CHEMOTHERAPY

ANTIMICROBIAL AGENTS
ANTIBACTERIAL AGENTS.
ANTIVIRAL AGENTS.
ANTIPROTOZOAL AGENTS.
ANTIFUNGAL AGENTS.
ANTIHELMINTIC AGENTS.
CHEMOTHERAPY
It refers to drug treatment of parasitic infections in which the parasites
(bacteria, viruses, protozoa, fungi, and worms) are destroyed or
removed without injuring the host.
ANTIMICROBIAL AGENTS
These are agents that kill microorganisms or suppress their
multiplication or growth.
Classification of Antimicrobials
(1) Antibacterial agents.
(2) Antiviral agents.
(3) Antiprotozoal agents.
(4) Antifungal agents.
(5) Antihelmintic agents.
Antibiotics

These are soluble compounds that are derived from certain

microorganisms & that inhibit the growth of other microorganisms.
Bacteriostatic Drugs
These are drugs that temporarily inhibits the growth of a
microorganism. When the drug is removed, organism will resume
growth & infection or disease may recur.
Typical bacteriostatics: Tetracyclines, sulfonamides.
Bactericidal Drugs
These are a drug that attaches to its receptor on micro- organisms, &
causes their death.
Typical bactericidals: Penicillins, cephalosporins, aminoglycosides.
MECHANISM OF ACTION OF ANTIMICROBIALS
• Drugs that inhibit bacterial cell wall synthesis or activate enzymes
that disrupt the cell wall. These drugs (e.g., penicillins, cephalosporins)
weaken the cell wall and thereby promote bacterial lysis and death.
• Drugs that increase cell membrane permeability. Drugs in this
group (e.g., amphotericin B) increase the permeability of cell
membranes, causing leakage of intracellular material.
• Drugs that cause lethal inhibition of bacterial protein synthesis.
The aminoglycosides (e.g., gentamicin) are the only drugs in this group.
We do not know why inhibition of protein synthesis by these agents
results in cell death.
• Drugs that cause nonlethal inhibition of protein synthesis. Like the
aminoglycosides, these drugs (e.g., tetracyclines) inhibit bacterial
protein synthesis. However, in contrast to the aminoglycosides, these
agents only slow microbial growth—they do not kill bacteria at
clinically achievable concentrations.
• Drugs that inhibit bacterial synthesis of DNA and RNA or disrupt
DNA function. These drugs inhibit synthesis of DNA or RNA by binding
directly to nucleic acids or by interacting with enzymes required for
nucleic acid synthesis. They may also bind with DNA and disrupt its
function. Members of this group include rifampcin, metronidazole, and
the fluoroquinolones (e.g., ciprofloxacin).
• Antimetabolites. These drugs disrupt specific biochemical reactions.
The result is either a decrease in the synthesis of essential cell
constituents or synthesis of non-functional analogs of normal
metabolites. Examples of antimetabolites include trimethoprim and the
sulfonamides.
• Drugs that suppress viral replication. Most of these drugs inhibit
specific enzymes—DNA polymerase, reverse transcriptase, protease,
integrase, or neuraminidase—required for viral replication and
infectivity.
 Thru inhibition of nucleic acid synthesis
Eg Sulfonamides, Trimethoprim. Pyrimethamine, Rifampin, Quinolines,
Novobiocin.
USE OF ANTIMICROBIALS
(1) Choice of Antimicrobials
(a) It follows automatically from the clinical diagnosis.
(b) It should be based, wherever possible, on bacteriological
identification & sensitivity test.
(2) Administration of Antimicrobials
(a) Oral: It is convenient & less unpleasant but the food retards
absorption & peak plasma conc. are therefore lower. So, in general,
antimicrobials should be taken, b/w meals or at least one hour before a
meal.
(b) Parenteral: It is used for serious infection. IV route is generally
preferred.
(3) Combinations of Antimicrobials 2 or more antimicrobials can be
used concomitantly:
(a) To obtain potentiation.
(b) To delay development of drug resistance.
(c) To broaden the spectrum of antibacterial activity.
Disadvantages of Combined Therapy
(a) A false sense of security, discouraging efforts towards accurate
diagnosis.
(b) Broader suppression of normal flora with inc. risk of opportunistic
infection with resistant organisms.
(c) Inc. incidence & variety of adverse effects.
PROBLEMS WITH ANTIMICROBIALS
(1) Microbial Resistance to Drugs
Mechanism of Resistance
(a) Via producing enzymes that destroy active drug, eg staphylococcal
resistance to penicillin G.
(b) Via altering memb. Permeability to drug, eg streptococcal resistance
to aminoglycosides.
(c) Via developing an altered structural target for drug, eg resistance to
aminoglycosides.
(d) Via developing an altered metabolic pathway that bypasses the
reaction inhibited by drug, eg resistance to sulphonamide.
(e) Via developing an altered enzyme that can still perform its
metabolic function but is much less affected by the drug, eg resistance
to sulphonamide.
Origin of Drug Resistance
(a) Nongenetic Origin
(i) Microorganisms that are metabolically inactive (non-multiplying)
may be resistant to drugs; however, their offspring are fully susceptible.
(ii) Microorganism may lose the specific target structure for a drug for
several generations &
(b) Genetic Origin thus be resistant.
(i) Chromosomal resistance: This develops as a result of spontaneous
mutation in a locus on bacterial chromosome that controls suscep-
tibility to a given antimicrobial. A change in the structural receptors for
the drug occur which causes resistance.
(ii) Extrachromosomal resistance: Plasmids are extrachromosomal
circular DNA molecules. Plasmid genes for antimicrobial resistance
control the formation of enzymes capable of destroying antimicrobial
drugs.
Cross Resistance
Microorganism resistant to a certain drug may also be resistant to other
drugs that share a mechanism of action or attachment, this is called
cross-resistance.
(2) Opportunistic Infection
When any antimicrobial drug is used, there is suppression of part of the
normal flora of pt, which varies according to drug. Often, this causes no
ill effects, but sometimes a drug-resistant organism, freed from
competition, proliferates to an extent that can be fatal. This is
opportunistic infection.
eg, Antibiotic-Associated Colitis With Drugs Esp. Lincomycin,
Clindamycin, Amoxycillin, Ampicillin & Cephalosporins.
(3) Adverse Effects of Antimicrobials
(a) Allergic-type effects occur commonly.
(b) Direct organ toxicity also occurs.
(4) Drug Interactions with Antimicrobials
(a) On absorption: Tetracycline chelates iron & Ca, & absorption of all
from the gut is dec.
(b) On metabolism: Rifampin induces hepatic drug metabolizing
enzymes & may cause an oral contraceptive to fail; metronidazole,
cefamandole & latamoxef inhibit alcohol metabolism to cause a
disulfiram-like reaction.
(c) On elimination: Probenecid competes with penicillin for renal
tubular anion transport mechanism, causing penicillin to be retained.
