Antibacterial agents

(chapters 43-46)
Beta-Lactam Antibiotics & Other Cell
Wall Synthesis Inhibitors
 Introduction
• The cell wall of bacteria contains peptidoglycan, a substance
that does not occur in eukaryotes

• The Gram-positive cell wall is composed of a :

– thick, multilayered peptidoglycan sheath
– outside of the cytoplasmic membrane

• The Gram-negative cell wall is composed of:

– an outer membrane linked by lipoproteins to thin, mainly, single-
layered peptidoglyca
Cell wall structure of gram positive (a) and gram
negative (b) bacteria
 B-lactam drugs
• Beta-lactam antibacterial drugs:
1. Penicillins
2. Cephalosporins & Cephamycins
3. Carbapenems: imipenem
4. Monobactams: aztreonam

• Beta-lactamase inhibitors:
– clavulanic acid,
– sulbactam,
– and tazobactam
Penicillins/structure

• All penicillins are:

– derivatives of 6-aminopenicillanic acid and
– contain a beta-lactam ring structure :
• that is essential for antibacterial activity.
 Penicillins/Pharmacokinetics
• Oral bioavailability of penicillins vary
– due to their variable resistance to gastric acid .

• Parenteral formulations of ampicillin, piperacillin, and ticarcillin

are available for injection.

• Metabolism:
– Penicillins are polar compounds and are not metabolized
extensively.
• They are usually excreted unchanged in the urine via glomerular
filtration and tubular secretion.
• Tubular secretion is inhibited by probenecid (plasma conc↑)

– Exception: Nafcillin is excreted mainly in the bile.

 Penicillins/Pharmacokinetics

• Procaine and benzathine forms of penicillin G

(Benzylpenicillin) are:
– administered intramuscularly (acid labile orally)
– and have long plasma half-lives because the active drug is released
very slowly into the bloodstream. (lower solubility)

• Most penicillins cross the BBB only when the meninges are
inflamed.
Penicillins/Mechanisms of Action and Resistance

• Beta-lactam antibiotics are bactericidal drugs.

• They act to inhibit cell wall synthesis by the following steps:

– (1) binding of the drug to specific enzymes (penicillin-binding
proteins[PBPs]) located in the bacterial cytoplasmic membrane;
• (structural analogs of the natural D-Ala-D-Ala substrate)

– (2) inhibition of the transpeptidation reaction

• the final step in cell wall synthesis that cross-links the linear
peptidoglycan chain constituents of the cell wall;

– (3) this results in cell lysis through:

• osmotic pressure
• or activation of autolytic enzymes that cause lesions in the bacterial cell
wall.
 Bacterial resistance to penicillins
1. The formation of beta-lactamases (penicillinases)
• Beta-lactamases causes the enzymatic hydrolysis of the
beta-lactam ring resulting in loss of antibacterial activity.

• Inhibitors of Beta-lactamases e.g,:

• clavulanic acid,
• sulbactam,
• Tazobactam
…………….. are often used in combination with penicillins to
prevent their inactivation.
 Bacterial resistance to penicillins
2. Structural change in target PBPs , such as:
– methicillin resistance in staphylococci
– resistance to penicillin G in:
• pneumococci (eg, PRSP, penicillin resistant Streptococcus
pneumoniae)

3. Changes in the porin structures in the outer cell wall

membrane in some G-ve rods (eg, Pseudomonas
aeruginosa),
– may contribute to resistance by impeding access of penicillins to
PBPs.
 Penicillin subclasses
1. Narrow-Spectrum Penicillinase-Susceptible Agents:
– penicillin G (the prototype),
– penicillin V

2. Very-Narrow-Spectrum Penicillinase-Resistant Drugs

– methicillin (the prototype),
– nafcillin,
– oxacillin.

3. Wider-Spectrum Penicillinase-Susceptible Drugs

1. amoxicillin,
2. ampicillin,
3. Piperacillin
4. and Ticarcillin
 Penicillins/clinical uses/
Narrow-Spectrum Penicillinase-Susceptible Agents

• Penicillin G (acid labile, IV or IM) is the prototype of a

subclass of penicillins that have :
– a limited spectrum of antibacterial activity
– and are susceptible to beta-lactamases.

