number

31

Done by Rama Nada

Corrected by Ensherah Mokheemer

Doctor Malik

Before we start the lecture it will be more benefial to revise some information

Penicillins Main usage

Penicillin G Strep throat (empirically) Rheumatic fever (prophylactically) N.meningitidis (definitive)

Penicillin V Oral infections (empirically)

Beta-Lactamase resistant penicillins (cloxa/ flucloxa/oxa/methicillin)

Skin infections (empirically)

Broad spectrum penicillins (Ampicillin/Amoxacillin)

Upper respiratory tract infections (empirically) Endocarditis

Extended spectrum penicillins (piparcillin)

Hospital acquired infections to cover G-ve spectrum (mainly: pseudomonads)

Note: the last two types are used with clavulonic acid (or another drug similar

to its action) to over come beta-lactamase resistance

Cephalosporins Main usage

First generation Cefazolin Skin infections (second line therapy) Before surgary (prophylactically)

Cephalexin Skin infections (second line therapy) post-treatment after suturing (prophylactically)

Second generation Cefuroxime (Zinat) Upper respiratory tract infections (second line therapy)

Cefoxitin+ Cefotetan Before abdominal surgary (bacteroides fragilis)

Third generation Cefdinir + Cefixime Upper respiratory tract infections UTI (first line for children,second line for adults)

otitis media (seconde line therapy)

Ceftazidime Hospital acquired infections to cover G-ve spectrum (mainly: pseudomonads)

Ceftriaxone Meningitis (empirically), N.gonorrhoeae

Carbapenems Monobactams Vancomycin Penicillins

Cell wall inhibitors

Cephalosporins

Tetracyclins (rarely used)

Doxycycline Atypical spectrum (Mycoplasma,chlamydis,Legionella) Main usage: Cholera, Brucella

Tigecycline Atypical spectrum (Mycoplasma,chlamydis,Legionella) Upper/lower respiratory tract infection(very rare usage)

Macrolides Azithromycin It’s the drug of chocice sor CA-Pneumonia Upper/lower respiratory tract infection for patient with allergy toward penicillins and cephalosporins

This was the most important inforamtion that was discussed in the last 7

lectures, in this sheet we will continue to talk about :

- Tetracyclins

- Macrolides

- Aminoglycosides

Before we start remember that pharmacology is a dynamic science, so

as a good doctor you need to update your self

Now enjoy studying the sheet 😉

Fourth generation Cefapim Resistant pseudomonads

Fifth generation Ceftaroline MRSA, resistant enterococcus, penicillin resistant S.Pneumonia

Carbapenems (imipenem) Mixed infections (lung with pus)

Vancomycin + Teicoplanin G+ve infections that are resistant to penicillins and cephalosporins (MRSA, enterococcus, C.diffecil)

Monobactams (Aztreonam) G-ve infections that are resistant to penicillins and cephalosporins

Clindamycin Aminoglycosides

Protein wall inhibitors

Tetracyclins Macrolides

Last lectue we started talking about protein synthesis inhibitors, the first

group was Tetracyclines, we said that most of them are becoming inactive on

gram positive and most of gram negative because of the action of plasmid

mediated energy dependent pump that is pumping tetracyclines out of the

microorganism. However we manipulated the situation by producing a drug

that is not a substrate for this pump called tigecycline.

Tigecycline is a drug that is active for upper and lower respiratory tract

infections (except for K.Pneumoniae which is not common). However it

becomes a not favourable drug (not a first line therapy for upper nor lower

respiratory tract infections) , why?

Because its associated with the increase of the mortality rate in comparison

with other drugs that are used for Pneumoniae such as: Azithromycin,

levofloxacin and ofloxacin, so for this reason tigecycline has become a last

drug resort; the last drug of choice.

Macrolides

It is a very important group work as protein synthesis inhibitors (bind to 50s),

contains a famous drug called Azithromycin (this drug is taken as 6 tablets on 3 days), it’s a great drug as it solves the compliance problem that we discussed in previous lectures.

Macrolides group composed of Clarithromycin, Azithromycin, erythromycin and telithromycin.

Macrolides spectrum:

Active on upper respiratory tract infections (pink rectangles): S.pneumonia, S.pyogens, H.influenzea and M.catarrhalis.

Active on lower respiratory tract infections (green rectangles):

Leogenilla, chlamydia and Mycoplasma.

