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Marc Imhotep Cray, M.D.

Respiratory Infections
Upper respiratory infection
 Most are viral: common cold, pharyngitis, rhinitis, sinusitis
etc.
Lower respiratory infection
 Frequently viral
 Bronchitis (or) asthma: cough, wheezing, dyspnea
 Pneumonia: cough, fever, (chills), rapid respiration, dyspnea

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Marc Imhotep Cray, M.D.
Case 1
A 68-year-old man presents to the emergency department complaining of a
fever, dyspnea, and a cough productive of green sputum. Physical
examination reveals an ill-appearing man, breathing heavily.
On lung examination, you note bronchial breath sounds and dullness to
percussion over the right lower lung lobe. A chest x-ray demonstrates
circumscribed opacity over the region of his right lower lung lobe. You obtain
sputum and blood cultures and then admit this patient to the hospital for
antibiotic treatment.

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Marc Imhotep Cray, M.D.
Pneumonia: Overview
 Pneumonia is a respiratory disease characterized by inflammation of lung
parenchyma (excluding bronchi) caused by viruses, bacteria, fungi, or
irritants
 Treatment varies according to the situation

 General clinical signs and symptoms of pneumonia include:
 Fever, chills, muscle stiffness, pleuritic chest pain, cough, blood-tinged or rusty sputum,
shortness of breath, rapid heart rate, and difficulty breathing

 Diagnosis is made by several laboratory methods and (or) diagnostic
procedures, including:
 Chest x-ray; Gram stain and culture (bacterial); bronchoalveolar lavage (Pneumocystis
carinii pneumonia [PCP]); serodiagnosis (Mycoplasma)

 Classic laboratory findings associated with bacterial pneumonia are a
neutrophilic leukocytosis with an increase in band neutrophils (left shift)
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Marc Imhotep Cray, M.D.
Pneumonia: Overview (2)
The four most common bacteria causing sinus and respiratory
infections are:
1. Streptococcus pneumoniae
2. Hemophilus influenzae
3. Staphylococcus aureus
4. Mycoplasma pneumoniae

Three common morphologic patterns of pneumonia are:
1. Lobar pneumonia
2. Bronchopneumonia and
3. Interstitial pneumonia
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Marc Imhotep Cray, M.D.
Pneumonias: Classification

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)
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Marc Imhotep Cray, M.D.
Common causes of pneumonia
Neonates Children Adults Adults Elderly
(< 4 Wks.) (4 Wks.–18 Yrs.) (18–40 Yrs.) (40–65 Yrs.)
Group B Viruses (RSV) Mycoplasma S. pneumoniae S. pneumoniae
streptococci Mycoplasma C. pneumoniae H. influenzae Influenza virus
E. coli C. trachomatis S. pneumoniae Anaerobes Anaerobes
(infants–3 yr.) Viruses H. influenzae
C. pneumoniae Mycoplasma Gram-negative
(school-aged rods
children)
S. pneumoniae
Redrawn and modified from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015

Note: Most common pneumonias in childhood are Viral pneumonias
Most commonly implicated viruses are Influenza, parainfluenza,
respiratory syncytial virus, rhinovirus, and adenovirus
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Marc Imhotep Cray, M.D.
Common causes of pneumonia (2)
Special groups
Alcoholic/IV drug user S. pneumoniae, Klebsiella, S. aureus
Aspiration Anaerobes (e.g., Peptostreptococcus, Fusobacterium,
Prevotella, Bacteroides)
Atypical Mycoplasma, Legionella, Chlamydia
Cystic fibrosis Pseudomonas, S. aureus, S. pneumoniae

Immunocompromised S. aureus, enteric gram-negative rods, fungi, viruses, P.
jirovecii (with HIV)
Nosocomial (hospital S. aureus, Pseudomonas, other enteric gram-negative rods
acquired)

Postviral S. aureus, H. influenzae, S. pneumoniae
Redrawn from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015

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Marc Imhotep Cray, M.D.
Lobar Pneumonia
 S. pneumoniae most frequently, also Legionella, Klebsiella
Intra-alveolar exudate consolidation (A) may involve entire lobe (B) or lung

A B
Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

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Marc Imhotep Cray, M.D.
Bronchopneumonia
 S. pneumoniae, S. aureus, H. influenzae, Klebsiella
 Acute inflammatory infiltrates (C) from bronchioles into adjacent alveoli
 patchy distribution involving ≥ 1 lobe (D)

