Lecture 3 Antimicrobial Pharmacology 10/21/2021

Vanessa Mahfouz (sbobinatore)-Maria Luban (reviewer)

Antimicrobial Pharmacology – 03
10/28/2021 – prof. Federico Pea

Pharmacology of Antibiotics

This lesson is dedicated to the pharmacology of the different classes of antibiotics. This class covers:
Macrolides, Lincosamides, Glycopeptides, Oxazolidinones, Lipopeptides, Lipoglycopeptides, Glycylcycline,
Tetracyclines, Fosfomycin and Colistin.

Macrolides
Macrolides are an old class of antibiotics, they were developed over 60 years ago. Keep in
mind their lipophilic nature, macrocyclic structure (we will see what does it mean from an
immunomodulatory point of view) and their high molecular weight.

From a pharmacokinetic point of view, being lipophilic but having a high molecular weight
means that the drug can penetrate the cells, so they are active against intracellular
pathogens but their high Molecular weight prevents their diffusion through the Blood Brain
Barrier (CNS), so we cannot use these drugs against CNS infections.

For the Chemical Classification we have three different kinds of Compounds: 14C, 15C, 16C.
Erythromycin (14C), Clarithromycin (14C) and Azithromycin (15C) are the most important
Macrolides.

All of the noted Macrolides can be used for therapeutic treatment. However, we have guidelines only for
Clarithromycin and Azithromycin.

Mechanism of action of Macrolides

If we look at the old specification, Macrolides are considered Bacteriostatic which is not important from a
clinical standpoint because what modulates the activity of this drug is not only the type of antimicrobial
activity but also what I am going to explain in a moment.

Macrolides inhibit protein synthesis because they interact and bind with bacterial 50S ribosomal subunit,
inhibiting tranlocation during protein synthesis.

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
The spectrum of activity is quite wide against Gram positive aerobes.

The most important pathogens we have in community acquired pneumonia is especially Streptococcus
Pneumonia and other kinds of Streptococcus involved in oral infection are covered by this type of
antibiotic and also 2 important Gram negative Bacilli that are involved in CAP (H.Influenza, Legionella
pneumophilia) are covered by macrolides.

There are several intracellular pathogens both regarding lung infection and sexually transmitted disease
like U. urealyticum that are covered by macrolides and other bacteria such as Mycobacterium Tuberculosis
and M. avium complex.

Macrolides can also be important in treating mouth infections since anaerobes have a great role in that
kind of infection. They are important in dental infections.

In terms of activity, Macrolides are not active against Enterobacteriaceae and non fermented gram
negative pathogens like Pseudomonas aeruginosa. What does this mean from a therapeutic point of view?
Essentially all the infections that are located in the urinary tract are not treated with macrolides and in
general all infections related to gram negative infections in other sites.

The type of activity is different according to the type of chemical synthesis and essentially the so called
natural macrolides such as erythromycin and clarithromycin are time dependent agents so it is important
the dosing interval because we know these agents have their activity related to the curve of MIC whereas
on the other hand the so called Azalytes like azithromycin are concentration dependent agents for which it
is very important the overall exposure (AUC and MIC ratio).

MECHANISM OF RESISTENCE:

Regarding the performance of Macrolides, what is very relevant

nowadays for macrolides for the treatment of CAP is the fact
that most of the Strep. Pneumonia we have nowadays are
resistant to Macrolides. There are 2 mechanisms of resistance:
one related to Efflux pump (excretes the drug through the
membrane of the bacterial cell) and the other one is a change in
the target site in the ribosome unit. The difference between

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
these two types of mechanisms is that the first mechanism can be overcome by using high dosage of
Macrolides while the second one can’t be overcome.

Pharmacokinetics of Macrolides:

What characterizes Macrolides is their very high volume of distribution, but irrespective of this we have a
low CNS distribution due to the high Molecular weight. Another important characteristic is that
Macrolides are poorly eliminated by the kidney so we don’t have to change the dosage based on the renal
function of the patient. Here are summarized the pharmacokinetic characteristics of these drugs:

We are going to focus on Azithromycin and Clarithromycin. These two drugs have a different
pharmacokinetic behavior and a very different volume of distribution. These two drugs are orally
bioavailable but what is different between them is the volume of distribution. Azithromycin has higher Vd
than Clarithromycin which from a therapeutic stand point means that Azithromycin can accumulate in the
cells and within neutrophils which act as a reservoir of the drug and that’s why looking at the scale of
treatment with Azithromycin we have to administer it for 3 days and this reservoir acts in a therapeutic way
more or less for one week. Clarithromycin has a much lower volume of distribution and has to be
administered twice daily for at least 5 days to achieve optimal results.