(d) On organs: Gentamicin & furosemide in high dose create inc. risk of
ototoxicity.
( 5) Treatment Failure
(a) It may be due to drug resistance.
Penicillins
DRUG CLASSIFICATION
(A) According to Nature
(1) Natural Penicillins Penicillin G or Benzyl Penicillin.
(2) Semisynthetic Penicillins
(a) Long Acting Penicillins-Procaine Penicillin, Benzathine Penicillin G.
(b) Orally Effective Penicillins -Phenoxymethyl Penicillin (Penicillin V).
Phenbenicillin, Propicillin.
(c) Penicillinase - Resistant (Antistaphylococcal) Penicillins
(i) Methicillin. (ii) Nafcillin.
(iii) Isoxazolyl penicillins: Oxacillin, Cloxacillin, Dicloxacillin,
Flucloxacillin.
(d) Broad-spectrum Penicillins (Aminopenicillins) .
Ampicillin, Amoxycillin, Bacampicillin, Pivampicillin, Cyclacillin,
Hetacillin, Amoxycillin plus Clavulanic acid, Ampicillin plus Cloxacillin,
Amdinocillin/Mecillinam.
(e) Anti-Pseudomonal Penicillins
(i) Carboxypenicillins: Carbenicillin, Carbenicillin indanyl Na,
Ticarcillin.
(ii) Ureidopenicillins: Azlocillin, Mezlocillin,Piperacillin.
(B) On the Basis of Penicillinase Sensitivity
(1) Penicillinase Sensitive
(a) Acid Labile
Penicillin G, Procaine Penicillin, Benzathine.
Penicillin G. Carbenicillin, Ticarcillin,
Azlocillin, Mezlocillin, Piperacillin, Amdinocillin/Mecillinam.
(b) Acid Stable. Penicillin V. Phenbenicillin, Propicillin, Ampicillin,
Amoxycillin, Bacampicillin, Pivampicillin, Amoxycillin plus Clavulanic
acid, Ampicillin plus Cloxacillin, Carbenicillin indanyl.
(2) Penicillinase Resistant
(a) Acid Labile-Methicillin, Nafcillin.
(b) Acid Stable Flucloxacillin. Oxacillin, Cloxacillin, Dicloxacillin,
Mechanism of Action
Penicillins inhibit bacterial cell wall synthesis by binding to specific PBP
(penicillin binding protein) receptors on bacteria 2 This results in;
(1) Inhibition of cell wall synthesis by blocking trans- peptidation of
peptidoglycan by interfering with the enzymes transpeptidase &
endopeptidase.
(2) Activation of autolytic enzymes in cell wall resulting in lesions that
causes bacterial death.
PHARMACOKINETICS
Absorption of Penicillin-G from the GIT is incomplete and variable. Also
Penicillin-G is inactivated by gastric juice, so that Penicillin-V which is
more resistant to acid is the preferred oral form against streptococcal
organisms.
Penicillin is considerably bound to plasma proteins and is not
uniformly distributed to most regions of the body. It achieves adequate
concentrations in pleural and synovial spaces but penetrates poorly
into CSF and aqueous humor. However, inflammation increases
meningeal permeability so that concentration, effective for treatment of
meningitis can be achieved within 24hours of treatment inpatient of
meningitis. Repository preparations such as Penicillin-G procaine and
Penicillin-G
Benzathine can be used when sustained blood concentration in the
range of 0.03microgram/ml or so, are required for10days or longer.
Penicillin is eliminated from the body primarily by rapid renal
clearance. With severe renal failure the half-life increases so that the
dose interval is must be extended.Penicillin is actively secreted by renal
tubules. Probenecid, which blocks the tubular secretory mechanism, is
occasionally used with Penicillin to prolong its action after IM or oral
administration.
RESISTANCE
(1) Certain bacteria (eg many Staphylococcus Aureus, some H.
Influenzae, Gonococci) produce beta-lactamases (penicillinases) which
opens up beta-lactam ring & hydrolyzes it to penicilloic acid, a harmless
form.
(2) Certain bacteria lack specific receptors.
(3) In some bacteria autolytic enzyme in cell wall is not activated, eg
streptococci.
(4) Certain organisms lack cell wall, eg mycoplasma.
CLINICAL USES
A) Penicillin G
(1) Pneumococcal infections, eg pneumonia, meningitis supportive
arthritis, mastoiditis, endocarditis, pericarditis, osteomyelitis.
(2) Group A streptococcal infections, eg pharyngitis, scarlet fever,
impetigo, puerperal sepsis, rheumatic
(3) Meningococcal Infections, eg Nasopharyngitis, Fever.
Meningococcemia, Waterhouse-Friderichsen Synd., Arthritis,
Endocarditis, Meningitis.
(4) Non-beta lactamase producing staphylococcal & gonococcal
infections.
(5) Treponema pallidum inf., eg syphilis.
(6) Bacillus anthracis inf., eg anthrax.
(7) Clostridial inf., eg tetanus, gas gangrene.
(8) Actinomycosis.
(9) Listeria infections.
(10) Diphtheria.
(11) Rat bite fever.
(12) Bacteroides inf. (except of B. fragilis).
(B) Penicillin V
(1) Pneumococcal infections.
(2) Group 'A' streptococcal infections
(3) Staphylococcal infections
(4) Meningococcal infections
(5) Gonococcal infections
(C) Procaine Penicillin
Gonococcal inf., eg Gonorrhoea, Prostatitis, Arthritis, Salpingitis,
Urethritis, Meningitis.
(D) Broad-spectrum Penicillins
(1) Uncomplicated gonorrhea.
(2) H. influenza inf., eg Meningitis, Osteomyelitis, Epiglottitis.
Pneumonia, Septic Arthritis.
(3) Acute urinary tract inf. (caused by gram negative bacteria).
(4) Salmonella inf., eg Typhoid & Paratyphoid Fever.
(5) Mixed bacterial inf. of Respiratory Tract, Eg Sinusitis, Otitis, and
Bronchitis.
(6) In inf. where penicillin G is the drug of choice but oral therapy is
preferred.
(E) Antipseudomonal Penicillins
By gram-negative bacteria esp. Infection caused pseudomonas
aeruginosa, indole-positive proteus & enterobacter (eg bacteremia,
pneumonia, burn inf., urinary tract inf.)
 Penicillinase-Resistant Penicillins
Beta-lactamase producing staphylococcal inf., cg bacteremia, cellulitis,
osteomyelitis, carbuncles, enteritis, wound inf. osteomyelitis,
pneumonia,
ADVERSE EFFECTS
(1) GIT
Nausea, Vomiting, Diarrhoea, & Enteritis Occur With Oral Therapy (Due
To Luxuriant Overgrowth Of Staphylococci, Pseudomonas, Proteus Or
Yeasts).
(2) Liver Hepatitis.
(3) Bone Marrow-Bone marrow depression, agranulocytosis.
(4) Blood-Impairment of platelet aggregation, hypokalemia elevated
serum transaminase with carbenicillin.
(5) Allergic Reactions
(a) Anaphylaxis:
Severe hypotension & shock, or laryngeal edema, or diffuse pruritus,
urticaria & flushing.
(b) Serum sickness reactions:
Urticaria, fever, joint swelling, angioneurotic edema, intense pruritus, &
respiratory embarrassment.
(c) Skin lesions:
Skin rashes, stevens-johnson synd...morbilliform eruptions,
erythematous eruptions, urticaria, dermatitis.
(d) Oral lesions: Glossitis, stomatitis, furred tongue, chellosis.
(e) Blood dyscrasias: Eosinophilia, haemolytic anemia,
thrombocytopenia.
(f) Drug fever
(g) Interstitial nephritis
(h) Vasculitis
(6) IV Administration
Causes phlebitis, thrombophlebitis, local pain, induration or
degeneration of accidentally injected nerve.
CONTRAINDICATIONS
(1) History of previous hypersensitivity penicillins &/or
cephalosporins. Reaction to
(2) Parenteral inj. into or near an artery or nerve.