C D
Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

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Marc Imhotep Cray, M.D.
Interstitial (atypical) pneumonia
 Viruses (influenza, CMV, RSV, adenoviruses), Mycoplasma, Legionella,
Chlamydia
 Diffuse patchy inflammation localized to interstitial areas at alveolar walls;
diffuse distribution involving ≥ 1 lobe (E)
 Generally follows a more indolent course (“walking” pneumonia)

Le T and Bhushan V. First Aid for the USMLE
Step 1 2015 (McGraw-Hill 2015) 11
Marc Imhotep Cray, M.D.
Interstitial & Lobar Pneumonias Compared

A B
Le T and Bhushan V. First Aid for the USMLE Step 1 2015 (McGraw-Hill 2015)

Compare diffuse, patchy bilateral infiltrates of “atypical” interstitial
pneumonia (A) with the localized, dense lesion of lobar pneumonia (B)

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Marc Imhotep Cray, M.D.
Companion Notes:
 MedPharm Digital Guidebook 2015, UNIT 10 Drugs Used In Infectious Disease
 eNotes Infectious Diseases Pharmacology
 Rapid Review Antimicrobial Drugs and Vaccines
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Marc Imhotep Cray, M.D.
Key Concepts
 Antibiotics exploit differences between prokaryotic and
eukaryotic cells to promote specificity and limit toxicity
 For example, bacterial enzymes involved in DNA replication
and RNA synthesis are different from those found in
eukaryotic cells
 bacterial ribosome is also significantly different, allowing
selective targeting

 One of major differences between bacteria and eukaryotic cells
is peptidoglycan-containing bacterial cell wall whose synthesis
is inhibited by several antibiotics

Marc Imhotep Cray, M.D.
Antibiotics target bacteria by five major
mechanisms
1. Inhibition of cell wall synthesis
2. Inhibition of protein synthesis
3. Inhibition of nucleic acids
4. Alterations of cellular membranes
5. Antimetabolites

Marc Imhotep Cray, M.D.
Mechanisms of antibiotic action
A: Schematic showing cell wall–active, membrane-active, & cytoplasm-active antimicrobial agents
B: Antibiotics that inhibit protein synthesis by interacting with different ribosome subunits
C: Antibiotics that inhibit nucleic acid synthesis

Somers KD and Morse SA. Lange Flash Cards: Microbiology & Infectious Diseases. New York: McGraw-Hill, 2010
Marc Imhotep Cray, M.D.
1. Inhibition of cell wall synthesis
β-lactam antibiotics such as penicillin and cephalosporins
target peptidoglycan cross-linking by binding to and inhibiting
action of transpeptidase enzymes
 Vancomycin inhibits cross-linking by binding terminal D-
alanine- D-alanine precursor and preventing transpeptidation
Cycloserine inhibits formation of D-alanine-D-alanine linkage
Bacitracin inhibits transport of new peptidoglycan precursors
through cell membrane
 Isoniazid and ethionamide inhibit mycolic acid synthesis in
mycobacteria

Marc Imhotep Cray, M.D.
2. Inhibition of protein synthesis
Aminoglycosides such as gentamicin, neomycin, and kanamycin
irreversibly bind and inhibit function of 30S ribosomal subunits
 contrast to most inhibitors of microbial protein synthesis, which are
bacteriostatic, aminoglycosides are bactericidal
Tetracyclines reversibly inhibits binding of aminoacyl-tRNA to
30S subunit

Macrolides such as erythromycin, azithromycin, and
clarithromycin attach to a 23S RNA on 50S subunit resulting in
its inhibition

Chloramphenicol blocks attachment of amino acids to nascent
peptide chain on 50S subunit resulting in its inhibition
Marc Imhotep Cray, M.D.
3.Inhibition of nucleic acids
 Quinolones and fluoroquinolones such as ciprofloxacin inhibit
DNA synthesis by blocking DNA gyrase

 Rifampin binds strongly to DNA-dependent RNA polymerase
and thus inhibits RNA synthesis

 Metronidazole interacts with DNA, altering its helical structure
and causing DNA fragmentation

Marc Imhotep Cray, M.D.
4. Alterations of cellular membranes
 Polymyxin targets cell membranes rich in
phosphatidylethanolamine, causing an increase in cellular
permeability

