Chapter 44: Macrolides, Ketolides

Clindamycin,
Chloramphenicol, Streptogramins
& Oxazolidinones

Dr. Abdifetah Ibrahim Omar

PhD Candidate, Siriraj Hospital
Mahidol University
Classification of antibiotics based on Mechanism of Action

DNA
RNA

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 MACROLIDES
• Erythromycin is the prototype, 14-atom
lactone ring,
• Newer macrolides: Clarithromycin,
azithromycin and Roxithromycin are
semisynthetic derivatives of erythromycin.
• Anti-inflammatory action
 New macrolides antibiotics
(derivatives of erythromycin)
• Advantage :
– higher activity – Gram +Ve
– Orally effective
– High blood concentration
– Longer half life(once- or twice-daily administration)
– Less toxicity
– Mainly used in respiratory tract infection
Disadvantage
Streptococcus pneumoniae – macrolide resistant
Streptococcus pyogenes – macrolide resistant
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 ERYTHROMYCIN
• Source: was obtained in 1952 from Streptomyces
erythreus.
• Poor water solubility, Unstable in acid (which causes GI
irritation, hence coating of tablets made to reduce this
effect)
• Dose: 0.25–0.5 g every 6 hours (for children, 40
mg/kg/d).
 Antibacterial action of Macrolides
• Macrolides are broad-spectrum antibiotics
• Active against many Gram positive and some Gram negative
bacteria
• Antibacterial action is similar to penicillins, hence often used
as an alternative in patients who are allergic to penicillin.
• Macrolides are also active against bacteria that do not
possess a cell wall (e.g. mycoplasma), such bacterial are
resistant to penicillins.
 ….Cont
• Macrolides are generally effective in pneumococcal,
streptococcal, and Legionella infections, making them useful
agents for the treatment of community-acquired pneumonia.
• Azithromycin appears to show activity against Haemophilus
influenzae, Toxoplasma gondii and Pneumocystis carinii
(Jiroveci) causes pneumonia in immunocompromised patients
(Eg. HIV)
- Generally “more effective” against gram-positives than gram-
negatives because macrolides have a bulky structure that does
not penetrate through membranes in gram-negative bacteria
- Bacteriostatic in nature, but attains bactericidal in high
concentration
 …Cont
• Clarithromycin is more active against Mycobacterium avium
complex, Clarithromycin also has activity against M leprae
and Toxoplasma gondii and H. Pylori.
• Erythromycin-resistant streptococci and staphylococci are
also resistant to clarithromycin (Cross-resistant)
• Azithromycin is active against M ovium complex and T
gondii, chlamydia. Less active against gram +ve bacteria
• Erythromycin (Gram +V): alternative to penicillins (Allergy,
resistance)
• Clarithromycin (Less active Gram +V, more active Gram -V
• Azithromycin: (less active Gram +V, More active Gram –V)
• Antimicrobial for Peptic ulcer (Triple therapy): 1 Anti-
secretory+ 2 ABX
- Amoxicillin (1gm)
- Tetracyclines
- Clarithromycin

Peptic ulcer: H. pylori

 Mechanism of action of Macrolides
- Inhibit bacterial protein synthesis
- By binding reversible to 50 subunit ribosome (The
binding site is near the peptidyltransferase center)
- Block the polypeptide exit tunnel, which prevents
peptide chain prolongation
- Erythromycin also inhibits the formation of the 50S
ribosomal subunit
- All macrolides have similar mechanism of action
- Anti-inflammatory effect in Community-Acquired
Pneumonia (CAP) & other chronic inflammatory lung
diseases
 Antibiotic Action on Protein synthesis

Chloramphenicol Erythromycin
Binds to 50S unit
Binds to 50S unit, prevents
preventing peptide
The translocation-movement
bond formation
50S of the ribosome along the mRNA

mRNA
Tetracyclines
30S Interfere with the
Streptomycin
Changes 30S so that attachment of tRNA
mRNA is misread to mRNA ribosome complex