DOSAGE
Penicillin Units
Activity of penicillin G was originally defined in units. Crystalline Na
penicillin G contains approx 1600 unit/mg (i-unit = 0.6 µg 1million
units= 0.6g). Most semisynthetic penicillins are prescribed by
weights rather units.
(1) Penicillin G 2 0.65 million units (0.36-3 g) per day; IM, QID.
(2) Procaine penicillin 2 4.8 to 10 million units (2.8-6 g) ,OD, IM.
(3) Ampicillin 2 300-500 mg QID; orally, IM or IV.
(4) Cloxacillin 2 0.25 -0.5 g orally every 4 - 6 hrs.
(5) Carbenicillin 2 300 - 500 mg/kg/d; IV.
 BETA-LACTAMASE INHIBITORS
Beta-lactamase is an enzyme capable of hydrolyzing β-lactam antibiotics. β-
lactamase degrade β-lactam antibiotics by opening the β-lactam ring. The
microorganisms producing beta-lactamase enzyme become resistant β-lactam
antibiotics.
Classification of β-lactamase enzyme on the basis of function:
Group 1 β-Lactamase:
 These are class-C enzyme and are cephalosporinase which are not
inhibited by clavulanic acid.
 They are also resistant to cefamycin
Group 2 β-lactamase:
 These include class- A enzyme and are penicillinase and
cephalosporinase.
 Inhibited by clavulanic acid.