5. Antimetabolites
 Sulfonamides and trimethoprim inhibit folic acid metabolism

Marc Imhotep Cray, M.D.
Sites of Action of Major Antibacterials
Summary Table
Folate DNA RNA Ribosomal subunit Cell wall
pathway 30S 50S
Antimetabolites Quinolones Inhibits RNA Aminoglycosides Macrolides β-lactam
Sulfamethoxazole Ciprofloxacin synthesis Gentamicin and Erythromycin antibiotics
Trimethoprim Rifampin Tetracyclines Lincosamides Penicillins
Doxycycline Clindamycin Cephalosporin
Chloramphenicol s
Oxazolidinones Aztreonam
Linezolid Imipenem
Streptogramins Vancomycin
Quinupristin/ Polymyxin B
dalfopristin

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Marc Imhotep Cray, M.D.
Antibacterials Summary Schematic

Marc Imhotep Cray, M.D. Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010 22
Antibiotic Resistance Mechanisms

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Marc Imhotep Cray, M.D.
Antibiotic Resistance Mechanisms
 Bacteria have evolved a number of mechanisms to protect themselves
from action of antibiotics Altered expression of proteins in drug-
resistant organisms

 Often genes encoding antibiotic resistance are carried on transposons
and plasmids, and are therefore easily transferred from one organism to
another, creating bacteria resistant to multiple antibiotics
 Drug resistance is mediated by a variety of mechanisms, such as:
 alteration in antibiotic target site lowered penetrability of drug due to
o decreased permeability
o increased efflux of drug, or
o presence of antibiotic-inactivating enzymes
o modification of target sites
Marc Imhotep Cray, M.D.
Four major mechanisms are involved
1. Inactivation of antibiotic through hydrolysis
 An example is β-lactamases that cleave β-lactam ring of
penicillins and cephalosporins

2. Chemical modification of antibiotic through acetylation,
phosphorylation, or adenylylation
 An example is chloramphenicol acetyl transferase that transfers
an acetyl group from acetyl CoA to chloramphenicol, resulting in
its inactivation

Marc Imhotep Cray, M.D.
Four major Ab resistance mechanisms cont.
3. Alteration of antibiotic targets through mutation
 An example is alteration of a single amino acid in ribosomal
protein S12 prevents streptomycin binding to 30S ribosome
subunit without affecting protein synthesis (See next slide for
more)

4. Alterations that affect permeability (ie, decrease
intracellular concentration of antibiotic) are used by a variety of
antibiotics
 This can involve a decreased influx or an increased efflux from
bacterial cell

Marc Imhotep Cray, M.D.
Examples of bacterial resistance due to
alterations of antibiotic targets
Pneumococcal resistance to penicillins is due to changes in
chemical structures of target penicillin-binding proteins
located in bacterial cytoplasmic membrane
 A similar mechanism underlies resistance of
staphylococci to methicillin (MRSA strains)

 A structural alteration in the d-Ala-d-Ala component of
pentapeptide side chains of peptidoglycans is basis for a
mechanism of resistance to vancomycin

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Marc Imhotep Cray, M.D.
“An Admonition” Mild, kind , yet earnest
reproof. Cautionary advice or warning.
“Learning the characteristics of antibiotics
simplifies learning infectious disease
pharmacotherapy. Students and clinicians who
attempt to learn the antibiotics of choice for
different types of infections before knowing the
characteristics of those drugs never truly
understand the context of what they are
attempting to learn. Once the characteristics
of the antibiotics are known, making a logical
choice to treat an infection is much easier.”
Gallagher JC, MacDougall C. Antibiotics simplified. 2nd Ed.
Jones & Bartlett Learning, 2012