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 Mechanism of Resistance
1. Modification of ribosomal binding site (Ribosomal protection):
low affinity between erythromycin and 50s Ribosome
(Methylation of the 50S ribosome)
2. Reduced permeability of the cell membrane or active efflux Activate
efflux pump
3. Production of Enterobacteriaceae of esterases that hydrolyze
macrolides.
4. Cross resistance between erythromycin and other macrolides.
5. Constitutive methylase production also confers resistance to
structurally unrelated but mechanistically similar compounds such as
clindamycin and streptogramin B (socalled macrolide-lincosamide-
streptogramin, or MLS-type B, resistance),
 Pharmacokinetics of Macrolides
• Erythromycin base is destroyed by stomach acid and must be administered with enteric
coating (prodrug), Stearates and esters are fairly acid-resistant
• Even the use of an enteric coating does not completely solve this problem, as the pH of
the small intestine is 6.5–8.0, which still leads to appreciable degradation.
• The acid stability of the other macrolides is considerably better.
• Absorption of erythromycin is affected by food, should be administered on empty
stomach.
• Bioavailability of other macrolides, such as azithromycin, clarithyromycin, and the
newest relative, telithromycin is 37, 52, and 57% respectively, and their absorption is
less affected by food
 …Cont
• Highly distributed including CNS (CSF penetration is poor) and placenta,
concentration similar regardless to formulation.
• Macrolides accumulate in phagocytic cells, such as polymorphonuclear
leukocytes (PMNLs) and macrophages, and are transported to, and
subsequently released at, the site of infection, which enhances the
macrolide concentration in the presence of the bacteria.
• Azithromycin, in particular, displays extensive selective tissue
accumulation into PMNLs and macrophages and a very long tissue half-
life.
• Erythromycin and Clarithromycin is metabolized in the liver by CYP3A4.
• Clarithromycin is metabolized in the liver. The major metabolite is 14-
hydroxyclarithromycin, has antibacterial action.
 …Cont
• The plasma half life of Erythromycin is 1.5 hours, Clarithromycin 6
hours and Azithromycin 2-4 days.
• Single dose of azithromycin is as active as 7 days dose of
doxycycline and Amoxicillin.
• The majority of the macrolide antibiotics are mostly eliminated
through the intestinal tract (Biliary excretion), with a variable, but
minor, amount excreted renally.
• The exception is clarithromycin and its active metabolite, 14(R)-
hydroxyclarithromycin, which are primarily excreted renally in the
urine, hence dose adjustment In case of Renal insufficiency (RI)
• Excretion is mainly through bile and feces, only 5% is excreted
through urine.
• Azithromycin is excreted all into the Bile.
 Adverse effects of Macrolides
1. GI toxicity:
- Increased incidence of GI disturbances which includes nausea,
vomiting, abdominal discomfort, and diarrhoea.
- Incidence of GI toxicity is 7% In patients treated with erythromycin
and 2.5% in patients treated with azithromycin.
- This adverse effect is associated with motilin. increase motilin
receptor stimulation increases peristalsis and accelerates gastric
emptying.
- Most common with erythromycin; less with new agents.
- Cholestatic jaundice (caused by erythromycin estolate)
 …Cont
2. Pro-arrhythmic potential
• Macrolides prolong the QT-wave interval, thus increasing the
likelihood of cardiac arrhythmias through blockage of inwardly
delayed rectifying potassium channels (inwardly rectifying K
channels which is classified as rapid or slow acting, support the flow
of positively charged K+ ions into the cell, pushing the membrane
potential back to the resting potential).
• Blockage of inward rectifying K channel causes prolonged cardiac
repolarization, consequently potential for arrhythmia (torsade des
pointes)
• The affect is more when macrolide are administered in combination
with other agents like 5-HT4 agonist (Cisapride), anti-arrhythmic
drugs (Quinidine).
 …Cont
3. Skin Rashes: Nearly 14 % of patients who had previously
reported hypersensitivity to one or more drugs were
hypersensitive to macrolide antibiotics.
4. Autotoxicity (Auditory damage): although extremely rare,
macrolides especially Erythromycin is associated reversible
hearing impairment in some patients with renal impairment.
Hearing was stored in all cases once drug administration is
ceased.
5. Thrombophlebitis (blood clotting at the site of inj) – IV
Erythromycin and Azithromycin
–Dilution of dose; slow administration
 Drug Interactions
• Erythromycin & its metabolites & Clarithromycin can inhibit