The picture with rectangles in the next page……

Macrolides usage (Clarithromycin and Azithromycin): -Azithromycin is the drug of choice for CA-Pneumonia -Upper respiratory tract infections for penicillin and cephalosporins allergic patients, so usually prescribed for children but they are Not prescribed usually for otitis media as their activity there less than Augmentin and cephalosporins. They are good alternatives for Augmentin, cefuroxime, cefdinir and cefixime (respiratory antibiotics). If you read the slides, you’ll notice that these sentences are written: -Augmentin can be used to treat CA-Pneumonia -Cefuroxime is used for upper respiratory tract infections and can be used to treat CA-Pneumonia Azithromycin used to cover all causes of CA-Pneumonia, but sometimes there is no need to cover all causes as in children CA-Pneumonia. -For children who don’t go to kindergarten (don’t exposed to close defined areas), they won’t be exposed to atypical causes (Leogenilla, chlamydia and

Mycoplasma) so you don’t need to cover them, in this case you prescribe anyone from respiratory antibiotics (Augmentin, cefuroxime, cefdinir, cefixime) as here you need antibiotic to cover only S.pneumonia and H.influenzea.

Conclusion:

Until now we said that macrolides are three drugs: Clarithromycin ,

Azithromycin and erythromycin, the last one doesn’t have a real activity

against gram positive so its not a drug for upper respiratory tract infections,

but it can be used for other indications such as ; Chlamydia, Mycoplasma,

Legionella and Syphilis (erythromycin is not available in markets and it’s the

drug of choice because its alternatives “Clarithromycin , Azithromycin” are

more better than it).

Remember Clarithromycin and Azithromycin are very active drugs for upper

and lower tract infections (specially Azithromycin because it has better

penetration) and they are the drugs of choice for community acquired

Pneumoniae except in a case that we will talk about next lecture Inshallah.

**to be very precise Clarithromycin is more active than Azithromycin for

upper respiratory tract infections (its more active on S.Pneumoniae) , but

both of them are active on it, why?

Because they cover S.Pneumoniae, S.pyogenes, M. catarrhalis and

H. influenzae.

But Azithromycin has better activity on lower respiratory tract infections than

Clarithromycin (it’s more active on Legionella pneumophila Mycoplasma and

Chlamydia.)

CA-Pneumonia

Augmentin, cefuroxime, cefdinir, cefixime

Azithromycin

Definitive therapy to cover typical causes and for children who don’t exposed to close defined areas

Empirical therapy to cover typical and Atypical causes and for children who exposed to close defined areas

When you give a patient augmentin, cefuroxime, cefdinir or cefixime for

upper respiratory tract infections you prescribe them for 5 to 7 days, but if

you give them Clarithromycin or Azithromycin you prescribe them just for

three days(5 milligram for three successive days), why?

Because Clarithromycin and Azithromycin have a long half life called tissue

half life, Azithromycin penetrates into most tissues (except cerebrospinal

fluid), with tissue concentrations exceeding serum concentrations by 10- to

100-fold; Azithromycin make a reservoir in patient tissues (remember from

pharmacokinetics that the drug penetrate the tissue and preserves a

balanced situation in which the concentration of the the drug in the blood is

equal to it in the tissuse (equilibrium) , as blood is more exposed to the

kidney, which is responsible for the elimination of the drug (excretion), than

the tissue. so the drug is released from the tissue to the blood slowly to keep

a balanced concentration (reservoir).

So a therapy for three days by Azithromycin stays in a patient body for at

least 9 days (it needs 12 days to be eliminated totally from the body “4 half

lives”, but it needs 9 days to reach a concentration below the MIC “minimum

inhibitory concentration”.

It’s gonna kept over the MIC for 9 days, which is enough to treat upper and

lower respiratory tract infections.

For chlamydia Urethritis you prescribe 250 milligram of Doxacyclin twice daily

for 5 to 7 days or 1 gram of Azithromycin in a single dose which will kept for 5

days in the patient body over the MIC, as the MIC for chlamydia is lower than

it is for S,pneumoniae, H. influenzae, M. catarrhalis and S. pyogenes.

Azithromycin has a special dosage “loading dose” to reach over the MIC faster

, given as the following:

First day 1 gram in single dose

Second day 500 milligram in the morning 500 milligram at night

Third day 500 milligram in the morning 500 milligram at night

So it’s a drug to be loaded

There is some indications in which you give the patient 500 milligram at the

fist day then 250/250 milligram in the second day and so on in the third day.

Don’t complicate your self with pharmacokinetics just know these

information.

**Refer to sheet index in the last page

We divided Macrolides into two generations:

New generation

(Clarithromycin and Azithromycin )

• Dont have real side effects

Macrolides side effects:

- Mainly Gastrointestinal disturbances; diarrhea (mainly) and some nausea.

- Cholestatic jaundice especially with the estolate form of erythromycin;

causes blocking in gall bladder and building up of the billrubine.This side

effect is related only to erythromycin.