Macrolides and CYP3A4-5:

Another important point is the difference in terms of the interaction with the system of cytochrome p450.
Clarithromycin interacts with CYP3A while Azithromycin doesn’t. From a therapeutic stand point, when
treating a patient undergoing cotreatment with one or more of the drugs that are substrates of CYP3A4 you
have to keep in mind that Clarithromycin may inhibit the metabolism of this drug while Azithromycin does
not. There is a huge difference regarding the drug-drug interaction potential because for example a
transplanted patient treated with cyclosporin (immunosuppressive) and who also had CAP and was
treated with Clarithromycin which causes his exposure to immunosuppressive drugs and the patient might
have adverse effects. However if the patient is taking Azithromycin he won’t have adverse effects since
there won’t be a blockage of CYP3A activity. The impact of Azithromycin is lower than that of
Clarithromycin.

Another important Drug-Drug interaction potential is with statins. We

know that statins are used to decrease the hypercholesterolemia in
old patients with Cardiovascular diseases. Some Statins (not all) are
substrates of CYP3A4 and the most important adverse event we may
experience with statin treatment is rhabdomyolysis with AKI which is
life threatening for some patients who are admitted to the ICU. It is
important to know that some Statins (not all) are substrates of

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
CYP3A4. For example, if a patient is being treated with rosuvastatin along with Clarithromycin, there is no
risk of having a drug-drug interaction but if the same patient is undergoing treatment with simvastatin this
is very important because the patient can experience very important adverse effects.

Adverse effects of Macrolides:

Most of these adverse events are not so toxic: dose-dependeant gastrointestinal disorders (diarrhea,
vomiting). We have to note that its important to administer Macrolytes in a fed state in order to lower the
interaction of this drug with motoneuron receptors in the gut that are responsible for these adverse effects
of vomiting and diarrhea.

Hepatotoxicity is not so frequent, however, there are some risk factors (prolonged treatment, elderly
subjects, hepatic insufficiency) that increase adverse effects.

Macrolides can cause skin reactions.

Indications:

The most common indication is Community Acquired Pneumonia CAP. We never use them alone but we
use them in combination with Beta lactams because it has been highlighted in the past 20 years that
thanks to their peculiar structure, Macrolides share their immunomodulatory activity with other
immunosuppressive drugs such as tacrolimus and Sirolimus.

When you have CAP, in the lungs the bacterial infection may stimulate the chemoprophylaxis activity with
a cytokine storm and the production of several types of cytokines (IL-6, IL-8) along with macrophages that
may produce cytokines and chemokines. According to
this, we use Macrolides in patients with severe CAP in
which we have a cytokine storms, we may counteract
this activity just because we know that macrolides
with 14C are able to block the production of
Interleukins, Leukotrienes and ICAM. According to
this, if we have a severe CAP and the patient is
admitted to the ICU, the best treatment is beta-
lactam with Macrolides because this combination has
an important immunomodulatory activity in reducing
the cytokine storm.

Question: Can we use this treatment without knowing the microorganism behind this pneumonia? This
combination widens the range of activity against intracellular and extracellular pathogens. Nowadays, we
are able by testing for urinary antigens to know if we have Legionellosis (suspend Macrolides because of
unnecessary treatment).

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Another important indication for Macrolides is for the treatment of H.Pylori related peptic Ulcer in
combination with Amoxycillin and PPI. It is also indicated in patients allergic to Beta-lactams and in
pediatrics.

Uppr respiratory tract infections

Lowr respiratory tract infections
Stomato-dental infections
Skin and soft tissue infetions
Genitourinary infections

Posology:

There is a peculiar dosing regimen for Azithromycin

related to the so called Troya horse behavior
according to accumulation within neutrophils.

Contraindications:

Pregnancy (potentially teratogenic)

QT prolongation (macrolides could promote arrythmias)
Severe hepatic insufficiency

LINCOSAMIDES:
These are similar to macrolides. They are classified into LINCOMYCIN and CLINDAMYCIN (semi-synthetic
derivative of lincomycin). They are much less used than 50 years ago because of the cross resistance with
Macrolides (increased during the last year) and also because of tolerability. Clindamycin especially has anti
anaerobe action.

Nowadays we use Clindamycin which could be used orally and is useful in some peculiar conditions. When
treating a patient with Clindamycin we should take into account the high risk of developing G.I. disorder
and specifically Acute pseudomembranous colitis related to the selection of Clostridium difficile present in
the gut that sometimes become toxin producing. Rarely we have the occurrence of other adverse events
that are not so relevant in general.

Indications:

It can be used in different conditions but mainly in Acute

Bacterial Skin and Soft Tissue Infections with beta-lactams
because this drug is able of counteracting the production of
some toxins like Staphylococci and Streptococci that may be

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responsible for Toxic Shock Syndrome (TSS), a very impacting disease that can cause necrotizing fascitis.
Another indication is Toxoplasmosis and P.Jerovecii pneumonia. Another possibility of use is when we
have allergy to beta-lactams and we have to treat Ab-ingestis pneumoniae in which anaerobes are
involved.