• Clinical uses , infections caused by:

– common streptococci,
– meningococci,
– gram-positive bacilli,
– and spirochetes.
• penicillin G remains the drug of choice for syphilis (caused by
spirochetes, Treponema pallidum) (although no longer
suitable for treatment of gonorrhea)
 Penicillins/clinical uses/
Narrow-Spectrum Penicillinase-Susceptible Agents
• Activity against enterococci is enhanced by aminoglycoside
antibiotics. (combination)

• Many strains of pneumococci are now resistant to penicillins

(penicillin-resistant Streptococcus pneumoniae [PRSP] strains)
(changes in PBP).

• Penicillin V is an oral drug (acid-resistant)

– used mainly in oropharyngeal infections.
 Penicillins/clinical uses
Very-Narrow-Spectrum Penicillinase-Resistant Drugs
(antistaphylococcal penicillins)
• This subclass of penicillins includes:
– methicillin (the prototype, but rarely used owing to its
nephrotoxic potential),
– Nafcillin (IV),
– oxacillin.

• primary use is in the treatment of known or suspected

staphylococcal infections.

• Methicillin-resistant (MR) staphylococci (S aureus [MRSA]

and S epidermidis [MRSE]) are:
– resistant to all penicillins
– and are often resistant to multiple antimicrobial drug
 Penicillins/clinical uses
Wider-Spectrum Penicillinase-Susceptible Drugs
(Extended spectrum penicilllins)
Ampicillin and Amoxicillin
• These drugs have a wider spectrum of antibacterial activity than
penicillin G but remains susceptible to penicillinases.
• clinical uses:
– indications similar to penicillin G
– infections resulting from:
• enterococci (entercoccal endocarditis),
• Listeria monocytogenes, G+ve (meningitis), Escherichia coli (G –ve),
Proteus mirabilis,
• Haemophilus influenzae (G-ve)(pneumonia), and Moraxella catarrhalis
(G-ve)

• In combination with inhibitors of penicillinases (eg, clavulanic

acid), their antibacterial activity is often enhanced.
 Penicillins/clinical uses
Wider-Spectrum Penicillinase-Susceptible Drugs
(antipseudomonal penicillins)
Piperacillin and Ticarcillin
• These drugs have activity against several gram-negative rods,
– Pseudomonas,
– Enterobacter,

• Most drugs in this subgroup have synergistic actions when

used with aminoglycosides against such organisms.

• Piperacillin and ticarcillin are often used in combination with

penicillinase inhibitors (eg, tazobactam or clavulanic acid) to
↑ activity
 Penicillins/Toxicity
1. (the most common), allergic reactions include:
– urticaria, severe pruritus, fever, joint swelling,
– hemolytic anemia,
– nephritis,
– bronchospasm
– anaphylaxis.
• Methicillin causes interstitial nephritis (allergic).
• nafcillin is associated with neutropenia.

2. GIT Disturbances: (N and D with oral peniciliins):

– direct irritation or
– by overgrowth of gram-positive organisms or yeasts.
– Ampicillin has been implicated in pseudomembranous colitis (clostridium
difficile, Gram +ve)
 Cephalosporins/ Pharmacokinetics
• Derivatives of 7-aminocephalosporanic acid with beta-lactam
ring structure.

• Several cephalosporins are available for oral use, but most are
administered parenterally.

• The major elimination mechanism for drugs in this class is

– renal excretion via active tubular secretion.

• Cefoperazone and ceftriaxone are excreted mainly in the bile.

• Most first- and second-generation cephalosporins do not

enter the cerebrospinal fluid even when the meninges are
inflamed.
 Cephalosporins/Mechanisms of Action and
Resistance
• MOA
– is similar to penicillins (Bind PBP…inhibit cell wall synthesis)
– Cephalosporins are bactericidal antibiotics.

Resistance:
• many bacteria are resistant through the production of beta-
lactamases that can inactivate cephalosporins.

• Resistance can also result from decreases in membrane

permeability to cephalosporins and from changes in PBPs.