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Marc Imhotep Cray, M.D.
Pharmacology of Common Antibiotics
Used to Treat Bacterial Pneumonia
Penicillin
Azithromycin
Amoxicillin
Ciprofloxacin
Amoxicillin/clavulanate
Clarithromycin
Cefaclor
Erythromycin
Cefotaxime
Imipenem
Ceftazidime
Metronidazole
Ceftriaxone
Rifampin
Cefuroxime
Tetracycline
Cefuroxime axetil
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Marc Imhotep Cray, M.D.
Penicillins
EXAMPLES (in order of narrowest to broadest spectrum)
 Natural penicillins – benzylpenicillin, phenoxymethylpenicillin
 Antistaphylococcal penicillins – nafcillin, oxacillin
 Aminopenicillins– ampicillin, amoxicillin
MECHANISM OF ACTION (MOA)
 β lactam moiety binds to and inhibits transpeptidase required for
formation of peptidoglycan cross-links within bacterial cell wall results in
defective bacterial cell wall synthesis and subsequent cytolysis
 Nafcillin & oxacillin are relatively resistant to staphylococcal β lactamases
 Aminopenicillins have enhanced activity against aerobic Gram-negative
bacilli
 Piperacillin when combined with tazobactam (a β-lactamase inhibitor) has
good activity against Pseudomonas spp.
 Augmentin (or) Co-amoxiclav is a combination of amoxicillin and clavulanic
acid (a β lactamase inhibitor)
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Marc Imhotep Cray, M.D.
Penicillins cont. SIDE-EFFECTS
 Urticarial rash
INDICATIONS  Anaphylaxis
 Pharyngitis/tonsillitis  GI disturbance
 Pneumonia  Antibiotic-associated colitis
 Otitis media  Stevens–Johnson syndrome
 Cellulitis  Fever
 Meningitis  Joint pains
 Endocarditis  Rarely cholestatic jaundice w co-
 Rheumatic fever amoxiclav
 Osteomyelitis METABOLISM AND HALF-LIFE
 UTI Elimination is via kidneys and biliary tract
CAUTIONS & CONTRA-INDICATIONS t½ for benzylpenicillin is ~30 min; t½ for
 Hypersensitivity flucloxacillin is ~50 min; t½ for amoxicillin
(rashes, urticaria, angioedema, fever, is ~1h
arthralgia, acute interstitial nephritis (AIN) , MONITORING No specific drug
anaphylaxis) monitoring required 31
Marc Imhotep Cray, M.D.
Penicillins cont.
DRUG INTERACTIONS
 Reduced efficacy of OCP when taking penicillins Women should be
warned of this and advised to use alternative contraceptive methods

IMPORTANT POINTS
 Benzylpenicillin (penicillin G) must be administered parenterally because it
is inactivated by gastric acid secretions

 Phenoxymethylpenicillin (penicillin V) has a similar spectrum of activity to
benzylpenicillin but can be administered orally

 Patients with infectious mononucleosis may get a diffuse, erythematous,
maculopapular rash when treated with ampicillin or amoxicillin
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Marc Imhotep Cray, M.D.
Penicillins cont.
 Pneumococcal isolates causing meningitis with a minimal inhibitory
concentration (MIC) for penicillin G of greater than 2 mcg/mL are highly
resistant
 Such strains are not killed by concentrations of penicillin G or
ampicillin that can be achieved in the cerebrospinal fluid
 Nafcillin has minimal activity against penicillin-resistant pneumococci
 piperacillin is mainly used for infections caused by gram-negative rods

 Cefotaxime and ceftriaxone are the most active cephalosporins against
penicillin-resistant pneumococci
o addition of vancomycin is recommended in case of highly resistant
strains

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Marc Imhotep Cray, M.D.
Penicillin Antibacterials Summary Table

Marc Imhotep Cray, M.D.
Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010 34
Cephalosporins and other β-lactams
EXAMPLES:
 first-generation– cefalexin, cefradine
 second-generation – cefuroxime
 third-generation – cefotaxime, ceftriaxone, ceftazidime
 carbapenems – imipenem, ertapenem

MECHANISM OF ACTION:
 MOA similar to penicillins except cephalosporins are relatively resistant to
staphylococcal β lactamases
o All beta-lactams share a MOA inhibition of transpeptidases (that is,
penicillin binding proteins) in the bacterial cell wall
 Penetrate CSF poorly unless meningeal inflammation is present

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Marc Imhotep Cray, M.D.
Cephalosporins and other β-lactams cont.
INDICATIONS SIDE-EFFECTS
 Pneumonia  Urticarial rash
 Sepsis  Anaphylaxis
 Biliary tract infection  GI disturbance
 UTI  Stevens–Johnson syndrome
 Peritonitis  Cholestatic jaundice (ceftriaxone)
 Meningitis

CAUTIONS AND CONTRA-INDICATIONS
 Hypersensitivity
 Caution in renal impairment
(dose adjustment required)
 Antibiotic-associated colitis
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Marc Imhotep Cray, M.D.
Cephalosporins and other β-lactams cont.
METABOLISM AND HALF-LIFE Excreted via the kidneys
 t½ for cefotaxime is ~1h
 t½ for ceftriaxone is 6–9 h
 t½ for imipenem is ~1h
 t½ for piperacillin–tazobactam is 36–72 min
MONITORING No specific drug monitoring required