- Ototoxicity: Transient deafness has been associated with erythromycin,

especially at high dosages (very rare).

Azithromycin doesn’t have a real side effect rather than diarrhea because it’s a

broad spectrum drug.

Drug Interactions of Macrolides:

Mainly Erythromycin and to a lesser extent Clarithromycin.

The gene that encodes CYP3A4, which is responsible for metabolism of 40% of

the drug (a large amount), if you interfere with CYP3A4 by inducing or inhibiting,

you change the kinetics of other drugs, but How can you interfere with CYP3A4?

Either, activate “induce” it by Rifampicin; which is an antibiotic.

OR inhibit it by Erythromycin and Clarithromycin, so if the patient takes another

drug with any one of them the drug concentration in the blood will increase, so

for a drug with narrow therapeutic index they Will cause a toxicity to the patient,

such as:

- Corticosteroids

- Cyclosporin: it’s a drug that is given to patients who have recently

transplanted an organ (such as: liver, heart and kidney) as an

immunosuppressor, its is a drug wih a very narrow therapeutic index.

Old generation

(Erythromycin)

• Have side effects

It is given to patients with transplanted kidney although it causes

nephrotoxicity, so if you give Erythromycin and Clarithromycin with

Cyclosporin its metabolism will decrease and its concentration will

increase and disrupte the newly transplanted kidney.

- Digoxin (a drug for patients with heart failure): which is metabolized by

the normal flora in the body, if you manipulate with the patients normal

flora its concentration in the blood will change and cause toxicity (very

narrow therapeutic index), so if the patient takes Erythromycin and

Clarithromycin its metabolism will decrease and its concentration will

increase causing toxicity to the patient.

Remember that the drugs which increase the mortality rate are digoxin

and tigecycline so be careful.

- Warfarin: this is the most common drug to admit patients to the hospital

because of bleeding (its affected higly with things that the patients eat or

drink), so if the patient takes Erythromycin and Clarithromycin its

metabolism will decease and its concentration will increase causing

toxicity to the patient.

So be careful and don’t prescribe Erythromycin and Clarithromycin to patient

who take any of these drugs.

Simply its like this:

Causes Causes Causes

Aminoglycosides:

- They are protein synthesis inhibitors

- They interfere with the cell membrane of the bacteria

- They produce multiple mechanism of action against bacteria

- They are the only bactericidal protein synthesis inhibitor (because they

have multiple mechanism of action against bacteria)

- They stay in the body for a long time

- They have something called post treatment effect

- Their spectrum: Gram neagative bacteria

- There is no real resistance against them until now (because they have

multiple mechanism of action against bacteria)

Increase in drug

level in the blood

Toxicity in drugs with narrow

therapeutic index

Decrease in drugs

metabolism Inhibition

in CYP3A4

They are similar to monobactam (aztreonam) and both are reverse drugs to

vancomycin.

The family members:

Streptomycin, Amikacin, Gentamicin, Tobramycin, Netilmycin, and

Neomycin.

Gentamycin is an old drug used to treat gram negative infections including

pseudomonads.

Why we need it although we have many other antipseudomonal

alternatives?

Refer to slide#36 where you can find this paragraph:

• Although supportive clinical data are lacking for superiority of

combination therapy over single-drug therapy, because of the propensity of

P aeruginosa to develop resistance during treatment, an antipseudomonal

penicillin is frequently used in combination with an aminoglycoside or

fluoroquinolone for pseudomonal infections outside the urinary tract.

So what does this mean?

All cell wall inhibitors that are antipseudomonal antibiotics (imipenem,

ceftazidime, piparcillin, cefapim and aztreonam) have one mechanism of

action and this is not enough to treat pseudomonal infections, you have to

apply a dual mechanism of action on pseudomonads, you should give two

drugs with two different mechanisms; one is a cell wall inhibitor and the

other is protein synthesis inhibitor or quinolones.

So previously gentamycin was used in combination with other

antipseudomonal cell wall inhibitors, but nowadays fluoroquinolone is used

instead of it.

**The only real benefit for Aminoglycosides is for it to be used in

combination with other cell wall inhibitors for treatment of hospital gram

negative infections.

**pseudomonal infections are treated with dual mechanism of action (Note: it

doesn’t make sense to combine two drugs which have the same mechanism of

action such as: imipenem and ceftazidime)

** Aminoglycosides spectrum is similar to Aztreonam

**streptomycin is the first drug used to treat TB

**Bind to the ribosomal 30S subunit

**Inhibit initiation of peptide synthesis and cause misreading of the

genetic code.