This is the reason why essentially it is proposed to use Clindamycin in the prevention of Toxic Shock
Syndrome not essentially for its spectrum of activity but due to the fact that it is able to counteract the
production of the different types of toxins by Staphylococci and Streptococci.

Skipped the posology slide, chemical structure slide and role of neutrophil accumulation in chronic
inflammation of Airway disease slide.

GLYCOPEPTIDES:

Glycopeptides are very old drugs with Vancomycin being the oldest and
another drug called Teicoplanin (present in Italy, Europe but not in the
US). Vancomycin being originally extracted from Mississippi river but
nowadays in the lab.

They are cyclic drugs with a very high molecular weight which affects
their pharmacokinetic behavior.

We should understand the difference between Vancomycin and

Teicoplanin. Essentially the mechanism of action of Glycopeptides is the
inhibition of the bacterial cell wall which is related to the fact that both Vancomycin and Teicoplanin inhibit
a pentapeptide which is present in the different units involved in the bacterial cell wall synthesis.

The spectrum of action:

The spectrum of activity of these drugs is quite narrow where they are used as anti-gram positive agents
and even though theoretically they are active against Methicillin-sensitive S. aureus and Methicillin-
resistant S. Aureus, they must be used only to treat Methicillin-resistant infections. This is because if we
have a Methicillin sensitive infection the activity of beta-lactam is much higher and much better than that
of glycopeptides. Another important activity shared by glycopeptides is the activity against Enterococci
(E.faecalis and E. faecium). When there is the occasion of a patient with acute pseudomembranous colitis,
the treatment of toxin producing C. difficile is with Vancomycin via the oral route because it is very
effective agent in this kind of infections.

We have to keep in mind that the spectrum is narrow and gram negative bacilli cannot be treated with this
agent since these agents have high molecular weight and preclude to this hydrophilic agent to penetrate
through porins that are present on the outer membrane.

Resistance:

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
Unfortunately, nowadays we have a high rate of resistance and you have to become familiar with some
acronyms (GISA,VISA,VRSA,VRE).

GISA = Glycopeptide Intermediate S. aureus

VISA = Vancomycin Intermediate S. aureus
VRSA = Vancomycin Resistant S. aureus
VRE = Vancomycin Resistant Entoerococcus

All these types are very frequent nowadays except for VRSA. Whereas fully resistant strains of
Staphylococcus Aureus against Vancomycin are not so relevant. What characterizes VISA is the very
heterogeneous behavior from a clinical stand point and this means that whenever you have a pathogen
that is borderline in terms of susceptibility for Vancomycin, it is better to use different kind of antibiotics to
prevent any clinical therapy.

Characteristics of these drugs:

The most important feature is that the bacterial cell

wall would thicken in VISA compared to VSSA and
another behavior is the ability that the pathogen
acquired to leave the pentapeptide alone as a bomb in
which the drug is blocked but is not active because the
pentapeptide is not linked to the structure of the
bacterial cell wall but is free in the environment.
According to this the activity of VISA is very
unpredictable from the clinical standpoint when we use
Vancomycin.

Glycopeptides are considered time-dependent agents

so it is very important to maintain the drug level above the MIC, similar to what we have observed with
beta-lactams.

Pharmacokinetics:

Glycopeptides are time dependant agents, so it is important to maintain the drug level of MIC similar to
beta lactams.

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From the pharmacokinetic standpoint, these two drugs are very interesting because they have a very
different pharmacokinetic behavior. Irrespective of the fact that Vancomycin is used not only by the
intravenous root similar to Teicoplanin but also by the oral root (only for topical action in the gut since it is
not absorbable from the gut).

Also, we can note the difference between the protein

binding ability of Teicoplanin (90%-95%) and Vancomycin
(30-50%) which justifies the difference with respect to half-
life where Vancomycin has a longer half-life with respect to
Teicoplanin. This is also related to the different dosing
regimens for both drugs. Teicoplanin has a very long
elimination half-life this means that if you want to achieve
a very rapid therapeutic effective concentration, you need a
loading dose that allows to achieve rapidly such kind of
concentration similar to what would occur at a steady state
condition that is reached after several days or few weeks of
treatment. In the first 2 days of treatment we use loading dose that is double or three times higher than
the maintenance dose we use subsequently whereas for Vancomycin this is not needed since the
elimination half life is quite short. So for Vancomycin we use 30mg per kg per day in 4 administrations or
through continuous infusion in severe cases. Both drugs are eliminated by the kidneys (we adjust the
dosage based on renal dysfunction).