• Methicillin-resistant staphylococci are also resistant to

cephalosporins.
 First-Generation Drugs
• Cefazolin (parenteral) and cephalexin (oral) are examples of
this subgroup.

• They are active against gram-positive cocci, including

staphylococci and common streptococci.
• Clinical uses include:
– treatment of infections caused by these organisms
– and surgical prophylaxis in selected conditions (Cefazolin
penetrates well into most tissues).

• These drugs have minimal activity against:

– gram-negative cocci,
– methicillin-resistant staphylococci,
– and most gram-negative rods.
 Second-Generation Drugs
• slightly less activity against gram-positive organisms than the
first-generation drugs but have an extended gram-negative
coverage.

• cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil,

loracarbef, and ceforanide, cephamycins, cefoxitin,
cefmetazole, and cefotetan

• Examples of clinical uses :

– infections caused by the anaerobe Bacteroides fragilis (
cefotetan, cefoxitin ) , such as peritonitis or diverticulitis

– and sinus (sinusitis), ear (otitis), and respiratory infections

caused by H influenzae or M catarrhalis (cefamandole,
cefuroxime, cefaclor )
 Third-Generation Drugs
• Characteristic features of third-generation drugs (eg,
ceftazidime,cefoperazone, cefotaxime ) include:
– increased activity against G-ve organisms resistant to other
beta-lactam drugs
– penetrate the BBB (except cefoperazone and cefixime).

• active against:
– Providencia,Serratia marcescens, and beta-lactamase-producing
strains of H influenzae and Neisseria.

• Ceftriaxone and cefotaxime …..most active cephalosporins

against PRSP strains.

• Active against Pseudomonas ……(cefoperazone, ceftazidime)

 Third-Generation Drugs
• Individual drugs also have activity against Pseudomonas
(cefoperazone, ceftazidime) and B fragilis ( ceftizoxime ).

• Drugs in this subclass should usually be reserved for

treatment of serious infections. Exceptions:
– Ceftriaxone (parenteral) and cefixime (oral), currently
DOC in gonorrhea.

– acute otitis media, a single injection of ceftriaxone

• is usually as effective as a 10-day course of amoxicillin.
 Fourth-Generation Drugs

• Cefepime is more resistant to beta-lactamases produced by:

– G-ve organisms, including:
• Enterobacter (Tx of enterobacter infection),
– some penicillin-resistant pneumococci.

• Cefepime combines the G+ve activity of first-generation

agents with the wider G-ve spectrum of third-generation
cephalosporins.
 Fifth generation
• — Ceftaroline is a fifth generation
cephalosporin .
– active metabolite has a spectrum of in vitro
activity similar to ceftriaxone
• but with improved gram-positive activity.

– has activity against MRSA, as well as vancomycin-

intermediate Staphylococcus aureus (VISA)
 Cephalosporins/Toxicity/Allergy
1. Cephalosporins cause allergic reactions from skin rashes to
anaphylactic shock. (less frequently than penicillins)

incomplete (5–10%) cross-reactivity with penicillins …so penicillin-

allergic patients are sometimes treated successfully with a
cephalosporin. (not if anaphylactic shock to penicillin)
2. pain at IM injection sites and phlebitis after IV administration.

3. ↑nephrotoxicity of aminoglycosides.

4. Hypoprothrombinemia

5. disulfiram-like reactions with ethanol

 Other Beta-Lactam Drugs/ Monobactams
(Aztreonam)
• Aztreonam is a monobactam : Spectrum of activity is limited to:
– aerobic gram-negative rods, including P. aeruginosa
– no activity against G+ve bacteria or anaerobes.

• inhibitor of cell wall synthesis, bind PBP3

• administered IV or IM, eliminated via renal tubular secretion.

• ADRs: GI upset (possible superinfection), vertigo, headache,

and rarely hepatotoxicity.

• no cross-allergenicity with penicillins.

 Other Beta-Lactam Drugs/ Carbapenems:
Imipenem, meropenem
• carbapenems have low susceptibility to beta-lactamases. wide
activity against :
– G+ve cocci (including some penicillin-resistant pneumococci),
– gram-negative rods,
– and anaerobes.

• For pseudomonal infections…often used in combination with an

aminoglycoside.