Cytochrome P450 enzymes and thus increase the plasma concentrations
of numerous drugs
• The macrolide antibiotics are categorised into three groups according to
their ability to inhibit the CYP 3A4
1. Group I has strong ligand affinity and is represented by erythromycin
2. Group II has intermediate affinity and is represented by clarithromycin;
and
3. Group III has low-affinity and is represented by azithromycin.
 …Cont
1. Benzodiazepines (alprazolam, midazolam): increased serum half
life
2. Neuroleptics (Clozapine): reduce hepatic clearance, concurrent
use cause seizure, difficult of coordination and disorientation
3. Statins: increased toxicity when used with macrolides
4. Theophylline: decrease clearance
5. Carbamazepine: increase toxicity
6. Class IA antiarrhythmic agents: 50% decrease of quinidine
metabolism, increase toxicity.
 Therapeutic uses of Macrolides
Erythromycin
Rarely used to treat infections due to increasing resistance & more
favorable alternatives, including clarithromycin & azithromycin
Common Therapeutic Uses include
1. Erythromycin is a drug of choice in corynebacterial infections
(diphtheria, corynebacterial sepsis, erythrasma)
2. Respiratory infections
3. Ocular infections
4. Genital chlamydial infections
5. Skin and soft tissue infections
 …..Cont
6. Erythromycin has been recommended as prophylaxis against
endocarditis during dental procedures in individuals with
valvular heart disease, although clindamycin is commonly
used, which is better tolerated.
7. Penicillin resistance pneumonia
8. Erythromycin is also useful as a penicillin substitute in
penicillin allergic individuals
 Other Therapeutic Uses of Erythromycin (Off-
Label)
1. Prokinetics to treat gastroparesis (Increase gastric
emptying): IV Erythromycin
2. To cleanse bowel of bacteria before surgery (Pre-operative
bowel preparation): Its given orally along with neomycin
3. Erythromycin infusion used for Upper GIT bleeding prior to
endoscopy.
 ….Cont
Clarithromycin
1. Common therapeutic use is respiratory tract infections
2. Sinusitis
3. H. Pylori Eradication
4. H. Influenza and Mycobacterium Ovium Complex (MAC)
5. Dose: 500-mg loading dose, then 250 mg once or twice daily)
 …Cont
Azithromycin
1. Respiratory tract infections
2. Skin infections
3. STD: chancroid, Chlamydia
4. Traveller’s diarrhea
5. Mycobacterium Ovium complex (MAC)
 Ketolides
• Semisynthetic macrolides
• Telithromycin is approved clinically
• Oral bioavailability 57%
• ADR: liver toxicity, liver failure
• Uses: Community acquired pneumonia
Common Therapeutic Uses of Macrolides
 Donovanosis
• Chronic cause of genital ulceration
• Initially, the condition presents as a papule or nodule on the genital
region, which then begins to ulcerate. The resulting ulcers are
described as ‘beefy red’ and can bleed to the touch. If the ulcers are
left untreated, they become very unsightly, causing significant
psychological distress to the patient
• and as a result patients with this condition may not seek medical
advice due to embarrassment or shame
• Donovanosis is generally considered to be a sexually transmitted
infection (STI) and is caused by the Gram negative bacterium
Calymmatobacterium granulomatis
 …Cont
• Diagnosis of donovanosis is made by the presence of Donovan
bodies (encapsulated forms of the causative organism, C.
granulomatis) in tissue or biopsy samples
• Treatment include: Azithromycin (either 1 g weekly or 500 mg
daily) as first-line therapy. Weekly dosing is allows azithromycin
to be given by DOT.
• Where the patient is pregnant, erythromycin, at a dose of 500 mg
four times daily
• Treatment should generally continue until the lesions have
healed, and if they are not resolved within 6 weeks further tests
should be performed to exclude the possibility of cancer.
 Community-acquired pneumonia
• The condition can also be caused by multiple pathogens
(when this occurs the condition is known as polymicrobial
CAP). S. pneumoniae is the commonest cause.
• but other pathogens, such as H. influenzae, Mycoplasma
pneumoniae, and Legionella pneumophila, can cause CAP.
• Clinical features of the condition include fever, cough, chest
pain, and shortness of breath
• To assess the severity of CAP, a tool known as the CURB65
score is used when the patient in hospital. CURB65 stands
for:-
- Confusion (does the patient show signs of new mental confusion?),
- Urea (a level raised above 7 mmol/L),
- Respiratory rate (raised above 30 breaths/min),
- Blood pressure (does the patient have a low blood pressure – either
systolic (less than 90mmHg) or diastolic (less than 60mmHg?)), and
finally,
- Age (is the patient aged 65 years or more?)
Treatment of CAP
