdominal

infection and is prescribed cefotetan. After drinking, a disulfiram-like

effect occurred. Why?

- These same 4 drugs also bind to VKOR.

Vitamin K is highly associated with coagulation. Coagulation factors are

normally inactive in our bodies. Their activation occurs through the

action of the enzyme VKOR; Vitamin K epoxide reductase, which turns

the pre-coagulation factors to coagulation factors.

- Just as these 4 drugs bind to aldehyde dehydrogenase, they also have a

pocket for binding to VKOR, and can cause bleeding.

2) Bleeding: some cephalosporins have an anti vitamin K effect, and may

cause bleeding (hypoprothrombinemia) (Slide 63)

- Since activation of coagulation factors in the body depends on the action

of the enzyme VKOR, their binding to VKOR prevents the inactive form

from turning to the active form that causes coagulation. Prevention of

coagulation causes bleeding.

- You should know cefotetan most importantly (and cefoperazone if you

like).

- Other than ceftriaxone’s effect on neonates, which was discussed in

previous lectures, it can also bind with calcium. As a result, ceftriaxone

should not be given with calcium products in the same intravenous line

during injection, since the product of calcium would bind to ceftriaxone

causing its inactivation, and precipitation of the drug in the body might

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occur. So, they shouldn’t be given together. It is also indicated in a black

box on the syringe of ceftriaxone that it is not to be given with a solution

containing calcium, and should be given 1 or 2 hours before or after; not

at the same time. Otherwise, they must be given in 2 different lines; one

in each arm.

•Ceftriaxone and calcium product, FDA warning.

(Slide 64)

- When it comes to metabolism and excretion of drugs, elimination

through kidneys is completely different than the elimination through

bile.

*Bile = feces

*Kidney = urine

- The site of elimination is of great significance, especially in the case of

kidney-compromised patients who are given drugs excreted through

kidneys. In which case, adjustment of the dose is necessary, since the

glomerular filtration rate is usually lower in those who are kidney-

compromised (such as in cases of kidney failure).

- Sometimes, the drug is avoided altogether in the case of kidney failure,

since its toxicity would increase a lot. Prescribing drugs metabolized in

the liver and elimination through bile is then necessary, such as:

Cefoperazone and ceftriaxone are exceptions because they are excreted

predominantly in the bile.

(Slide 64)

… while all others are excreted through kidneys.

- You don’t have to memorize the previous 2 examples. They’re just to

give you an idea of the importance of the route of excretion of the drug

(bile or urine) and the importance of knowing the contents of the drug’s

leaflet.

- The patient may also have problems in the bile duct. In this case, the

drug prescribed must be excreted through the kidneys.

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- Of the cell wall inhibitors, 3 types of drugs are left to be discussed;

carbapenems, monopenems, and vancomycin. We will link them to

what has already been discussed.

Carbapenems

- Carbapenems are considered very important drugs.

Doripenem, ertapenem, imipenem, and meropenem are licensed for use

in the USA.

(Slide 65)

- They are widely available in Jordan.

Imipenem has a wide spectrum with good activity against many Gram-

negative rods, including P aeruginosa, gram-positive organisms, and

anaerobes.

(Slide 65)

- The above paragraph is very important. In most exams, you’ll probably

be asked the following question: which of the following is the widest

spectrum antibiotic?

Imipenem is the widest. It is even wider than cefamax. It is very similar

to cefamax, but its activity on anaerobes is better than that of cefamax.

- During a certain period of time – and up until now - it was believed that

the widest spectrum is always the best. Therefore, a drug called

imipenem was released in 1996. And due to that notion, it gained

tremendous popularity. It goes by the commercial name: Tienam “ الذي ال

”ينام

- It “doesn’t sleep” due to the fact that medical workers, doctors,

pharmacists, and nurses just love this drug. You don’t need a spectrum

(Knowing whether an infection is caused by Gram + or Gram–) and you

don’t need any microbiology whatsoever.

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- As soon as a patient with an infection enters the hospital in Jordan, they

are given tienam, and that is absolutely wrong, as you’ll see.

It does cover everything (except for MRSA). It covers Gram+ and Gram-

and anaerobes, even. So, tienam is prescribed along with vancomycin

(common clinical use in the Arab world), and that is making us lose

tienam. Due to the excessive use of tienam, bacteria developed an

enzyme called carbapenemase.

- So far, bacteria have developed penicillinase, extended-spectrum beta-

lactamases (in other words, cephalosporinase) and carbapenemase.

- First bacteria to do so is called Klebsiella pneumoniae.