Sub class:

i. Group 2b e (extended spectrum) β-lactamase:

 These are ESBL capable of hydrolyzing penicillin even 3rd and
4th generation cephalosporin but are hydrolyzed by clavulanic acid.

ii. Group 2b r β-lactamase:

 These include inhibitor resistant β-lactamase. These may be resistant to
sulbactum and clavulanic acid but are susceptible to inhibition by
tazobactum.

iii. Group 2c β-lactamase:

 These include carbenicillinase. These enzymes hydrolyses carbenicillin
more than Benzylpenicillin. These are class-A enzyme. They also show
activity towards Oxacillin.

iv. Group 2d (extended spectrum) β-lactamase:

 These are class-A or D enzyme and includes Cloxacillinase (oxacillinase).
These enzymes hydrolyse cloxacillin more than Benzylpenicillin and also
have activity against carbenicillin.

v. Group 2e β-lactamase:
 These are class-A enzyme. These include cephalosporinase. These are
inhibited by clavulanic acid.
vi. Group 2f β-lactamase:
 These are class-A enzyme. These include carbapenimase. These are
serine based enzymes which are also inhibited by clavulanic acid.
Group 3 β-lactamase:
 These includes class-B enzyme and are zinc based metalloenzyme. Eg.
Carbapenimase
 These are not inhibited by clavulanic acid.
 They are chromosomal mediated enzymes
Group 4 β-lactamase:
 These includes penicillinase
 These are not inhibited by clavulanic acid.
Examples-Clavulanic acid, Sulbactam, Tazobactam.
Mechanism of Action
They are B-lactamase inhibitors that extend antibacterial spectrum
of the companion B-lactam antibiotics irreversibly binding to &
inhibiting the enzyme.
Clinical Uses
(1) Combination of clavulanic acid & amoxycillin is used to treat
infections caused by beta-lactamase producing strains of H.
influenza, B. catarrhalis, S. aureus, E. coli, Klebsiella & enterobacter.
(2) Combination of sulbactam & ampicillin or cefoperazone
is used to treat infections caused by beta-lactamase producing
strains of H. influenza, N gonorrheae, S. aureus, E. coli, salmonella,
shigella, & K pneumoniae.
(3) Combination of tazobactam & piperacillin is also used to treat
infections caused by beta-lactamase producing strains of H.
influenza, N gonorrheae, S. aureus, E. coli, salmonella, shigella, & K
pneumoniae
Adverse Effects
There are no serious adverse effects associated with B-lactamase
inhibitors.
 MONOBACTAMS
Aztreonam.
Mechanism of Action
Aztreonam is similar in action to penicillin. It inhibits mucopeptide
synthesis in the bacterial cell wall.
Clinical Uses
Effective against a wide range of gram-negative bacteria including
Citrobacter, Enterobacter, E coli, Hemophilus, Klebsiella, Proteus, &
Serratia species.
Adverse Effects
(1) Skin: Injection site reactions, rash , toxic epidermal necrolysis.
(2) GIT: Nausea, vomiting, diarrhoea.
(3) Blood: Drug-induced eosinophilia.

CARBAPENEMS
Entapenem, Imipenem, Meropenem.
Mechanism of Action
(1) Imipenem acts as an antimicrobial thru inhibiting cell wall
synthesis of various aerobic & anaerobic Gram positive as well as
Gram negative bacteria, including P aeruginosa & the Enterococcus
species.
(2) It remains very stable in the presence of beta-lactamase (both
penicillinase & cephalosporinase)
Adverse Effects
(1) CNS: Seizures (imipenem).
(2) Skin: Injection site reactions, rash.
(3) GIT: Nausea, vomiting, diarrhoea.
Dosage
Imipenem: 0.25-0.5 gm, TDS or QID, intravenously.
VANCOMYCIN
Mechanism of Action
Similar to penicillins.
Clinical Uses
(1) Serious staphylococcal inf.
(2) Endocarditis not responding to other treatment.
(3) Pseudomembranous colitis (caused by clostridium difficile).
Adverse Effects
(1) Allergic reactions: Skin rashes, anaphylaxis
(2) ENT: Deafness.
(3) Nephrotoxicity
(4) IV injection : Thrombophlebitis Dosage 0.5 gm, QID.
Sulfonamides