• If the condition is low-severity (e.g. a CURB65 score of 0 or 1, or a
CRB65 score of 0), amoxicillin is recommended as monotherapy, but
in cases of penicillin allergy, clarithromycin is used.
• When the condition is of moderate severity (e.g. a CURB65 score of
2), amoxicillin should be combined with clarithromycin.
• In cases of high severity (e.g. a CURB65 score of 3–5), co-amoxiclav
should be combined with clarithromycin
• One form of pneumonia that deserves a special mention is that
caused by Legionella species (e.g. Legionella pneumophila)
• it is actually contracted by inhaling water vapour containing
Legionella bacteria
• Erythromycin was once considered the agent of choice to treat
legionnaires but now quinolone antibiotic is recommended as
first-line therapy.
• In case where quinolone can not be used or not well tolerated,
clarithromycin is recommended.
 Eradication of Helicobacter pylori
• The macrolides are also used (alongside other antibiotics) to
eradicate H. pylori
– PAC, which consists of a proton pump inhibitor, clarithromycin
(500mg dose is recommended), and amoxicillin.
– PCM, which consists of a proton pump inhibitor, clarithromycin
(lower dose 250mg is recommended), and metronidazole.
 Pertussis
• Pertussis is an acute respiratory tract infection caused by the Gram negative
bacterium Bordetella pertussis.
• It is highly contagious and is spread by inhaling contaminated aerosol
droplets in the air (which are released through coughing or sneezing).
• It is characterised by bouts of severe coughing, which are often followed by a
characteristic ‘whoop’ sound as the patient inhales to get their breath.
• The condition, also referred to as whooping cough
• The condition has three phases: a catarrhal phase (a dry cough may develop
with signs of an upper RTI), a paroxysmal phase (the severe coughing stage
often accompanied by the whoop), and a convalescent phase (when the
patient starts to get better). Most people who develop pertussis make a full
recovery, but complications can occasionally occur, and these include
pneumonia, seizures, and, rarely, encephalopathy
• Macrolides are used first-line to treat pertussis and should be
taken within 21 days of the onset of the cough
• Generally, erythromycin is the agent of choice for treatment
of the infection
• Azithromycin is considered the best choice, As erythromycin
has been associated with hypertrophic pyloric stenosis (a
narrowing of the pylorus, the lower part of the stomach) in
this patient group.
Miscellaneous Use of Macrolides
• The prophylaxis and treatment of mycobacterium avium
complex (MAC) infection when clarithromycin or
azithromycin is used
• Treatment of chlamydia with a one-off single dose of
azithromycin
• Primary prophylaxis of rheumatic fever in penicillin allergy
• Treatment of typhoid fever caused by multiple antibacterial
resistant organisms with Azithromycin
Newer macrolides
• Fidaxomicin, a minimally absorbed macrolide used to treat
Clostridioides difficile (formerly Clostridium difficile)
infections, is discussed in Chapter 50.
• KETOLIDES: Telithromycin, Solithromycin.
• Ketolides are used macrolide-resistant strains.
CLINDAMYCIN
• Derivative of lincomycin, an antibiotic that is elaborated by
Streptomyces lincolnensis
Mechanism of action
• The binding site for clindamycin on the 50S subunit of the
bacterial ribosome is identical with that for erythromycin.
• Clindamycin, like erythromycin, inhibits bacterial protein
synthesis by interfering with the formation of initiation
complexes and with aminoacyl translocation reactions
(blocking the polypeptide exit tunnel, which prevents
peptide chain prolongation)
 Antimicrobial Activity of Clindamycin
1. Broad spectrum
2. Both gram positive (Especially Gram positive cocci such as
staphylococci and streptococci) and gram negative
3. Anaerobic infections
– Gram-positive: peptostreptococci, Clostridium perfringes, actinomyces
– Gram-negative: Prevotella species, most Bacteroides fragilis, fusobacteria
4. Toxin production inhibition of Group A streptococci and MRSA
5. Bacteriostatic in nature
 Mechanism of Clindamycin Resistance
1. Mutations in the ribosomal receptor site
2. Modification of the receptor by a constitutively expressed
methylase (Similar to erythromycin)
3. Enzymatic inactivation of clindamycin.
Gram-negative aerobic species are intrinsically resistant
because of poor permeability of the outer membrane
 Pharmacokinetics of Clindamycin
• Good oral absorption, can be given Intravenously as well as topically.
• Oral dose of clindamycin is 0.15–0.3 g every 8 hours (10–20 mg/kg/d for
children)
• Intravenous dose of Clindamycin is 600 mg every 8 hours
• Food does not interfere absorption