• MRSA strains of staphylococci are resistant

• administered parenterally.

• Carbapenems are currently DOC for enterobacter infections.

 Carbapenems: Imipenem
• Imipenem is rapidly inactivated by renal dehydropeptidase
I… combined with cilastatin, an inhibitor of this enzyme.
– Cilastatin increases the plasma t1/2 of imipenem
– inhibits the formation of a potentially nephrotoxic metabolite.

• ADR of imipenem-cilastatin:
– GI distress, skin rash,
– at very high plasma levels, CNS toxicity (confusion,
encephalopathy, seizures).
– partial cross-allergenicity with the penicillins.

• Meropenem is similar to imipenem except that:

– it is not metabolized by renal dehydropeptidases and
– is less likely to cause seizures.
 Beta-Lactamase Inhibitors

• Clavulanic acid, sulbactam, and tazobactam

• They Contain β-lactam ring but no antibacterial activity

• They bind to & inactivate β-lactamases

Penicillin plus β-lactamase Inhibitors:

1) Amoxicillin-clavulanic acid
2) Ticarcillin-clavulanic acid
3) Ampicillin-sulbactam
4) Piperacillin-tazobactam
 Other Cell Wall or Membrane-Active Agents/
Vancomycin
• Vancomycin is a bactericidal glycoprotein, MOA:
– binds to the D-Ala-D-Ala terminal of the nascent peptidoglycan
pentapeptide side chain and inhibits
transglycosylation…prevents elongation and cross-linking.

• Resistance: Decreased affinity of vancomycin for the binding

site because of the replacement of the terminal D-Ala by D-
lactate, e.g in strains of:
– enterocci (vancomycin-resistant enterococci [VRE])
– and staphylococci (vancomycin-resistant S aureus [VRSA]).
 Other Cell Wall or Membrane-Active Agents/
Vancomycin
• Vancomycin has a narrow spectrum of activity (only G+ve),
used for (IV):
– methicillin-resistant staphylococci (MRSA) infection (sepsis or
endocarditis)
– in combination with a 3rd-generation cephalosporin e.g. ceftriaxone
for Tx of infections due to PRSP (causing meningitis).
– Vancomycin is also used for treatment of infections caused by
Clostridium difficile.

• Vancomycin is not absorbed from the GI tract

– …given orally for bacterial enterocolitis.
 Other Cell Wall Active Agents/ Vancomycin

• Toxic effects of vancomycin include:

– Chill, fever, phlebitis at site of injection.
– Rare ototoxicity,
– rare nephrotoxicity.
– Rapid IV infusion may cause diffuse flushing ("red man
syndrome") from histamine release

• Teicoplanin, another glycopeptide, has similar characteristics

 Antimetabolites
(Antifolate drugs)
Sulfonamides and trimethoprim
Indirect nucleic acid synthesis inhibitors
Chapter 46
 Sulfonamides/ Pharmacokinetics

• The sulfonamides may be classified as:

– short-acting (eg, sulfisoxazole),
– intermediate-acting (eg, sulfamethoxazole),
– and long-acting (eg, sulfadoxine).

• Sulfonamides bind to plasma proteins at sites shared by

bilirubin and by other drugs.
 Sulfonamide/Mechanisms of Action

• bacteriostatic inhibitors of folic acid synthesis.

• The sulfonamides are structural analogue p-aminobenzoic

acid (PABA )…….
– competitive inhibitors of dihydropteroate synthase.
– Also act as substrates for this enzyme, resulting in the synthesis
of nonfunctional forms of folic acid.

• The selective toxicity of sulfonamides results from the

inability of mammalian cells to synthesize folic acid (depends
on folic acid from the diet).
• Inhibitory effects of
sulfonamides and
trimethoprim on folic
acid synthesis.

• Inhibition of 2
successive steps in the
formation of
tetrahydrofolic acid
constitutes sequential
blockade and results in
antibacterial synergy.
 Sulfonamide/Clinical uses

1. Simple UTIs
– …Oral… (eg, triple sulfa, sulfisoxazole).

2. Ocular Infections (e.g bacterila conjunctivitis)

– ……Topical… (eg, sulfacetamide).