1. Sulfadiazine: 0.5–2.0 g TDS; 0.5 g tab.

2. Sulfamethoxazole: 1 g BD for 2 days, then 0.5 g BD
3. Sulfacetamide sodium: 6%–30% topically in the eye;
10%, 20%, 30% eye drops, 6% eye oint.
4. Mafenide: 1% topical application; 1% skin cream.
5. Silver sulfadiazine: 1% topical application;
1% cream with chlorhexidine 0.2%.
Cotrimoxazole
Trimethoprim Sulfamethoxazole
a. 80 mg + 400 mg tab: 2 BD for 2 days then 1 BD.
b. 160 mg + 800 mg tab: double strength (DS); 1 BD.
c. 20 mg + 100 mg paediatric tab.
d. 40 mg + 200 mg per 5 ml susp; infant 2.5 ml (not to be used in
new borns), children 1–5 yr 5 ml, 6–12 year 10 ml (all BD).
e. 160 mg + 800 mg per 3 ml for i.m. injection 12 hourly.
f. 80 mg + 400 mg per 5 ml for I.V. injection
g. 10–15 ml BD.
Cephalosporins
(A) First Generation Cephalosporins
Narrow-spectrum, beta-lactamase sensitive antibiotics, having
poor CSF penetrability.
(1) Oral drugs: Cefadroxil, Cephalexin, Cephradine.
(2) Parenteral drugs: Cefazolin, Cephalothin Cephapirin,
Cephaloridine.
B) Second Generation Cephalosporins
Intermediate-spectrum antibiotics, variably stable to beta-
lactamase, having unreliable CSF penetrability.
(1) Oral drug: Cefaclor.
(2) Parenteral drugs: Cefamandole, Cefonicid Ceforanide,
Cefoxitin, Cefuroxime, Cefmetazole, Cefotetan, Cefprozil,
Cefpodoxime, Loracarbef.
(C) Third Generation Cephalosporins
Broad-spectrum, beta-lactamase resistant antibiotics, having
good CSF penetrability.
(1) Oral drug: Cefixime, Cefdinir, Cefditoren pivoxil, Ceftibuten.
(2) Parenteral drugs: Cefoperazone, Cefotaxime, Cefixime,
Ceftazidime, Ceftizoxime, Ceftriaxone, Moxalactam.
(D) Fourth Generation Cephalosporins
More broad-spectrum & more beta-lactamase resistant than third
generation cephalosporins, & also have good CSF penetrability.
Parenteral drugs: Cefepime.
(E)Fifth generation Cephalosporin:
 They are extended cephalosporin with extended spectrum of activities
against MRSA- Ceftaroline ,Ceftabiprole
Mode of Action of Cephalosporin:
i. Binds to penicillin Binding Protein (PBP):
Many of the cephalosporin eg. Cephalexin, cefotaxime and ceftazidime binds to
Penicillin binding protein 3 (PBP3) similar to action of penicillin and results in
formation of elongated and filamentous cell. Transpeptidase is the enzyme
present in bacteria that cross linked with existing peptidoglycan chain and
maintain integrity of cell wall. Binding of cephalosporin on PBP3 receptor
deforms cell wall and kills bacteria.
Ii. Activation of Autolysin:
Cephalosporin also activates autolytic enzymes in bacteria and causes lysis of
bacteria
RESISTANCE
(1) Poor penetration of bacteria by the drugs.
(2) Lack of PBP for a specific drug.
(3) Degradation of drug by beta-lactamases (cephalo- sporinases).
(4) Failure of activation of autolytic enzymes in cell wall.
CLINICAL USES
(A) First Generation Cephalosporin
(1) Oral Drugs
(a) Urinary tract infections
(b) Staphylococcal inf., eg skin inf endocarditis. ., osteomyelitis,
(c) Minor polymicrobial inf., eg cellulitis, soft tissue abscess.
(2) Parenteral Drugs
(a) Surgical prophylaxis during the insertion of prosthetic devices.
(b) K. pneumonia inf.
(c) As an alternative in penicillin allergic pts.
(B) Second Generation Cephalosporins
(1) Branhamella catarrhalis inf., eg sinusitis, otitis media.
(2) H. influenzae inf., eg sinusitis, otitis media.
(3) H. influenza meningitis (only cefuroxime is used).
(4) Mixed anaerobic inf., eg peritonitis, diverticulitis.
(5) Sepsis.
(C) Third Generation Cephalosporins
(1) Meningitis caused by pneumococci, meningococci, H. influenza
& enteric gram negative rods (except cefoperazone).
 (2) Sepsis.
(D) Fourth Generation Cephalosporins
Infections caused by P aeruginosa, S aureus, multiple drug
resistant S pneumonia & Enterobacteriaceae.
ADVERSE EFFECTS
 Anorexia, Nausea, Vomiting, Diarrhoea.
 Blood Dyscrasias
 Leukopenia, Haemolytic Anemia, Neutropenia, Thrombocytopenia,
Hypoprothrombinemia. Granulocytopenia
 Renal- Nephritis & Tubular Necrosis with Cephaloridine.
 Allergic Reactions fever, skin rashes,
 Note: Cross-allergenicity to cephalosporins in penicillin allergic
pts occurs in about 10% cases.
 Local irritation causing severe pain.
 IV injection Thrombophlebitis
 Superinfection Resistant gram positive organisms esp.
staphylococci & enterococci, as well as fungi often proliferate &
induce superinfection.
CONTRAINDICATION
(1) Hypersensitivity to Cephalosporins or penicillins.
(2) Combination with aminoglycosides & loop diuretics, b/c of
their potential of causing nephrotoxicity.
DOSAGE
a. Cefadroxil 2 0.5-1g BD, orally.
b. Cephalexin 2 0.25-0.5 g QID, orally.
c. Cephradine 2 same as cephalexin.
d. Cefazolin 2 1-2 g TDS, IV.
e. Cefaclor 2 10-15 mg/kg/d in 3-4 divided doses, orally.
f. Cefuroxime 2 0.75-1.5 g, IV every 8-12 hrs.
g. Cefoperazone 2 25-100 mg/kg/d, IV every 8-12 hrs.
h. Ceftriaxone 2 15-30 mg/kg/d, IV every 12-24 hrs.
 Cephalosporins
Compounds containing 7-aminocephalosporanic acid are relatively stable in
dilute acid and relatively resistant to penicillinase regardless of the nature of their
side chains and their affinity for the enzyme.
Modifications at position 7 of the β-lactam ring are associated with alteration in
antibacterial activity; substitutions at position 3 of the dihydrothiazine ring alter
the metabolism and pharmacokinetic properties of the drugs.
The cephamycins are similar to the cephalosporins but have a methoxy group at
position 7 of the β-lactam ring of the 7-aminocephalosporanic acid nucleus.