• Clindamycin penetrates well into most tissues including bones, joints as
well as abscesses, but poor distribution to brain and CSF.
• The drug is about 90% protein bound.
• Hepatic metabolism (CYP3A4), renal and biliary excretion
• The half-life is about 3 hours in normal individuals, increasing to 6 hours in
patients with anuria (No dose adjustment in patients with renal
impairment)
 Adverse Effects of Clindamycin
• Common adverse effects are diarrhea, nausea, and skin
rashes.
• Impaired liver function (with or without jaundice) and
neutropenia (Rare ADR)
• Administration of clindamycin is a risk factor for diarrhea and
psuedomembranous enterocolitis caused by Clostridium
difficile (antibiotic associated colitis) can be fatal (6% of
incidence)
 Therapeutic Uses of Clindamycin
• MRSA soft tissue infections (methicillin-resistant S aureus, an
increasing cause of soft tissue and skin infections)
• Lung abscesses
• Gynecological infections such as pelvic inflammatory disease (PID)
• Clindamycin is also indicated for treatment of infections caused by
Bacteroides sp and other anaerobes
• Clindamycin, sometimes in combination with an aminoglycoside or
cephalosporin, is used to treat penetrating wounds of the abdomen
and the gut
 ….Cont
• Prophylaxis of endocarditis in patients with specific valvular heart disease
who are undergoing certain dental procedures and have significant
penicillin allergies (recommended more than erythromycin)
• It is also used in combination with pyrimethamine for AIDS-related
toxoplasmosis of the brain (Toxoplasmic encephalitis in sulfa allergy)
• Combined with primaquine as alternative to Sulfamethaxazole-
Trimethoprim for moderate to severe Pneumocystis jiroveci pneumonia in
AIDS patients.
• Plasmodium resistance (Doxycycline, Clindamycin: Antibiotic antimalaria)
• Effective against beta-lactamase producing bacteria & can be used in
patients allergic to penicillin or cephalosporins.
Linezolid
• Linezolid is a member of the oxazolidinones, a newer
class of synthetic antimicrobials
• It is protein synthesis inhibitors
• Dose: 600mg oral/IV twice dose per day
 Mechanism of action of Linezolid
• Binds to 23 S ribosomal RNA of the 50 S subunit during early
ribosomal assembly & inhibits protein synthesis.
• competitive inhibition by chloramphenicol has been
observed.
• mutations in the 23 rRNA result in resistance to linezolid.
• inhibits both A & B subtypes of monoamine oxidase (MAO)
 Antimicrobial activity of Linezolid
• Aerobic gram-positive bacteria
S. aureus
Coagulation-negative Staph
Enterococci
Streptococci
• Spectrum of activity also includes some gram-negative bacteria
(Neisseria spp), anaerobic bacteria & mycobacterium
tuberculosis.
• Bacteriostatic in nature (bactericidal only against streptococci)
 Pharmacokinetics of Linezolid
• Linezolid is 100% bioavailable after oral administration
• It has half-life of 4–6 hours.
• It is metabolized by oxidative metabolism, yielding two
inactive metabolites.
• It is neither an inducer nor an inhibitor of cytochrome P450
enzymes.
• The recommended dosage for most indications is 600 mg
twice daily, either orally or intravenously.
 Adverse effects of Linezolid
1. Hematological Toxicity (Very common)
• The principal toxicity of linezolid is hematologic; the effects
are reversible and generally mild. Thrombocytopenia is the
most common manifestation (seen in approximately 3% of
treatment courses), particularly when the drug is
administered for longer than 2 weeks.
• Anemia and neutropenia may also occur, most commonly in
patients with a predisposition to or underlying bone marrow
suppression
 ….Cont
2. Peripheral neuropathy, optic neuropathy (Peripheral neuropathy
of Grade 2 or Higher and optic Neuritis of any grade 1-4 should
lead to permanent discontinuation of Linezolid)
3. SEROTONIN SYNDROME. Linezolid is a reversible inhibitor of
MAO, and can result in clinically significant drug interactions with
adrenergic or serotonergic drugs (e.g. SSRI antidepressants) &
tyramine containing foods (increase in BP with tyramine
containing foods or vasopressor “cold medications”): The FDA
has issued a warning regarding the use of the drug with
serotonergic agents.
4. Lactic acidosis
 Therapeutic uses of Linezolid
• Infections caused by Multidrug resistant Gram+ bacteria
• vancomycin-resistant Enterococcus faecium (VRE)
• Skin & skin structure infections including diabetic foot ulcers
(without osteomyelitis):
• hospital acquired (nosocomial) pneumonia caused by
MRSA, MSSA & S. pneumoniae; but generally reserved for
MRSA.
• Off-label uses of linezolid include treatment of multidrug-
resistant tuberculosis and Nocardia infections
Chloramphenicol