We should highlight that despite that vancomycin is important in guidelines as a potential treatment of
MRSA related meningitis, it is not so clever from the pharmacokinetic stand point and nowadays we use
Oxazolidinone.

ADVERSE REACTIONS OF GLYCOPEPTIDES:

Why do we have to reduce the dosage in the presence of renal dysfunction? The tolerability of this drug is
not so good especially for Vancomycin which causes dose-dependent nephrotoxicity. This event is
highlighted by the increase in the level of serum creatinine that the patient may experience during
treatment. There are some risk factors that are prevented using TDM (measures the level of drug in the
blood especially to see if its effective but at the same time not too high to cause adverse effects).

If we administer Vancomycin very rapidly by the intravenous route the patient might develop the Red Man
Syndrome. The Red Man Syndrome has a clinical picture that is associated to the release of histamine
(diffuse neck shoulder erythema, itching, urticaria and arterial hypotension). We can prevent this
syndrome by infusing slowly Vancomycin (not more than 10mg/min).

Thrombophlebitis is another adverse event that is not so relevant and frequent.

INDICATIONS OF GLYCOPEPTIDES

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• Nosocomial infections due to multidrug-resistant Gram positive (MDR) (bacteremia, penumonia,
endocarditis, peritonitis, meningitis, osteomelytis). The professor thinks it is better to use
Oxazolidinones in the case of meningitis.

• Nosocomial infections due to susceptible Gram-positive only in subjects with allergy to beta-
lactams

• Acute peudomembranous colitis (topical use)

OXAZOLIDINONES
These are an alternative to glycopeptides and the most relevant are LINEZOLID and TEDIZOLID.

Mechanism of action:

Linezolid is a synthetic agent, it acts differently from other

agents that inhibit the synthesis of proteins in the initiation
complex. Despite the fact that several other classes of
antibiotics may have cross resistance between each other,
this isn’t the case with Linezolid because the target of action
is different from other agents that act on the elongation site.

In vitro Activity:

Now concerning the in vitro activity, Linezolid is an anti-gram positive agent. The most peculiar aspect is
related to the fact that Linezolid may overcome resistance to Glycopeptides and not only to MRSA.

Linezolid is active against VISA and against VRA and this means that we have another agent to treat MDR
gram positives.

The PK/PD behavior of Linezolid is very important for us because it is a time dependent agent and is
moderately lipophilic which is an advantage from the pharmacokinetic point of view because moderate
lipophilicity means that you have the drug available via oral and intravenous route with very high
bioavailability. It distributes into many tissues including bone, CNS and bile and so you can treat very
difficult infections like bone and joint infections and meningitis. The other important aspect related to the
moderate lipophilicity is that it is not metabolized and eliminated by non-renal elimination (70%) and 40%
eliminated by the kidney. Nowadays it is recommended that we adjust the dosage only in patients with
severe renal dysfunction (<30ml/min).

Pharmacokinetics:

Linezolid half life is short that’s why we need a double administration a day for 12 hrs in order to maintain
adequate exposure in terms of activity against antigens.
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Adverse Events:

Its very important to describe adverse events which are dose dependent. Nowadays, there are strong
therapeutic indications for long term treatment. The most important dose dependent effect is
Thrombocytopenia and that’s why we have to avoid the usage of Linezolid for more than 28 days. This
event is dose-dependent and it appears during the early phase of the exposure to this drug that may occur
because of renal dysfunction or because of other underlying diseases. So it is very important to perform
TDM to prevent thrombocytopenia.

Less frequently patients may experience anemia related to immune basis.

This drug also has an anti-MAO activity, meaning that if you reach high concentration or are using other
drugs that are able to block such kind of enzymes you may experience the serotonin syndrome.

Serotonin syndrome: characterized by several adverse events that involve neuromuscular systems and
gastrointestinal activity and also cardiovascular event with hypertension.

This study (slide 44) was published 15yrs ago and it suggests that the incidence of serotonins syndrome
when using Linezolid may be especially relevant if cotreating the patients with SSRI. This issue may arise
especially when treating elderly patients with depression.

Adverse events of Linezolid:

• Lactic acidosis is relevant in the ICU setting and is an effect that is dose dependent that depends on
the block of the mitochondrial activity related to the inhibition of protein synthesis.
• Peripheral neuropathies
• Gastrointestinal- nausea, vomiting, diarrhea

Indications of Linezolid:

Linezolid has an immunomodulatory activity able to counteract a cytokine storm so we use it to treat
pneumonia of Multi-resistant gram positive infections. It is also indicated in biliary tract infections
especially in Liver transplantation.

It is indicated also for Nocardiosis.

It is an alternative treatment in TB, which is based on 4 different agents combined (Isoniazid, ethambutol,
Rifampicin and Periositamide) but when we have resistance against one or more of these agents Linezolid
would be a valid alternative.