- In Jordan, patients with pneumonia, especially if hospital-acquired,

Klebsiella should be considered, and we are obliged to see if it’s

carbapenemase-producing Klebsiella pneumonia, which is a horrible

type.

- Carbapenemase has a very wide spectrum activity of resistance to many

antibiotics.

- As a result, we are definitely losing imipenem. Consequently, patients

with Klebsiella pneumonia producing carbapenemase (imipenem

resistance), are prescribed meropenem, which is still active against

Klebsiella pneumonia producing carbapenemase. (Percentage of these

patients does not exceed 1% though).

- Contrary to what the name implies,carbapenemase does not really

inactivate meropenem. It’s only active against imipenem and

ertapenem.

In other words, Klebsiella pneumonia producing carbapenemase is still

sensitive to meropenem.

- The previous indication discussed above was wrong. However, the

proper indication for tienam is mixed infections; meaning the presence

of pus.

- Secretion of pus is very common in lungs due to infection and infiltration

(which are accompanied by the presence of pus inside the lungs).

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- The presence of pus inside the lungs usually indicates an anaerobic

infection. As long as pus is present and bacteria are residing inside that

pus in the lungs, the most likely type of bacteria is anaerobes. But since

Gram+ and Gram- bacteria are also possibilities, and the cause is not

definite, such as in the previously described case of mixed infection with

pus, tienam should be prescribed.

- So, tienam is indicated in what’s called a “mixed infection”.

A carbapenem is indicated for infections caused by susceptible organisms

that are resistant to other available drugs, eg, P aeruginosa, and for

treatment of mixed aerobic and anaerobic infections.

(Slide 66)

- That is the only proper usage of tienam, because there are other

narrower spectrum drugs out there that cover the causes to be treated.

- For example, why prescribe tienam if we have piperacillin and

tazobactam (tazocin)? Or ceftazidime? These are antipseudomonal drugs

that cover all Gram-negatives.

To cover Gram-positives, vancomycin should be prescribed in all cases.

So why run to tienam if there are narrower spectrum drugs that treat

your problem? Excessive use of tienam is making us lose it.

It is also the treatment of choice for infections caused by extended-

spectrum beta-lactamases–producing gram-negatives.

Example:

A carbapenem is the beta-lactam antibiotic of choice for treatment of

enterobacterinfections because it is resistant to destruction by the

lactamase produced by these organisms.

(Slide 66)

- Normally, imipenem is sold under the name of: (tienam/cilastatin)

- Cilastatin isn’t a beta-lactamase inhibitor. It’s basically a

dehydropeptidase inhibitor.

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- A dehydropeptidase is an enzyme present in the kidneys, and it

metabolizes imipenem, causing its rapid inactivation and excretion

outside of the body, making the half-life of imipenem very short.

- One of the solutions used to lengthen the drug’s half-life and make it

more active is the inhibition of dehydropeptidase by giving cilastatin.

This is an example of a potentiation effect (not synergistic, and not

additive either).

- Cilastatin is only given with imipenem, since only imipenem is affected

by the dehydropeptidases. Meropenem, ertapenem and doripenem are

given alone.

Imipenem is inactivated by dehydropeptidases in renal tubules, so

administered together with an inhibitor of renal dehydropeptidase,

cilastatin, for clinical use.

(Slide 65).

- Of all carbapenems, you should know imipenem aka tienam. The 2 drugs

that you’ll hear about the most are rocephin (ceftriaxone; drug of choice

in gonorrhea and meningitis) and tienam.

Side Effects

- Since tienam is a very wide-spectrum drug, diarrhea and an infection by

Clostridium difficileare very likely to occur.

- However, tienam can penetrate the CNS and enter the vomiting center.

Therefore, it is the antibiotic that causes the MOST vomiting and nausea.

- Since it enters the CNS, it can also cause neurotoxicity.

It causes seizures in patients with a history of seizures.

It interferes with the electricity of the brain and causes epilepsy.

Therefore, it is contraindicated to patients with a history of seizures.

- Tienam is probably the first drug we study that has REAL side effects.

(nausea, vomiting and neurotoxicity)

- Meropenem causes the same - but milder - side effects.

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- Hypersensitivity does exist in similar rates to that of cephalosporins; 1%

of the population or 10% of those allergic to penicillin.

•Its side-effects are similar to those seen with other b-lactam antibiotics.

•Nausea and vomiting been the most frequently encountered.

•At high doses neurotoxicity can occur.

•The cross-reactivity of carbapenems/penicillins is also around 10%

(similar to that of cephalosporins/penicillins)

(Slide 67).