3. Burn Infections…….Topical… (eg, mafenide, silver sulfadiazine).

4. Ulcerative Colitis, Rheumatoid Arthritis….Oral …(eg,

sulfasalazine).

5. Toxoplasmosis…..Oral sulfadiazine plus pyrimethamine (a

dihydrofolate reductase inhibitor) plus folinic acid.
 Toxicity of Sulfonamides
Hypersensitivity
Allergic reactions, including skin rashes and fever, occur
commonly.
– Cross-allergenicity between the individual sulfonamides should
be assumed and may also occur with chemically related drugs
(eg, oral hypoglycemics, thiazides).

Gastrointestinal N, V & D occur commonly.

Hematotoxicity
• Rare effects: granulocytopenia, thrombocytopenia, and
aplastic anemia.
• Acute hemolysis may occur in persons with glucose-6-
phosphate dehydrogenase deficiency.
 Sulfonamide/drug interaction
Nephrotoxicity
• may precipitate in the urine at acidic pH,
– causing crystalluria and hematuria.

Drug interactions:
• Competition with warfarin and methotrexate for plasma
protein binding
– transiently increases the plasma levels of these drugs.

• Sulfonamides can displace bilirubin from plasma proteins,

– with the risk of kernicterus in the neonate if used in the third
trimester of pregnancy.
 Trimethoprim/MOA
• Trimethoprim is a selective inhibitor of bacterial
dihydrofolate reductase
– that prevents formation of the active tetrahydro form of folic
acid.(analog of dihydrofolic acid)

• Bacterial dihydrofolate reductase is 4–5 orders of magnitude

more sensitive to inhibition by trimethoprim than the
mammalian enzyme.

• Use: Alone can be given in acute UTIs

• ADR: as antifolate drug: (decreased with folinic acid)
– megaloblastic anemia,
– leukopenia,
– and granulocytopenia.
 Trimethoprim-Sulfamethoxazole (TMP-SMZ)
Cotrimoxazole
• When the 2 drugs are used in combination, antimicrobial
synergy results from the sequential blockade of folate
synthesis (bactericidal ).
• This drug combination is effective orally in the treatment of:
– UTIs
– in respiratory, ear, and sinus infections caused by
Haemophilus influenzae and Moraxella catarrhalis.

• In the immunocompromised patient,

– TMP-SMZ is used for infections due to Aeromonas
hydrophila (gastroenteritis)
– and is the DOC for prevention and treatment of
pneumocystis pneumonia.
Trimethoprim-Sulfamethoxazole (TMP-
SMZ)
• TMP-SMZ is also the DOC in nocardiosis,

• has been used in the treatment of infections caused by

methicillin-resistant staphylococci and Listeria
monocytogenes.

• IV formulation is available.

adverse effects:
• as those associated with the sulfonamides.
• AIDS patients given TMP-SMZ have a high incidence of
adverse effects, including fever, rashes, leukopenia, and
diarrhea
Fluoroquinolones
Ciprofloxacin
Norflxacin
Moxifloxacin
Levofloxacin

Chapter 46
 Classification
• Norfloxacin, a first-generation, active against UTIs.

• Ciprofloxacin and ofloxacin (2nd-generation fluoroquinolones)

have greater activity against G-ve bacteria and are also active
against the gonococcus, many G+ve cocci.

• 3rd-generation fluoroquinolones ( levofloxacin, gemifloxacin,

and moxifloxacin )
– are slightly less active than ciprofloxacin and ofloxacin against G-ve
bacteria but have greater activity against G+ve cocci, including S
pneumoniae ."respiratory fluoroquinolones.“

– gemifloxacin, moxifloxacin are the broadest-spectrum

fluoroquinolones introduced to date,
• with enhanced activity against anaerobes
 fluoroquinolones /Pharmacokinetics

• Elimination of most fluoroquinolones is through the kidneys

via active tubular secretion, which can be blocked by
probenecid.

• Dosage reductions are usually needed in renal dysfunction

except for moxifloxacin which is eliminated partly by hepatic
metabolism + biliary excretion. …….