• Chloramphenicol is derived from the soil sample collected

in Venezuela Streptomyces venezuelae (1947)
• Chloramphenicol succinate is used for parenteral
 Mechanism of action of Chloramphenicol

1. Inhibit bacterial protein synthesis

2. Binds to specific nucleotides within the 50S ribosome
3. Inhibits peptidyl transferase activity & peptide bond
formation (Inhibit Transpeptidation)
 ….Cont
chloramphenicol can inhibit both bacterial and mitochondrial
ribosomes (but not cytoplasmic). This results in oxidative
stress (mitochondrial toxicity)
Inhibition of mitochondrial function is thought to be the
mechanism underlying dose-dependent reversible bone
marrow suppression.
There is some evidence that reactive metabolites of
chloramphenicol may be mutagenic, resulting in the
development of aplastic anemia.
 Antimicrobial action of Chloramphenicol

• Broad spectrum
• Both gram positive and gram negative bacteria
• Aerobic and anaerobic
• It is active also against Rickettsiae but not
Chlamydiae.
• Bacteriostatic
 Mechanism of Chloramphenicol Resistance
• Chloramphenicol resistance is due to production of
chloramphenicol acetyltransferase, a plasmid-encoded
enzyme that inactivates the drug.
• Decrease penetration of chloramphenicol into the bacteria
(mutation)
 Pharmacokinetics of Chloramphenicol
• Oral absorption, wide distribution in body including CSF (rapid):
such that the concentration of chloramphenicol in brain tissue
may be equal to that in serum
• hepatic metabolism to glucuronide and renal excretion
• Excretion mainly Urine, small amount is excreted into bile and
urine
• Its also given through I.V
• Plasma half-life is upto 3 ½ hours.
• The usual dosage of chloramphenicol is 50–100 mg/kg/d.
• Maximum dose: 1gm
 …Cont
• The systemic dosage of chloramphenicol need not be altered
in renal insufficiency, but it must be reduced markedly in
hepatic failure.
• Newborns less than a week old and premature infants also
clear chloramphenicol less well, and the dosage should be
reduced to 25 mg/kg/d.
 Adverse Effects of Chloramphenicol
1. Bone marrow suppression (dose-dependent & reversible)
2. APLASTIC ANEMIA (idiosyncratic, rare, lethal)
3. Gray baby syndrome
– Vomiting
– Limp body tone
– Gray skin color
– Cyanosis - blue lips & skin
– Hypotension
– Cardiovascular collapse
4. Superinfection (oral or vaginal candiasis)
 Gray Baby Syndrome of Chloramphenicol
1. Lower level of hepatic glucoronyl transferase enzyme activity
in the first 2 to 3 weeks resulting deficient conjugation of
chloramphenicol in the liver
2. Immaturity of renal tubules leading to impairment of
excretion of chloramphenicol
3. Symptoms of Gray baby syndrome includes: vomiting,
lethargy, anorexia, abdominal distension and shallow
respiration, later the conditions worsens (hypothermia,
flaccidity, peripheral vascular collapse, gray cyanosis and
death may occur)
 …Cont
• Adults occasionally develop gastrointestinal disturbances,
including nausea, vomiting, and diarrhea (Rare in children)
• CNS toxicity: headache, peripheral neuritis, optic neuritis
secondary to drug induced pyridoxine deficiency, mental
confusion, depression and it may effect cochlear function if
given during ear infection.