Posology: 600mg every 12h (IV-OS)

I mention also Tedizolid very rapidly because it is present in our therapeutica armamentarium but has not
gained evidence like Linezolid. These 2 drugs have a similar spectrum of activity but Tedizolid has a
different pharmacokinetic behavior because its half life is longer and that’s why we need to administer
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Tedizolid only once daily compared to twice daily with Linezolid. But irrespective of some differences from
the pharmacokinetic point what we have to keep in mind is that nowadays Tedizolid is indicated only for
treatment of acute bacterial skin and soft tissue infection due to Staphylococci that are resistant to the
Methicillin or Vancomycin so its therapeutic use is quite limited.

Lipopeptides:

Another interesting antigram positive class is represented by lipopeptides. Lipopeptides have a major drug
that is Daptomycin. Daptomycin has this peculiar structure it is a macrolide with a very big ring with a long
lepidic sidechain and it is extracted from this kind of streptococcus and what is very interesting is the fact
that these side chain allows this drug to block the bacterial cell wall synthesis without causing a
destruction of the pathogen so the pathogen does not release high amounts of endotoxins that may be
present in the bacterial cell wall. Differently from what occurs with beta lactam essentially this drug does
not promote an immune response from our organism so we avoid cytokine or chemokine storms when
using daptomycin.

Mechanism of action of Daptomycin:

In the presence of calcium, this side chain may block in the the activity and synthesis of the bacterial cell
wall and as I mentioned before this is non-bacteriolytic antibiotic.

Spectrum of Activity of Daptomycin

• S. aureus (MSSA, MRSA)

• S. epidermidis (MSSE, MRSE)
• E. faecalis (VSE, VRE)

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These are the antigens that are susceptible to the activity of
daptomycin, essentially all the gram positive that are resistant to
both Methicillin and Vancomycin.

What is very interesting from the pharmacodynamic view is that

this drug could be considered essentially what aminoglycosides
represent among gram negatives. Concentration dependent
agents with a very rapid activity so the activity is related to a high
MIC/AUC ratio and if we use this drug once daily, the pulse dose
is administered in bolus in 2 minutes we may achieve a very
effective activity especially in treatment of MRSA bacterimia.

Experimental model showing the effectiveness of Daptomycin:

This is an experimental animal model showing you what was explained earlier. In this experimental model,
the pharmacodynamic behavior of Daptomycin was compared with that of both Vancomycin and Linezolid.

Here are different mice that were treated with these agents
and their colour suggests essentially how high was the
bacteria burden. The mice were alive during this experiment
and with a microscope we were able to see what happened in
their peritoneum and we may observe here the red colour
highlights the higher bacterial burden.
After a 2/4 hour treatment this is what happens: the control
obviously the red colour rapidly increased due to bacterial
expansion. Whereas in animals treated with Daptomycin the
red colour almost disappears. The explanation is that
Daptomycin being a concentration dependent agent has a
very rapid activity differently from both Vancomycin and
Linezolid that are time dependent agents and they take much longer time to obtain the same effect. So
according to this, daptomycin has become the first choice for treatment of MRSA Bacteraemia due to the
fact that it is very effective in causing a rapid drop of bacteria.

Pharmacokinetics of Daptomycin:

Unfortunately Daptomycin has some limits. The first and perhaps the most important is that it is a
hydrophilic antibiotic so you cant use it for treating for example meningitis, but also we cant use it for
treating pneumonia, not related to its pharmacokinetic behavior but is related to the fact that daptomycin
is inactivated by the surfactant that we have in our epithelial iv fluid so this has to kept in mind because
daptomycin is surely an indication for the treatment of bacteremia endocarditis due to MRSA bacteria that
is absolutely not indicated for treating MRSA pneumonia.

Indications of Daptomycin:

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
The elimination half-life is more or less 8 hours so one daily dose is enough for such kind of agent and the
drug is renally eliminated. According to the rule that a concentration dependent gradient must maintain its
peak to mrsa ratio, if you have renal dysfunction keep in mind that the best way to adjust the dose is to
extend the dosing interval while maintaining the full dosage. Full dosage means 8-10 mg/kg that is
administered once daily in patients with nonrenal function every other day in patients with renal
disfunction so we extend the dosing interval to up to 48h. These are the indications as mentioned before.

It is indicated also for treatment of skin and soft tissue infection or in Bone and Joint infection but keep in
mind that its not used for treating pneumonia due to inactivation by the alveolar surfactant. It is very
challenging if you have a patient with bacterimia and at same time pneumonia due to MRSA and you
decide to use daptomycin to treat bacteraemia but you have to add something else to treat pneumonia or
you have to change your choice according to this aspect.

The only adverse event that we have to note is toxicity to skeletal muscle that’s why it is important to
monitor serum creatine kinase levels especially if we treat the patient for a long time for bone and joint
infections.