– Use of moxifloxacin in UTIs is not recommended..

 fluoroquinolones \Mechanism of Action
• They interfere with bacterial DNA synthesis by inhibiting :
1. topoisomerase II (DNA gyrase), especially in G-ve organisms:
– prevents the relaxation of positively supercoiled DNA that is required
for normal transcription and replication

2. topoisomerase IV, especially in G+ve organisms:

– interferes with separation of replicated chromosomal DNA into the
respective daughter cells during cell division

• Fluoroquinolones are usually bactericidal.

• Like aminoglycosides, the fluoroquinolones exhibit

postantibiotic effects.
 Fluoroquinolone/Clinical Use
• Fluoroquinolones are effective in the treatment of infections of
the urogenital and gastrointestinal tracts caused by gram-
negative organisms.

– UTI even when caused by multidrug-resistant bacteria, eg,

pseudomonas

– Bacterial diarrhea caused by shigella, salmonella, toxigenic

E coli, and campylobacter

• They have been used widely for respiratory tract, skin, and soft
tissue infections.
 Fluoroquinolone/Clinical Use
• Norfloxacin, a first-generation, active against UTIs.

• Ciprofloxacin is a DOC for prophylaxis and treatment of anthrax

• Ciprofloxacin and levofloxacin are effective in treating chlamydial

urethritis or cervicitis

• Upper and lower RTI: (respiratory fluoroquinolones)

1. Levofloxacin has activity against most organisms associated with
community-acquired pneumonia, including chlamydiae,
mycoplasma, and legionella species (atypical).

2. Gemifloxacin and moxifloxacin have the widest spectrum of

activity, includes: atypical pneumonia agents (chlamydiae,
mycoplasma, and legionella species), and some anaerobic
bacteria.
 Adverse effects
1. GIT distress: NVD (most common adverse effect.)

2. phototoxicity,

3. Connective tissue problems:

– tendinitis and tendon rupture. They are not recommended for
children or pregnant women b/c they may damage growing cartilage
and cause arthropathy.

4. Cardiotoxicity (QT interval prolongation):

– Newer fluoroquinolones (gemifloxacin, levofloxacin, moxifloxacin)
prolong the QTc interval.
– should be avoided in patients with known QTc prolongation or
patient on drugs that increase the QTc interval.
Protein Synthesis Inhibitors
Chapters 44, 45

1) Chloramphenicol
2) Tetracyclines
3) Macrolides
4) Clindamycin
5) Linezolide
6) Streptogramines
7) Aminoglycosides
 General MOA
• Target the bacterial ribosome, which has components that
differ structurally from those of mammalian cytoplasmic
ribosomes

• The bacterial ribosome consists of a 50S subunit and a 30S

subunit,
– whereas in the mammalian ribosome the subunits are 60S and 40S
(selective toxicity
 Tetracyclines
• broad-spectrum bacteriostatic antibiotics
– (aerobic and anaerobic G+ve and G-ve bacteria, some protozoa, eg,
amoeba)

• Agents: Tetracyclin, minocycline, doxycycline, demeclocycline,

& oxytetracycline, Tigecycline (IV only).

• MOA: Bind reversibly to 30S of bacterial ribosome, blocking

the binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex

• Oral absorption may be impaired by foods and multivalent

cations (calcium, iron, aluminum).

• Tetracyclines cross placenta and excreted in milk

 Tetracyclines/Clinical Uses
Primary Uses
• recommended in the Tx of infections caused by :
– Mycoplasma pneumoniae (in adults), chlamydiae, rickettsiae, vibrios, and
some spirochetes.

• Doxycycline is currently an alternative to macrolides in the initial

Tx of community-acquired pneumonia.

Secondary Uses
• Tetracyclines are alternative drugs in the Tx of syphilis
(spirochetes).
• Tx of respiratory infections (susceptible organisms)
• prophylaxis against infection in chronic bronchitis,
• Tx of leptospirosis (spirochetes),
• Tx of acne.
 Tetracyclines/selective uses
• Tx of GI ulcers caused by H. pylori (tetracycline).

• meningococcal carrier state (minocycline).

• Doxycycline is used for:

– the treatment of Lyme disease,
– and also used for the prevention of malaria
– and in the treatment of amebiasis.