DRUG INTERACTIONS
Reduced efficacy of OCP when taking cephalosporins women should be
warned and advised to use alternative contraceptive methods

IMPORTANT POINT
 10% of patients who are hypersensitive to penicillins may have a similar
reaction to cephalosporins and other β lactams 37
Marc Imhotep Cray, M.D.
Beta-lactam Antibacterials (Other than PCN)

AP, anti-pseudomonal Johannsen EC. & Sabatine MS. PharmCards, 4th ed. Lippincott Williams & Wilkins, 2010

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Marc Imhotep Cray, M.D.
Macrolides
EXAMPLES erythromycin, azithromycin, clarithromycin

MECHANISM OF ACTION
Inhibition of bacterial RNA-dependent protein synthesis by reversibly binding
to 50S subunit of ribosomes within organism This affects bacterial growth
and may be either bacteriostatic or bacteriocidal

INDICATIONS
Respiratory tract infections
 Campylobacter enteritis
 Urethritis (non-gonococcal)
 Pertussis infection
 Skin and soft tissue infections
 Otitis media
 Helicobacter pylori eradication
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Marc Imhotep Cray, M.D.
Macrolides cont.
CAUTIONS & CONTRA-INDICATIONS METABOLISM & HALF-LIFE
 Liver disease  Metabolized in liver and excreted via
 Hypersensitivity biliary route
 t½ is variable – t½ for erythromycin is
SIDE-EFFECTS 1–1.5 h; t½ for azithromycin is 2–4
 Nausea and vomiting days; t½ for clarithromycin is 3–7 h
 Diarrhea
 Hepatitis MONITORING No specific drug
 Anorexia monitoring required
 Pancreatitis
 Headaches

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Marc Imhotep Cray, M.D.
Macrolides cont.
DRUG INTERACTIONS
 Enhanced anticoagulant effect of warfarin
 Macrolides inhibit metabolism of theophylline thereby increasing plasma
levels
 Increased plasma levels of carbamazepine with concomitant use of
macrolides
 Increased risk of cardiac arrhythmias with amiodarone due to QT
prolongation

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Marc Imhotep Cray, M.D.
Macrolides cont.
IMPORTANT POINTS
 Erythromycin has similar bacterial sensitivity to penicillins and therefore
can be used as an alternative in penicillin allergic patients

 Helicobacter pylori eradication therapy consists of 2 antibiotics and a PPI
o Current guidance suggest 1week of either amoxicillin or metronidazole
and clarithromycin and a PPI

 Macrolides are effective against community-acquired pneumonia caused
by atypical organisms (Mycoplasma spp., Chlamydia spp., Legionella spp.)

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Marc Imhotep Cray, M.D.
Macrolides cont. Erythromycin
 Inhibition of liver cytochrome P450 by erythromycin has led to serious
drug interactions

 Erythromycin inhibits CYP1A2 form of cytochrome P450, which
metabolizes methylxanthines
 Consequently, cardiac and/or CNS toxicity may occur with
excessive ingestion of caffeine
 Unlike the tetracyclines, oral absorption of erythromycin is not
affected by cations and drug does not cause photosensitivity
 Because erythromycin undergoes biliary excretion, there is little
reason to assess renal function before treatment

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Marc Imhotep Cray, M.D.
Macrolides cont. Azithromycin
 Azithromycin has a half-life of more than 70 h, which allows for once-
daily dosing and a 5-d course of treatment for community-acquired
pneumonia

 Unlike other macrolides, azithromycin does not inhibit cytochrome
P450 enzymes involved in drug metabolism

 Depending on resistance patterns in community, it is possible to
treat community-acquired pneumonia (CAP) with a single
antibiotic, and azithromycin is one of the antibiotics commonly
used

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Marc Imhotep Cray, M.D.
Metronidazole
MECHANISM OF ACTION
Metronidazole possesses a nitro-group that becomes charged and trapped
within intracellular compartment of anaerobes leads to bacterial DNA
damage and ultimately strand breakage  cell death

INDICATIONS
 Surgical prophylaxis
 Anaerobic infections (including dental and abdominal sepsis)
 Aspiration pneumonia
 Protozoal infections
 Pelvic inflammatory disease