LIPOGLYCOPEPTIDES:

They are a better evolution of glycopeptides and

lipopeptides and have become recently available.

Dalbavancin is the first drug in this class and has a similar

structure to Vancomycin and has a lipophilic side chain that
ameliorates both its pharmacokinetic and
pharmacodynamic behavior. This side chain allows the drug
to bind effectively in the cell wall of the gram positive
bacteria. Another aspect is that the activity is maintained
for a very long time. This type of structure provides a
prolonged activity to the drug. One Administration is
enough for treating the patient for at least 2 weeks. This is a
very innovative aspect that has been very useful in treating
patients during the pandemic, since the drug could be
administered just once, without having to come back to the
hospital.

Spectrum of activity:

The spectrum of activity is very similar to other anti-gram positives. It has an advantage related to the fact
that its activity is not just against MRSA and MSSA but also against Vancomycin susceptible or resistant
Staphylococci. This means that with the dosage (single shot 1500mg) we are able to cover almost all the
spectrum of bacteria.

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Pharmacodynamic behavior:

Comparing AUC/MIC, Peak/MIC and time above MIC, the most

important pharmacodynamic determinant is the AUC to MIC
ratio. This is very important from the clinical standpoint
because it allows to administer the drug with a single shot to
obtain a very long treatment of 2 weeks.

Here are the characteristics of Dalbavancin which is still not

available in our therapeutic agenda. Dalbavancin has a very long
elimination half-life (200hrs). It persists in our body for weeks even after a single administration.

Dosing:

In this graph we are looking at the pharmacokinetic

profile of Dalbavancin. The dosing regimen of Dalbavancin
developed years ago indicates the administration of 1g of
dalbavancin the first week with an additional 500mg in
the second week. Nowadays, it is recommended to use
both doses in a unique administration starting treatment
(1.5g in one shot). Irrespective of this you have a
persistence of the drug in the blood for at least 2 weeks.
Comparing its effectiveness to that of 2 doses of
Vancomycin we can note that a single dose of
Dalbavancin is enough to treat a patient for 2 weeks.

Adverse events are not so frequent and not so important to note.

Indications of Dalbavancin:

Acute Bacterial SSSI treated with a single shot of 1500mg per day 1 or
1000 on day 1 followed by 500mg after a week.

TETRACYCLINES
Tetracyclines had an important role during the 60s and 70s. Nowadays,
their use is limited due to the development of resistance. We have two
second generation tetracyclines (doxycycline and minocycline). The
name of tetracycline is related to the four rings of the molecule.

Mechanism of action: they inhibit protein synthesis.

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Indications:

Tetracyclines act against mainly peculiar pathogens. For example, it can counteract Borrelia burgdoferi
responsible for Lyme disease. Also, we use it to treat Rickettsia. Others include:

• Brucella
• Leptospira
• Helicobacter Pilori
• Mycoplasma pneumonia
• Chlamydiae penumoniae
• Legionella pneumophila

Very large but rapid induction of resistance vs. many G+ and G- cocci and bacilli -> efflux pump.

Pharmacokinetic features:

It is orally bioavailable. They have the ability to chelate cations very well and that’s why we administer it in
fasting condition to decrease absorption at the gut level and to avoid coadministration of milk derivatives
or antiacids.

The most peculiar pharmacokinetic feature of tetracycline is the wide volume of distribution. They have a
very good tissue penetration but accordingly a very high Molecular weight so they cant pass through the
blood brain barrier (not effective for the treatment of Meningitis).

The long half life allows us to administer this drug once daily.

Adverse events:

ADRs are very frequent but not severe.

• Gastrointestinal events such as vomiting which limits the administration of this drug since most
patients are intolerant to this adverse event.

• Bone and / or dental Ca chelation during calcification processes -> possible alteration of bone
growth and permanent brownish discoloration of the teeth. The use of this drug is contraindicated
in children younger than 8 years old because the activity of chelation with calcium may cause some
discoloration of teeth.

• Neurotoxicity is not so frequent.

• This drug may photosynthesize our skin so its better to avoid sun exposure during treatment with
tetracycline. Not so frequently they may cause permanent skin hyperpigmentation.

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This is an example of an article sighting an adverse effect of

tetracyclines where we have Doxycycline-induced
phototoxicity. Another article sighting a case of permanent
discoloration and hyperpigmentation of the skin due to
Minocycline.