• Demeclocycline inhibits the renal actions of antidiuretic

hormone (ADH)
– and is used in the management of patients with ADH-secreting
tumors
 Tetracycline/toxicity
1. Hepatic Toxicity: especially in:
– pregnant patients
– and those with pre-existing hepatic disease

2. Photosensitivity: Tetracyclines, especially demeclocycline, may

cause enhanced skin sensitivity to UV light, sever sunburn.

3. Vestibular Toxicity: Dose-dependent reversible dizziness and

vertigo have been reported with doxycycline and minocycline.

4. GIT Disturbances:
– N and D,
– possibly life-threatening enterocolitis.
– Disturbances in the normal flora may lead to candidiasis (oral and
vaginal) and, more rarely, to bacterial superinfections with S aureus
or Clostridium difficile.
 Tetracycline/toxicity

5. Bony Structures and Teeth

• Fetal exposure to tetracyclines may lead to tooth enamel
dysplasia and irregularities in bone growth

• Treatment of younger children may cause enamel dysplasia

and crown deformation when permanent teeth appear

• Therefore, tetracyclines are generally avoided in pregnancy &

for long periods to children under 8 years of age
 Chloramphenicol

• wide spectrum , the drug is either bactericidal or (more

commonly) bacteriostatic, depending on the organism

• It binds reversibly to the 50S of bacterial ribosomes.

• It is effective orally and parenterally, cross placental and BBB.

• Because of its toxicity, it has very few uses as a systemic

drug.
•
 Chloramphenicol/ Clinical Uses
1. It is a backup (alternative) drug for severe infections caused by:
1. Salmonella species
2. treatment of pneumococcal and meningococcal meningitis in
beta-lactam–sensitive persons.

2. rickettsial diseases (such as typhus and Rocky Mountain spotted

fever).

3. for infections caused by anaerobes such as Bacteroides fragilis.

4. The drug is commonly used as a topical antimicrobial agent. E.g

eye infections b/c of:
– its broad spectrum
– and its penetration of ocular tissues and the aqueous humor
Rocky Mountain spotted fever
 Chloramphenicol/adverse effects
1. GIT Disturbances (NVD): from direct irritation and from
superinfections, especially candidiasis (oral or vaginal).

2. Bone Marrow:
– dose-dependent, reversible ↓ of RBC maturation leads to a ↓ in circulating
erythrocytes.
– Aplastic anemia is a rare idiosyncratic reaction (usually irreversible and may
be fatal).
3. Gray Baby Syndrome:
– occurs in infants (flaccidity, hypothermia, gray color,↓RBC, cyanosis, and
cardiovascular collapse).
– Neonates, especially premature, are deficient in hepatic
glucuronosyltransferase , and are sensitive to doses of chloramphenicol

Drug Interactions: it inhibits hepatic metabolizing enzymes, ↑ing the

elimination t1/2 of phenytoin, tolbutamide and warfarin.
 Macrolides
• Agents (macrolides): erythromycin, clarithromycin, azithromycin,

• The drugs have good oral bioavailability, but azithromycin

absorption is impeded by food.

• The macrolides, in general, are bacteriostatic

– Erythromycin may be bactericidal, particularly at higher
concentrations, for susceptible organisms

• MOA: Inhibition of protein synthesis occurs via binding to the 50S

ribosomal RNA

• Erythromycin base is destroyed by gastric acid. Thus, either:

– enteric-coated tablets or
– esterified forms of the antibiotic are administered (erythromycin
estolate)
 Macrolides/Clinical Uses
• Erythromycin is effective in the treatment :
– Mycoplasmal pneumonia (M pneumonia)
– Corynrbacterium diphtheriae (Corynebacterium),
– Chlamydial infections (Chlamydia trachomatis, Chlamydophila
pneumoniae)
– Legionellosis (Legionella pneumophila).
– Pertusis; Bordetella pertussis

• Azithromycin-similar to erythromycin…but is more active

against H influenzae, Moraxella catarrhalis, and Neisseria.
– Because of its long t1/2, a single dose of azithromycin is effective in
the treatment of urogenital infections caused by C trachomatis.