CAUTIONS AND CONTRA-INDICATIONS
 Known hypersensitivity to metronidazole
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Marc Imhotep Cray, M.D.
Metronidazole cont.
SIDE-EFFECTS
 GI disturbance
 Metallic taste in mouth
 Anorexia
 Rarely hepatitis
 Pancreatitis Peripheral neuropathy (with prolonged therapy)

METABOLISM AND HALF-LIFE
 t½ is ~8.5 h.
 Metabolized to active compounds by the liver with 75% excreted
in urine

MONITORING No specific drug monitoring required
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Marc Imhotep Cray, M.D.
Metronidazole cont.
DRUG INTERACTIONS
 Alcohol should be avoided while taking metronidazole (see below)
 Possible potentiation of anticoagulant therapy has been reported when
metronidazole is used with warfarin

IMPORTANT POINTS
 Metronidazole is a potent inhibitor of obligate anaerobes and protozoa such
as Trichomonas spp. and Entamoeba spp.
 Patients should be advised to completely avoid alcohol during and for 48 h
after a course of metronidazole due to the risk of a severe disulfiram-like
reaction (flushing and hypotension)
 Metronidazole can be used in chronic renal failure however, it is rapidly
removed from plasma by dialysis

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Marc Imhotep Cray, M.D.
Quinolones
EXAMPLES Ciprofloxacin, levofloxacin, ofloxacin

MECHANISM OF ACTION
 Bactericidal action of ciprofloxacin results from inhibition of both type II
(DNA gyrase) and type IV topoisomerases, required for bacterial DNA
replication, transcription, repair and recombination

INDICATIONS
 UTI
 Infections of the GI system
 Bronchopulmonary infections
 Typhoid fever
 Gonorrhea and non-gonococcal urethritis and cervicitis
 Anthrax
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Marc Imhotep Cray, M.D.
Quinolones cont.
CAUTIONS AND CONTRA-INDICATIONS SIDE-EFFECTS
Patients with a history of tendon disorders  GI disturbance
related to quinolones  Headaches
Pregnancy, children and growing  Dizziness
adolescents (due to risk of joint arthropathy)  Rashes
Avoid in patients with CNS disorders (including Stevens–Johnson syndrome)
(e.g. epilepsy -can reduce seizure threshold)  Tendon inflammation and
METABOLISM AND HALF-LIFE damage
 t½ for ciprofloxacin is 3-6 h  Confusion, anxiety and
 Ciprofloxacin is excreted predominately depression
unchanged in urine  Phototoxicity with excessive
sunlight
MONITORING No specific drug monitoring  Seizures
required
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Marc Imhotep Cray, M.D.
Quinolones cont.
DRUG INTERACTIONS
 Increased risk of nephrotoxicity when quinolones given with cyclosporin

 Possible increased risk of convulsions when quinolones given with NSAIDs or
theophylline (also increases theophylline levels)

 Ciprofloxacin enhances anticoagulant effect of warfarin

 Increased risk of torsades de pointes with other drugs that also prolong the
QT interval

 Reduced efficacy when given with aluminum- or magnesium-containing
antacids or iron preparations
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Marc Imhotep Cray, M.D.
Quinolones cont.
IMPORTANT POINTS
 Quinolones may impair performance of skilled tasks (e.g. driving); this
effect is enhanced by alcohol

 Discontinue if psychiatric, neurological or hypersensitivity reactions
(including severe rash) occur

 Ciprofloxacin is active against Gram-negative bacteria such as Salmonella
spp., Shigella spp., Campylobacter spp., Neisseria spp. and Pseudomonas
spp.

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Marc Imhotep Cray, M.D.
Tetracyclines
EXAMPLES Doxycycline, tetracycline, oxytetracycline

MECHANISM OF ACTION
 Active uptake into a susceptible organism results in inhibition of
protein synthesis
 Their bacteriostatic effect is achieved by binding to prokaryotic 30S
ribosomal subunit and inhibiting aminoacyl tRNA and mRNA
ribosomal complex formation