GENERAL PHARMACOLOGY
Many Cephalosporins (Cephalexin, Cephradine, Cefaclor, Cefadroxil,
Loracarbef, Cefprozil, Cefpodoxime Proxetil, Ceftibuten, Cefuroxime Axetil,
Cefdinir, and Cefditoren)

Are absorbed readily after oral administration; others can be administered

intramuscularly or intravenously.

Cephalosporins are excreted primarily by the kidney; thus the dosage should be
reduced in patients with renal insufficiency. Probenecid slows the tubular
secretion of most cephalosporins.

Exceptions are cefpiramide and cefoperazone, which are excreted predominantly

in the bile. Cefotaxime is deacetylated to a metabolite with less antimicrobial
activity than the parent compound that is excreted by the kidneys. The other
cephalosporins do not undergo appreciable metabolism.

Several cephalosporins penetrate into the CSF in sufficient concentration to be

useful for the treatment of meningitis.

Cephalosporins also cross the placenta, and they are found in high concentrations
in synovial and pericardial fluids. Penetration into the aqueous humor of the eye
is relatively good after systemic administration of third-generation agents, but
penetration into the vitreous humor is poor.

Concentrations in bile usually are high, especially with cefoperazone and

cefpiramide.
 SPECIFIC AGENTS
FIRST-GENERATION CEPHALOSPORINS

Cefazolin
Has an antibacterial spectrum that is typical of other first-generation
cephalosporins except that it also has activity against some Enterobacter spp.
Cefazolin is relatively well tolerated after either intramuscular or intravenous
administration; it is excreted by glomerular filtration and is ~85% bound to
plasma proteins. Cefazolin usually is preferred among the first-generation
cephalosporins because it can be administered less frequently owing to its
longer t1/2.
Cephalexin

has the same antibacterial spectrum as the other first-generation cephalosporins.

It is somewhat less active against penicillinase-producing staphylococci. Oral
therapy with cephalexin (usually 0.5 g) results in peak concentrations in plasma
adequate for the inhibition of many gram-positive and gram-negative pathogens.
The drug is not metabolized, and 70-100% is excreted in the urine.

Cephradine

is similar in structure to cephalexin, and its activity in vitro is almost identical.

Cephradine is not metabolized and, after rapid absorption from the GI tract, is
excreted unchanged in the urine. Because cephradine is so well absorbed, the
concentrations in plasma are nearly equivalent after oral or intramuscular
administration.

Cefadroxil is the para-hydroxy analog of cephalexin. Concentrations of cefadroxil

in plasma and urine are at somewhat higher levels than are those of cephalexin.
The drug is given orally once or twice a day for the treatment of urinary tract
infections. Its activity in vitro is similar to that of cephalexin.
Second-Generation Cephalosporins.
Second-generation Cephalosporins have a broader spectrum than do the first-
generation agents and are active against sensitive strains of Enterobacter spp.,
indole-positive Proteus spp., and Klebsiella spp.

Cefoxitin
is resistant to some β-lactamases produced by gram-negative rods. This antibiotic
is less active than the first-generation cephalosporins against gram-positive
bacteria, but is more active against anaerobes, especially B. fragilis. Cefoxitin’s
special role seems to be for treatment of certain anaerobic and mixed aerobic-
anaerobic infections, such as pelvic inflammatory disease and lung abscess.

Cefaclor’s concentration in plasma after oral administration is ~50% of that

achieved after an equivalent oral dose of cephalexin. However, cefaclor is more
active against H. influenzae and M. catarrhalis, although some β-lactamase-
producing strains of these organisms may be resistant.

Loracarbef is similar in activity to cefaclor and more stable against some β-

lactamases.