Indications of Tetracyclines

• Lyme disease
• Leptospirosis
• Rickettsiosis
• Brucellosis
• Pneumonia due to atypical pathogens
• Sexually transmitted diseases by: Chlamydia trachomatis and Ureaplasma urealyticum
• (Multi-resistant pathogen BJIs (MRSA, Corinebacterium))

Posology of Tetracyclines

Doxycycline: 100-200 mg q24h

Minocycline: 100 mg q12h

Contraindications to Tetracyclines

• Age <8 yrs

• Pregnancy
• Puerperium
• Hypersensitivity

Precautions for the use of Tetracyclines

• Avoid sun exposure

• Avoid simultaneous intake of milk and derivatives, antacids, Fe or Ca salts (laxatives,
multivitamins,…)

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Lecture 3 Antimicrobial Pharmacology 10/21/2021

GLYCILCYCLINE:
Glycilcycline are an important derivative of tetracycline. Tigecycline is the most important type of
GLYCILCYCLINE. Tigecycline has a side chain that gives it important characteristics because most of resistant
pathogens (MRSA,VRA,Psedomonas Aeruginosa resistant to Carbapenim,Acinetobacter resistant to
imipenem) are all susceptible to the actions of tigecycline except for Pseudomonas Aerogenosa. So,3 out of
4 of the major multidrug resistant pathogens respond to treatment with Tigecycline.

Spectrum of activity of Tigecycline:

In green = optimal function of

drug
In orange =intermediate situation
In red=no effect

Pharmacokinetics of Tigecycline:

IV administration and is heavily bound to proteins with a

volume of distribution one fold higher than that of tetracycline.
We have 9-10L/kg this means that the drug is almost completely
accumulated within the cell with a very low level in blood.
That’s why we cant use it to treat bacteremia because the level
in blood is very low.

Another important limit is that the high Molecular weight can

reduce the possibility to achieve therapeutic concentration in
the CSF. Essentially, Tigecycline has a measure indication in
relation to its elimination pathway which is through biliary
excretion. Meaning that in bile this drug is able to achieve concentration that is hundred folds higher than
what its able to achieve in the blood. It is clearly reported that in bile we have a concentration of hundreds
whereas in the blood we have less than a unit of concentration. This is very important since nowadays the
major indication for Tigecycline is intraabdominal infection.

Indications:

Another possible indication is MRSA skin and soft tissue infections but as mentioned before we have a lot
of agents that are available for this kind of indication. The only indication for Tigecycline that we use wildly

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
is intrabdominal and biliary tract infections due to an MDR pathogens those ones that are highlighted
(VRE, KPC + Enterobacterales, A. baumanii).

Dose: 100 mg LD -> 50 mg q12h IV

FOSFOMYCIN:
Another very old drug is FOSFOMYCIN. FOSFOMYCIN is a drug that has
been developed in the early 60s and nowadays has become important in
our theraupetic armamentarium essentially because a lot of pathogens
develop resistance against most of the classes of antibiotics. This view
point has been banished 10 years ago when it became the newly relevant
role of FOSFOMYCIN and essentially here we have listed some peculiar
aspects. FOSFOMYCIN is able to block the membrane cell wall section
because it inhibits an enzyme that is involved in this synthesis. Has a very
simple structure that gives the drug a very high hydrophilicity with also
important aspect in terms of distribution.

• Fosfomycin, the only member of the group of epoxide antibiotics, inhibits cell wall and early murein/peptidoglycan
synthesis in proliferating bacteria.

• Its simple structure consists of the active, bactericidal epoxy group and a directly bonded carbon atom to the centrally
positioned phosphorous

Here are the different formulations we have theoretically at our disposal. Nowadays we use 2 kinds of
formulation. One formulation is used by the oral route for treating very simple infections (simple UTI with a
single shot that is phosphomyosin Trometamol).

Characteristics of Fosfomycin:

Where the trimethyl used to counteract the multidrug resistant infection is Fosfomycin alone that is
administered by intravenous route. This is Trometamol formed with pharmacokinetic behaviour that is
here listed.It is orally bioavailable, is used to treat uncomplicated urinary tract infections with a single shot.
Is a single administration that is used to treat such kind of infection.

This is in our therapeutic momenterum since the early 60s and has not changed. We still have the same
indications we had 60 years ago. The dose is a single dose of 3 grams by the oral route.

On the other hand in the last 10 years Fosfomycin has gained a very
important role (Sodium Fosfomycin that is administered by the intravenous
route).The reason is that if you look at the most challenging resistant
pathogens that are listed ,you may observe that the activity of intravenous
Fosfomycin is very high against Carbapenem resistant Enterobacteriaceae,
Carbapenem resistant pseudomonas aeruginosa, ESBL-producing
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Lecture 3 Antimicrobial Pharmacology 10/21/2021
Enterobacteriaceae and against gram positive like
MRSA and VRE. So in other words the spectrum of
activity of Fosfomycin is very unique because it shared
an activity against both multi drug resistant gram
negative and gram positive that is a very unique
pharmacodynamic behaviour. That’s why its role is
increasing in our hospital when we have to deal with
multidrug resistant pathogens.