Vancomycin, the drug that saved lives.

- One of the drugs of paramount importance. Not a long while ago, it had

been the only drug used to treat MRSA, but then the 5th gen of

cephalosporins and linezolid came out. But more on that later.

- So, up until recently, vancomycin and teicoplanin were the drugs used to

treat MRSA.

- Vancomycin takes us back to drugs of the narrow spectrum.

- Vancomycin is a gram+ drug, and includes enterococci and MRSA.

(Just like the drugs we began the lecture with; 5th gen cephalosporins:

active against MRSA and enterococci).

- Their importance is prominent in hospital-acquired infections, which can

be caused by Klebsiella pneumonia and Pseudomonas aeruginosa,

enterobacter, serratia, and MRSA.

- Remember that MRSA of the hospital is resistant to everything while

that of the community is NOT.

- A community-acquired infection can be treated with ‘milder’ drugs like

augmentin and cefuroxime (2nd gen cephalosporins and below).

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- Hospital acquired infections are treated with more powerful drugs like

piperacillin (antipseudomonal), ceftriaxone, ceftazidime, cefamax,

tienam, and rocephin.

- HA-MRSA (hospital-acquired MRSA) unlike CA-MRSA (community-

acquired MRSA), has limited and expensive options of treatment.

Cheapest is vancomycin.

Vancomycin is bactericidal and acts by inhibiting cell wall synthesis.

It is active only against gram-positive bacteria, particularly

staphylococci.

Its special clinical use is in treating methicillin-resistant staphylococci,

resistant enterococci and Clostridium difficile (which causes

psuedomembranous colitis).

(Slide 68).

- A patient with an unknown cause of hospital-acquired infection, in CCU

or ICU, Gram-negatives should be covered by piperacillin with

tazobactamorceftazidime, orcefamax.

(Those are called antipseudomonal cell wall inhibitors;

antipseudomonalpenicillins and antipseudomonalcephalosporins).

(Recall that cefamax is not used and kept “hidden”).

- To cover gram+ including MRSA, vancomycin is used.

- Enterococci resistant towards ampicillin (and not cephalosporins since

they are not active against enterococci except for 5th gen) are treated

with vancomycin

- If vancomycin resistant, (VRE; vancomycin resistant enterococci), give

the patient ceftaroline.

- A patient with endocarditis who has an allergy to penicillins is treated

with Vancomycin. Vancomycin is the drug of choice to treat patients

allergic to penicillin with endocarditis, since it covers Staph, Strep, and

enterococci.

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So endocarditis is not only treated with vancomycin in case of resistant

enterococci; sensitive enterococci are also treated with vancomycin in

case of penicillin allergy, since ampicillin would cause an anaphylactic

shock in a patient with allergy.

- Up to now, the drug of choice in pseudomembranous colitis is flagyl aka

metronidazole.

- Clostridium difficile is resistant to all antibiotics except for 2; vancomycin

and metronidazole.

- If results of sensitivity test show that Clostridium difficile is resistant to

metronidazole, vancomycin is then the drug of choice.

- All around the world, vancomycin comes in the form of injections. So

when treating MRSA and enterococci, injections are given.

Vancomycin molecules are very large and cannot be absorbed orally.

However, in case of Clostridium difficile, it is given orally, since

absorption is not required; and a build-up of the concentration of

vancomycin in the GI tract is necessary, since it’s a GI tract disease.

The main indication for parenteral vancomycin is sepsis* or endocarditis

caused by methicillin-resistant staphylococci.

(Slide 68).

*especially by unknown causes so that we can cover MRSA.

It is also valuable in severe staphylococcal infections in patients allergic

to penicillins and cephalosporins.

Vancomycin in combination with gentamicin is used for treatment of

enterococcal endocarditis in a patient with serious penicillin allergy, (and

cephalosporins*)

*we now include 5th gen of cephalosporins to the previous statement

ever since 2013 (they are active on enterococci)

It is not absorbed from the gut and is only given orally for treatment of

GI infections. It is generally administered intravenously.

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Resistance can be caused by changing the permeability to the drug and

by decreasing the binding of Vancomycin to receptors.

(Slide 69)

- Recall that resistance to penicillin developed through mutations in the

penicillin-binding proteins.

- However, in VRE or VRSA, vancomycin can no longer bind to its

receptors.

Penicillins and cephalosporins bind to penicillin-binding proteins, while

vancomycin does not. It binds to the terminal alanine, preventing the

last cross-linking. Resistance occurs through the replacement of alanine

with glutamine.

Limits, like fears, are often just an illusion.