Cefuroxime is similar to loracarbef with broader gram-negative activity against

some Citrobacter and Enterobacter spp. Unlike cefoxitin, cefmetazole, and
cefotetan, cefuroxime lacks activity against B. fragilis. The drug can be given every
8 h. Concentrations in CSF are ~10% of those in plasma, and the drug is effective
(but inferior to ceftriaxone) for treatment of meningitis owing to H. influenzae
(including strains resistant to ampicillin), N. meningitides, and S. pneumoniae.

Cefpodoxime Proxetil is an orally administered third-generation agent that is

very similar in activity to the fourth-generation agent cefepime except that it is
not more active against Enterobacter or Pseudomonas spp.

Cefprozil is an orally administered agent that is more active than first-generation

cephalosporins against penicillin-sensitive streptococci, E. coli, P. mirabilis,
Klebsiella spp., and Citrobacter spp; serum t1/2is ~1.3 h.
THIRD-GENERATION CEPHALOSPORINS

Cefotaxime is highly resistant to many β-lactamases and has good activity against
many gram-positive and gram-negative aerobic bacteria. However, activity
against B. fragilis is poor compared with agents such as clindamycin and
metronidazole. Cefotaxime has a t1/2 in plasma of ~1 h and should be
administered every 4–8 h for serious infections. The drug is metabolized in vivo
to desacetylcefotaxime, which is less active than is the parent compound.
Cefotaxime has been used effectively for meningitis caused by H. influenzae,
penicillin-sensitive S. pneumoniae, and Neisseria meningitides.

Ceftizoxime has a spectrum of activity in vitro that is very similar to that of

cefotaxime, except that it is less active against S. pneumoniae and more active
against B. fragilis. The t1/2 is 1.8 h, and the drug thus can be administered every 8-
12 h for serious infections. Ceftizoxime is not metabolized; 90% is recovered in
urine.

Ceftriaxone has activity very similar to that of ceftizoxime and cefotaxime but a
longer t1/2 (~8 h). Administration of the drug once or twice daily has been
effective for patients with meningitis. About half the drug can be recovered from
the urine; the remainder is eliminated by biliary secretion. A single dose of
ceftriaxone (125-250 mg) is effective in the treatment of urethral, cervical, rectal,
or pharyngeal gonorrhea, including disease caused by penicillinase-producing
microorganisms.

Cefditoren Pivoxil is a prodrug that is hydrolyzed by esterases during absorption

to the active drug, cefditoren. Cefditoren is eliminated unchanged in the urine.
The drug is active against methicillin-susceptible strains of S. aureus, penicillin-
susceptible strains of S. pneumoniae, S. pyogenes, H. influenzae, H. parainfluenzae,
and M. catarrhalis. Cefditoren pivoxil is only indicated for the treatment of mild-
to-moderate pharyngitis, tonsillitis, uncomplicated skin and skin structure
infections, and acute exacerbations of chronic bronchitis.

Cefixime is orally effective against urinary tract infections caused by E. coli and P.
mirabilis, otitis media caused by H. influenza and S. pyogenes, pharyngitis due to S.
pyogenes, and uncomplicated gonorrhoea. It is available as an oral suspension.
Cefixime has a plasma t1/2 of 3-4 h and is both excreted in the urine and
eliminated in the bile. The standard dose for adults is 400 mg/day for 5-7 days,
and for a longer interval in patients with S. pyogenes. Doses must be reduced in
patients with renal impairment. Paediatric dosing varies with patient weight.
Ceftibuten is an orally effective cephalosporin that is less active against gram-
positive and gram-negative organisms than cefixime, with activity limited to S.
pneumonia and S. pyogenes, H. influenzae, and M. catarrhalis. Ceftibuten is only
indicated for acute bacterial exacerbations of chronic bronchitis, acute bacterial
otitis media, pharyngitis, and tonsillitis.

Cefdinir is effective orally; it is eliminated primarily unchanged in the urine.

Cefdinir has activity against facultative gram-negative bacteria but lacks
anaerobic activity. It is also inactive against Pseudomonas and Enterobacter spp.

Third-Generation Cephalosporins with Good Anti-Pseudomonal Activity.

Ceftazidime is one-quarter to one-half as active against gram-positive

microorganisms as is cefotaxime. Its activity against the Enterobacteriaceae is
very similar, but its major distinguishing feature is excellent activity
against Pseudomonas and other gram-negative bacteria. Ceftazidime has poor
activity against B. fragilis. Its t1/2 in plasma is ~1.5 h; the drug is not metabolized.

FOURTH-GENERATION CEPHALOSPORINS: CEFEPIME AND CEFPIROME

Only cefepime is available for use in the U.S. Cefepime resists hydrolysis by many
of the plasmid-encoded β-lactamases. It is a poor inducer of, and is relatively
resistant to, the type I chromosomally encoded and some extended-spectrum β-
lactamases. Thus, it is active against many Enterobacteriaceae that are resistant to
other cephalosporins via induction of type I β-lactamases. Cefepime is susceptible
hydrolysis by many bacteria expressing extended-spectrum plasmid-mediated β-
lactamases. Cefepime is excreted renally; doses should be adjusted for renal
failure. Cefepime has excellent penetration into the CSF in animal models of
meningitis. The recommended dosage for adults is 2 g intravenously every 12 h.
The serum t1/2 is 2 h.