 Additionally, topical tetracyclines are used in treatment of acne
 This effect is mediated through inhibition of neutrophil activity and
pro-inflammatory reactions, including those associated with
o phospholipase A2
o endogenous nitric oxide and
o interleukin-6
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Marc Imhotep Cray, M.D.
Tetracyclines cont.
INDICATIONS
SIDE-EFFECTS
 Urogenital tract infections (e.g. salpingitis,
 GI disturbance
urethritis caused by Chlamydia spp.)
 Dysphagia and esophageal
 LRTI (particularly Haemophilus influenzae
irritation
infections in COPD patients)
 Blood disorders
 Acne vulgaris and rosacea
 Hypersensitivity reactions
CAUTIONS AND CONTRA-INDICATIONS (including Stevens–Johnson
 Hypersensitivity to tetracyclines syndrome)
 Children under 12  Photosensitivity
(deposition in bone and teeth – risk of staining)
 Pregnancy and breastfeeding
 Acute porphyria
 Chronic kidney disease
 Tetracyclines’ oral absorption is impaired by
cations chelation 53
Marc Imhotep Cray, M.D.
Tetracyclines cont.
METABOLISM AND HALF-LIFE
t½ is variable depending on drug
Tetracyclines are concentrated by liver in bile and excreted in urine and feces at high
concentrations in a biologically active form

MONITORING No specific monitoring required

DRUG INTERACTIONS
Tetracyclines can enhance effects of warfarin (due to enzymatic inhibition)
Risk of idiopathic intracranial hypertension when tetracyclines used with retinoids
Doxycycline can increase plasma concentrations of cyclosporine

IMPORTANT POINTS
 Patients are advised to use high-factor sun protection and avoid direct sun exposure when
on doxycycline (due to photosensitivity)
 Tetracyclines should be avoided in anyone taking potentially hepatotoxic drugs
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Marc Imhotep Cray, M.D.
Trimethoprim
MECHANISM OF ACTION METABOLISM AND HALF-LIFE
Binds to bacterial dihydrofolate reductase and Approximately 50% is bound to plasma
irreversibly inhibits production of protein
tetrahydrofolate  a precursor for synthesis of t½ ranges from 8.6–17 h.
thymidine results in inhibition of bacterial Elimination is via kidneys
DNA synthesis
MONITORING No specific drug monitoring
INDICATIONS required
UTI
CAUTIONS AND CONTRA-INDICATIONS
. Blood dyscrasias
. Caution in patients with renal impairment
SIDE-EFFECTS
. GI disturbance
. Pruritis
. Rashes
. Hyperkaliemia
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Marc Imhotep Cray, M.D.
Trimethoprim cont.
DRUG INTERACTIONS
 Increased risk of ventricular arrhythmias with amiodarone
 Increased risk of nephrotoxicity when given with cyclosporine
 Increased risk of hematological toxicity when given with azathioprine and
methotrexate

IMPORTANT POINTS
 Commonly sensitive organisms include Gram-positive aerobes
(Staphylococcus spp.) and Gram-negative aerobes (Enterobacter spp.,
Haemophilus spp., Klebsiella spp.)

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Marc Imhotep Cray, M.D.
Co-trimoxazole
 A combination of trimethoprim
and sulfamethoxazole which
inhibits an earlier stage of
tetrahydrofolate synthesis
o Drug of choice in the treatment
of Pneumocystis jiroveci
pneumonia

Dale M M. , Haylett DG. Rang & Dales’ ‘Pharmacology Flashcards.
57
Marc Imhotep Cray, M.D. Churchill Livingstone, 2014
Treatment of bacterial pneumonia
First-line and second-line antibiotics for adults and children

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Marc Imhotep Cray, M.D.
In Re of community acquired pneumonia (CAP)
 It is often difficult to establish a definite cause of community acquired
pneumonia (CAP)
 More than 80% of cases are caused by typical pathogens such as S
pneumoniae, H influenzae, or M catarrhalis, and 15% are due to
nonzoonotic atypical pathogens such as Legionella species,
Mycoplasma species, or C pneumoniae
 Currently, monotherapy coverage of both typical and atypical pathogens in
CAP is preferred to double-drug therapy
 Preferred initial therapy includes a macrolide, doxycycline, or a
quinolone active against respiratory pathogens

 Ampicillin, clindamycin, and vancomycin have low activity against atypical
pathogens in CAP
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Marc Imhotep Cray, M.D.
community acquired vs hospital-acquired
pneumonia
 In a community-acquired pneumonia, a wider spectrum cephalosporin
(ceftriaxone) would cover typical organisms, and erythromycin would
be active against the atypical organisms