• Clarithromycin-similar to erythromycin. But is also used as a

component of drug regimens for ulcers caused by H pylori.
 Macrolides/ADE
ADE especially with erythromycin, include:
• GIT irritation (NVD) via stimulation of motolin receptors.
• A hypersensitivity-based acute cholestatic hepatitis may occur
with erythromycin estolate.

• Erythromycin inhibits several forms of hepatic cytochrome P450

(several D-D interactions e.g ↑ digoxin levels..
– It eliminates a species of intestinal flora that ordinarily inactivates digoxin..
reabsorption of the drug from the enterohepatic circulation.

• The lactone ring structure of azithromycin is slightly different from

that of other macrolides, and drug interactions are uncommon
because azithromycin does not inhibit hepatic cytochrome P450.
 Telithromycin

• Telithromycin is a ketolide structurally related to macrolides.

• same MOA and spectrum of activity as erythromycin.

• However, some macrolide-resistant strains are susceptible to

telithromycin b/c:
– it binds more tightly to ribosomes and
– is a poor substrate for bacterial efflux pumps that mediate resistance.

• ADE: include hepatic dysfunction and prolongation of the QTc

interval.
 Aminoglycosides
• Agents: streptomycin, neomycin, kanamycin, amikacin, gentamicin,
tobramycin, sisomicin, netilmicin

PK:
• Aminoglycosides have concentration-dependent killing (As the
plasma level is increased above the MIC, aminoglycosides kill an
increasing proportion of bacteria and do so at a more rapid rate).

• They also exhibit postantibiotic effect such that their killing action
continues when their plasma levels have declined below
measurable levels.

• Consequently, aminoglycosides have greater efficacy when

administered as a single large dose than when given as multiple
smaller doses.
 Aminoglycosides/PK
• The toxicity (in contrast to the antibacterial efficacy) of
aminoglycosides depends both on a critical plasma concentration
and on the time that such a level is exceeded.
– The time above such a threshold is shorter with administration
of a single large dose of an aminoglycoside than when multiple
smaller doses are given.

• Once-daily aminoglycoside dosing protocols....more effective and

less toxic than traditional dosing regimens.
• They are polar compounds, not absorbed after oral use… given IM,
or IV for systemic effect.

• Glomerular filtration is the major mode of excretion (Dosage

adjustments in renal insufficiency to prevent toxicity).
• Monitoring of plasma levels for safe and effective dosage.
 Aminoglycosides/MOA

• Aminoglycosides are bactericidal inhibitors of protein

synthesis.

• Their penetration through the bacterial cell envelope is

partly dependent on oxygen-dependent active transport,
– and they have minimal activity against strict anaerobes.

• Aminoglycoside transport can be enhanced by cell wall

synthesis inhibitors, which may be the basis of
antimicrobial synergism.

• Inside the cell, aminoglycosides bind to the 30S ribosomal

subunit .
 Aminoglycosides/Clinical uses
• Are useful mainly against aerobic G-ve microorganisms,
including Pseudomonas aeruginosa

• Streptomycin in combination with penicillins is often more

effective in enterococcal carditis than regimens that include
other aminoglycosides. This combination is also used in the
treatment of tuberculosis, plague, and tularemia.

– Because of the risk of ototoxicity, streptomycin should not be used

when other drugs will serve.

• Owing to their toxic potential, neomycin and kanamycin are

usually restricted to topical or oral use (eg, to eliminate
bowel flora). Gentamicin is also available for topical use.
 Aminoglycosides/ADE
1. Ototoxicity: Auditory or vestibular damage (or both) may be
irreversible. Ototoxicity risk is proportional to the plasma levels and
thus is especially high if dosage is not appropriately modified in a
patient with renal dysfunction.
– Ototoxicity may be increased by the use of loop diuretics.
– Because ototoxicity has been reported after fetal exposure, the
aminoglycosides are contraindicated in pregnancy unless their
potential benefits are judged to outweigh risk.

2. Nephrotoxicity (reversible acute tubular necrosis).

3. Neuromuscular Blockade: rare, a curare-like block, at high

doses…may result in respiratory paralysis.
– reversible by Tx with calcium or neostigmine,
– but ventilatory support may be required.