• Chloramphenicol inhibits hepatic microsomal enzymes that
metabolize several drugs. Half-lives of these drugs are
prolonged, and the serum concentrations of phenytoin,
Tolbutamide, Chlorpropamide, and warfarin are increased.
 Therapeutic uses of Chloramphenicol
• Because of potential toxicity, bacterial resistance, and the
availability of many other effective alternatives,
chloramphenicol (It is rarely used in the United States)
• it is used more commonly in developing countries because it
remains as an inexpensive and effective antibiotic
• A “treatment of last choice” for multiple drug-resistant
organisms (e.g. vancomycin-resistant Enterococcus)
 ….Cont
• It may be considered for treatment of serious rickettsial
infections such as typhus (Typhoid Fever is drug of choice)
and Rocky Mountain spotted fever. (First line typoid drugs:
Ampicillin, Cipropfloxacin, 3rd gen cephalosporins)
• It is an alternative to a β-lactam antibiotic for treatment of
bacterial meningitis occurring in patients who have major
hypersensitivity reactions to penicillin.
• Chloramphenicol is used topically in the treatment of eye &
ear infections
 Streptogramins
• Quinupristin-dalfopristin
• Similar to aminoglycosides
• Approved for infections caused by staphylococci or
vancomycin resistant strains
 Streptogramins
• Combination of dalfospristin (streptogramin A)
& quinupristin (streptogramin B)
Pharmacokinetics
1. Administered by intravenous infusion.
2. Concentration-dependent mechanism with a long post-
antibiotic effect against many gram-positive organisms
3. Hepatic metabolism (CYP3A4); metabolites have antimicrobial
activity
4. Biliary & fecal elimination; hepatic function should be normal
5. Does NOT reach therapeutic levels in the CSF
 Antimicrobial Spectrum of Streptogramins

• Active against most gram-positive organisms EXCEPT E. faecalis

• Active against some gram-negative organisms
• Bactericidal (when they are combined together; individually they
are bacteriostatic)
Resistance occurs by 3 mechanisms:
1. Conformational change at 23S target site
2. Enzymatic inactivation
3. Bacterial expression of efflux pumps
 Mechanism of action of Streptogramins

• Mechanism of action is similar to Macrolides

• The streptogramins binding site in the exit tunnel overlaps
the binding sites to which clindamycin and the macrolides
bind to.
• Hence when resistance develops due to ribosomal
methylation that reduces binding, all three antibiotics are
similarly affected
 …Cont
Adverse effects of Streptogramins
• Irritation at the infusion site (1/3rd)
• Arthralgias (9%); myalgias with normal CPK (7%) - seen more
in patients with chronic liver disease or receiving
cyclosporine or mycophenolate
Drug-Drug Interactions
• Drugs that inhibit CYP3A4 (e.g. diazepam, verapamil, statins,
most HIV protease inhibitors)
• Drugs that prolong the QTC
 Therapeutic Uses of Streptogramins
1. Treatment of patients with serious or life-threatening
infections caused by vancomycin-resistant Enterococcus
faecium (VRE) bacteremia
2. Complicated skin related infections caused by MSSA
or Streptococcus pyogenes
3. Clinical benefit has been shown in UTIs, catheter-related
blood stream infections & bone/joint infections due to
VRE & MRSA