Here we have a susceptibility according to the European regulatory agency and as we mentioned there is a
break point defined for both Enterobacteriaceae and Staphylococcus.

There is no breakpoint for pseudomonas because the susceptibility of pseudomonas may be very
fluctuating. It depends on the different characteristic of each hospital so it is very important to test the
susceptibility of this pathogenic Fosfomycin.

Pharmacokinetic characteristics:

Fosfomycin is hydrophilic so it is expected that its renal clearance and its distribution could be increased
in patients with severe infection affected by sepsis because of its time dependent activity. Which means
that we have to administer the drug at least 4 times a day but even better by giving continuous infusion
because short half life of 2 hours may become even shorter in patients who have the so called augmented
renal clearance that is a syndrome during which the elimination could be much faster for hydrophilic drugs.
The dosage is about 6 to 8 gram a day injected in 4 dosages or even better with continuous infusion.

Fosfomycin is formulated as the sodium Fosfomycin so for each gram of Fosfomycin we have administered
330 mg of sodium. This is very important if you have a patient with heart failure or patient who needs
restriction in terms of sodium load.

Fosfomycin is gaining a role also in the treatment of CNS related infections. So when we have to treat CNS
related infections the dosage could be increased up to 24 grams per day because in this way we can
achieve much higher concentration in the cerebrospinal fluid.

Colistin:

The last thing I would like to share with you is an even a worse old drug that is called Colistin.

Colistin indeed is a prodrug because it is not

administered as Colistin but is administered as
Colistin metate. Colistin metate is the real drug we
administer and then this drug is converted to Colistin
by Ubiquitous esterases that release this drug.
Indeed, Colistin is part of a measure class that is
called class of polymyxin and the other name of
Colistin is polymyxin b but if you compare polymyxin
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Lecture 3 Antimicrobial Pharmacology 10/21/2021
a with polymyxin b that is if you compare Colistin with polymyxin b, there is only 1 measure difference in
terms of pharmacokinetic behaviour because Colistin is eliminated in the urine differently from water
course with polymyxin b that have very low concentration in the urine. That’s why irrespective of the fact
that polymyxin a and b have similar spectrum of activity, in the hospital we use Colistin instead of
polymyxin b.

Due to the fact that it is a prodrug essentially, we need a peculiar way of administration that means initially
we need a loading dose and the loading dose should be administered to all of the patients irrespective of
the renal function. This is very important to keep in mind because this drug is very nephrotoxic but despite
the fact that it is very nephrotoxic even with patients with
renal dysfunction, we have to administer the loading dose.
Why? because the loading dose is related to the
pharmacokinetic point of view to the volume of
distribution of the drug and not to the clearance so
according to this rule the volume of distribution is the key
point that we must keep in mind to administer the loading
dose. In other words, the loading dose must be administered to all patients irrespective of the fact that the
patient has a normal or an impaired renal function.

Another reason to reduce the dosage is when we have renal dysfunction in the subsequent part of the
treatment due to the so-called maintenance treatment because maintenance dosage is dependent on renal
periods.

This is what happens with the loading dose. Essentially loading dose is a 9
million unit administered at the beginning of treatment and here is plasma
level of Colistin that can increase due to the release from Colistin metate
that is the precursor that was administered as prodrug.

Just to mention, Colistin has had a very important role from 2010 to 2018 during which we have no new
beta lactams and so we must treat multi drug and resistant gram-negative related infections only with what
we have in our therapeutic guidelines. Colistin was one of the drugs most wildly used during these years.
Nowadays this role has been significantly reduced but we must keep in mind that not all the guidelines
suggest the same unit of measure when we talk of Colistin.

This is the right proportion with different unit of measure. 1 million international unit is equal to 33.3 mg
of Colistin base that is equal to 80 mg of Colistin metate sodium and according to the guideline we have
the opportunity to use one or the other kind of dosage unit.

Here is the proportion of dosage adjustment that we must apply in patients

with renal dysfunction. I don’t want you to remember this table obviously but it
is simply to suggest that the different interval of renal function in which is
recommended an adjustment is very small ( 10 mm per minutes starting from
90 ml per minute) that is almost considered a normal renal function when we
use another kind of agent .This means that the risk of nephrotoxicity is very

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Lecture 3 Antimicrobial Pharmacology 10/21/2021
high, so in order to prevent this risk we have to adjust the dosage to very actively even with patient with a
renal function that is quite normal.

Indications for Colistin:

Colistin was never used alone because it very rapidly selects for resistance. In several cases it is used in
combination with beta lactams or aminoglycosides. What is important to keep in mind is that nowadays it
is used for topical treatment of VAP (Ventilator associated pneumonia) by administration with high rate
aerosols.

Adverse Reactions:

Nephrotoxicity

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