 Single antimicrobial drug therapy would be inadequate coverage in a
hospital-acquired pneumonia that could include possible infection due
to multidrug-resistant staphylococci as well as gram-negative bacilli
such as Pseudomonas aeruginosa

 Vancomycin should cover gram positive organisms, and piperacillin
plus a penicillinase inhibitor (tazobactam) would be active against most
strains of likely gram-negative pathogens
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Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia
Adults
Type of infection
 Community acquired and mild to moderate disease
 No comorbidity

 S. pneumoniae, M. pneumoniae, C. pneumoniae, H. influenzae
First-line antibiotics
 Tetracycline, erythromycin

Second-line antibiotics
 Doxycycline, clarithromycin
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Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Type of infection
 With comorbidity
 Mixed infections with S. pneumoniae, H. influenzae, oral
anaerobes, Gram negative bacilli, S. aureus, Legionella sp.

First-line antibiotics
 Cefaclor, cefuroxime axetil, amoxicillin/clavulanate or any
of these plus erythromycin or clarithromycin

Second-line antibiotics
 Trimethoprim/sulfamethoxazole plus erythromycin
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Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Type of infection
 When community acquired severe disease in hospital, with
or without comorbidity S. pneumoniae, H. influenzae,
Legionella sp., M. pneumoniae, S. aureus, C. pneumoniae
 Comorbidity pathogens: anaerobes, Gram negative bacilli

First-line antibiotics
 Cefuroxime axetil, cefuroxime, cefotaxime, ceftriaxone, or
any of these plus erythromycin or clarithromycin ± rifampin

63
Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Type of infection
 With severe disease in ICU environment S. pneumoniae,
H. influenzae, Legionella sp., Gram-negative bacilli, P.
aeruginosa, S. aureus, M. pneumoniae, C. pneumoniae

First-line antibiotics
 Erythromycin ± rifampin plus either ciprofloxacin,
imipenem, or ceftazidime

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Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Type of infection
 In institutionalized elderly patients with mild to moderate
disease S. pneumoniae, H. influenzae, oral anaerobes,
Gram negative bacilli, S. aureus, Legionella sp.

First-line antibiotics
 Trimethoprim/sulfamethoxazole, cefaclor, cefuroxime
axetil, amoxicillin/clavulanate, or any one of the above ±
erythromycin or clarithromycin

65
Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Type of infection
 With severe disease S. pneumoniae, H. influenzae, oral
anaerobes, Gram negative bacilli, S. aureus, Legionella sp.

First-line antibiotics
 Cefaclor or cefuroxime axetil or amoxicillin/clavulanate or
ceftriaxone or combinations, penicillin or amoxicillin plus
ciprofloxacin

Second-line antibiotics
 Ciprofloxacin plus clindamycin
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Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Children
Type of infection
 With mild disease S. pneumoniae, S. aureus, streptococci
Group A, M. pneumoniae, H. influenzae

First-line antibiotics
 Amoxicillin, erythromycin estolate

Second-line antibiotics
 Trimethoprim/sulfamethoxazole, clarithromycin,
erythromycin/sulfisoxazole, amoxicillin/clavulanate, cefixime,
cefaclor, cefuroxime axetil chloramphenicol ± erythromycin or
clarithromycin
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Marc Imhotep Cray, M.D.
Treatment of bacterial pneumonia cont.
Children
Type of infection
 With severe disease S. pneumoniae, S. aureus,
streptococci Group A, M. pneumoniae, H. influenzae

First-line antibiotics
 Cefuroxime ± erythromycin estolate or clarithromycin

Second-line antibiotics
 Trimethoprim/sulfamethoxazole, clarithromycin,
erythromycin/sulfisoxazole, amoxicillin/clavulanate, cefixime,
cefaclor, cefuroxime axetil, chloramphenicol ± erythromycin or
Marc Imhotep Cray, M.D.
clarithromycin 68
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Marc Imhotep Cray, M.D.
Further study:
eLearning (IVMS Cloud Folders)
 Pharmacology
 Infectious Disease
 Microbial biology & Immune System
Textbooks:
 Batchelder A. et al. Rapid Clinical Pharmacology- A Student Formulary. 1st
ed. John Wiley & Sons, 2011
 Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th
Ed. New York: McGraw-Hill, 2016
 Gallagher JC, MacDougall C. Antibiotics simplified. 2nd Ed. Jones & Bartlett
Learning, 2012
 Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York:
McGraw-Hill, 2010
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Marc Imhotep Cray, M.D.