** They are effective against many aerobic Gram-negative and some

Gram-positive bacteria (neglected) , finding their greatest use against

Gram-negative enteric organisms and in sepsis (in hospital acquired

infections generally).

They were used previously, but we stopped using them for a significant time due

to the use of alternatives (fluxacins), then we had to use them recently because

bacteria developed resistance against fluxacins but didn’t develop any against

aminoglycosides.

The question here is why don’t we prefer using aminoglycosides (or why we

stopped using them during that period)?

Because they developed a real nephrotoxicity and ototoxic.

The types of side effects:

Remember there is a resistance toward penicillins, cephalosporins,

carbapenems…..etc, but there is no resistance toward Amioglycosides

(amikacin still has 99% susceptibility on G-ve bacteria, gentamycin has

97%), for this reason we revive the usage of them toward many

indications, such as sepsis.

Aminoglycosides are time dependent; the more you give it to the patient

the more accumulation occurs, because they have a high penetration in

Pharmacological side effects

If you increase the dose and the duration of

treatment the incidince of side effect increase

Nephrotoxicity

Non pharmacological

side effects

not dose dependant, may occur and may not

Ototoxicity

the body (the same principle as Azithromycin but not to its extent), Its

built up in the body so when the patient stops taking it, it will still have a

effect in the patients body, we call it “post treatment effect” (Note: this

post treatment effect comes from the accumulated drug).

The problem in this case is the appearance of what we called accumulative

toxicity ( which comes from the accumulated dose); as the patient uses it

for a longer time the accumulation toxicity increase, so Aminoglycosides

should not be given to patients for more than one week (they are

administered via IV route),if the patient takes it for more than one week

the percentage of nephrotoxicity (pharmacological side effect) increases.

Note: Ototoxicity appears in the patient from the beginning of drug usage

but, Nephrotoxicity is dose dependent and appears upon accumulation.

Where can we use gentamycin?

1) Gram negative bacillary infection (septicaemia, pelvic and abdominal

sepsis).

2) Bacterial endocarditis: gentamycin with Ampicillin (cell wall inhibitors)

produce a synergistic effect (combination 1+1>2), but it’s no longer

used because you have to balance between the risks and the benefits

so there is no need to risk your patient for gentamycin as long as

endocarditis can be treated with Ampicillin or Vancomycin.

3) In Brucellosis, the patient is treated with two drugs: Doxacyclin twice

daily for one month with daily IM injection Gentamycin.

4) Can be used in HA-pneumoniae and pseudomonal pneumoniae in

combination with other cell wall inhibitors, but in reality they use

levofloxacin with one of the cell wall inhibitors, if they were ineffective

they add gentamycin while monitoring the toxicity

*In some cases some patients develop nephrotoxicity even though they

are given Aminoglycosides for less than one week (especially elderly and

young children) ,the solution for this problem is to monitor the

aminoglycosid level via a lab test to know the drug’s level in the patient’s

blood,that is necessary due to the penetration ability of aminoglycosides

which will lead to accumulation . To make sure that there is no

accumulation of the drug a Trough is required.

Peak: It is the highest concentration of the drug.

Trough: Lowest concentration of the drug before the next dose

When we give an aminoglycosides injection it means that it’s bioavalibilty

is 100%, with time elimination occurs through the kidney and so before

the next dose we will have reached the lowest concentration which is in

pharmacology, called the Trough (the concentration before the next

dose),If your patient is not excreting the drug normally the trough will be

higher than normal which indicates that the drug is accumulating in your

patient and that will cause nephrotoxicity.

So in some cases the doctor prescribes gentamycin with trough. what does

that mean ??

It means after giving the first dose of the drug and before giving the

second dose, a blood test should be done to the patient to make sure that

the drug did not accumulate after the first dose and that is so we can

avoid nephrotoxicity.

Don’t forget to refer to slides

CA>>Azithromycin

Refer to page6

Sheet index (its a colored page)

Due to the large number of antibiotics that are active on upper

respiratory tract infection you may feel confused about what is the drug

of choice these are some tips to help you 😉

For patients with penicillins allergy or the infections that are resistant to

augmentin prescribe cephalosporins (any one of these):

For patients with penicillins and cephalosporins allergy or the infections

that are resistant to penicillins and cephalosporins prescribe Quinolones

(which we will discuss in the next lecture Insallah), then if the infection

didn’t respond prescribe vancomycin

The last drug resort is Tigecycline

I hope that the picture has become clearer, sorry for any mistake 😊

Augmentin

except for: strep throat

use penicillin G

For non-allergic penicillin patients

you should use:

cefuroxime cefdinir cefixime

HA>>Vancomycin

Pneumoniae