Against the fastidious gram-negative bacteria (H. influenzae, Neisseria

gonorrhoeae, and N. Meningitides), cefepime has comparable or greater in vitro
activity than cefotaxime. For P. aeruginosa, cefepime has comparable activity to
ceftazidime, although it is less active than ceftazidime for other Pseudomonas spp.
and X. maltophilia. Cefepime has higher activity than ceftazidime and comparable
activity to cefotaxime for streptococci and methicillin-sensitive S. aureus. It is not
active against MRSA, penicillin-resistant pneumococci, enterococci, B. fragilis, L.
monocytogenes, Mycobacterium avium complex, or Mycobacterium tuberculosis.
ADVERSE REACTIONS

Hypersensitivity reactions to the cephalosporins are the most common side

effects; they are identical to those caused by the penicillins. Patients who are
allergic to 1 class of β-lactam antibiotics may manifest cross-reactivity to a
member of the other class.

Immediate reactions such as anaphylaxis, bronchospasm, and urticaria are

observed. More commonly, maculopapular rash develops, usually after several
days of therapy; this may or may not be accompanied by fever and eosinophilia.
Patients with a history of a mild or a temporally distant reaction to penicillin
appear to be at low risk of allergic reaction following the administration of a
cephalosporin. However, patients who have had a recent severe, immediate
reaction to penicillin should be given a cephalosporin with great caution, if at all.
A positive Coombs reaction appears frequently in patients who receive large
doses of a cephalosporin, but hemolysis is rare. Cephalosporins have produced
rare instances of bone marrow depression, characterized by granulocytopenia.

The cephalosporins are potentially nephrotoxic. Renal tubular necrosis has

followed the administration of cephaloridine in doses >4 g/day; this agent is no
longer available in the U.S. Other cephalosporins when used by themselves in
recommended doses rarely produce significant renal toxicity. High doses of
cephalothin (no longer available in the U.S.) have produced acute tubular necrosis
in certain instances, and usual doses (8-12 g/day) have caused nephrotoxicity in
patients with pre-existing renal disease. Diarrhea can result from the
administration of cephalosporins and may be more frequent with cefoperazone,
perhaps because of its greater biliary excretion. Intolerance to alcohol has been
noted with cephalosporins that contain the methylthiotetrazole (MTT) group.
Serious bleeding related either to hypoprothrombinemia owing to the MTT group,
thrombocytopenia, and/or platelet dysfunction has been reported.
THERAPEUTIC USES

The First-Generation Cephalosporins are excellent agents for skin and soft
tissue infections owing to S. pyogenes and methicillin-susceptible S. aureus. A
single dose of cefazolin just before surgery is the preferred prophylaxis for
procedures in which skin flora are the likely pathogens. For colorectal surgery,
where prophylaxis for intestinal anaerobes is desired, the second-generation
agent cefoxitin is preferred.

Second-Generation Cephalosporins generally have been displaced by third-

generation agents. The oral second-generation cephalosporins can be used to
treat respiratory tract infections, although they are suboptimal (compared with
oral amoxicillin) for treatment of penicillin-resistant S. pneumoniae pneumonia
and otitis media. In situations where facultative gram-negative bacteria and
anaerobes are involved, such as intra-abdominal infections, pelvic inflammatory
disease, and diabetic foot infection, cefoxitin and cefotetan both are effective.

The Third-Generation Cephalosporins are the drugs of choice for serious

infections caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia,
and Haemophilus spp. Ceftriaxone is the therapy of choice for all forms of
gonorrhoea and for severe forms of Lyme disease. Third-generation cephalosporins
cefotaxime or ceftriaxone are used for the initial treatment of meningitis in
nonimmunocompromised adults and children >3 months of age (in combination
with vancomycin and ampicillin pending identification of the causative agent).
They are the drugs of choice for the treatment of meningitis caused by H.
influenzae, sensitive S. pneumoniae, N. meningitidis, and gram-negative enteric
bacteria. Cefotaxime has failed in the treatment of meningitis owing to resistant S.
pneumoniae; thus vancomycin should be added. Ceftazidime plus an
aminoglycoside is the treatment of choice for Pseudomonas meningitis. Third-
generation cephalosporins lack activity against L. monocytogenes and penicillin-
resistant pneumococci, which may cause meningitis. The antimicrobial spectra of
cefotaxime and ceftriaxone are excellent for the treatment of community-acquired
pneumonia.

The Fourth-Generation Cephalosporins are indicated for the empirical

treatment of nosocomial infections where antibiotic resistance owing to
extended-spectrum β-lactamases or chromosomally induced β-lactamases are
anticipated. For example, cefepime has superior activity against nosocomial
isolates of Enterobacter, Citrobacter, and Serratia spp. compared with ceftazidime
and piperacillin. KPC- or metallo-β-lactamase expressing strains are resistant to
cefepime.

OTHER β-LACTAM ANTIBIOTICS

CARBAPENEMS

Carbapenems are β-lactams that contain a fused β-lactam ring and a 5-member
ring system that differs from the penicillins because it is unsaturated and contains
a carbon atom instead of the sulfur atom. This class of antibiotics has a broader
spectrum of activity than most other β-lactam antibiotics.

IMIPENEM.

Imipenem is marketed in combination with cilastatin, a drug that inhibits the

degradation of imipenem by a renal tubular dipeptidase.

Antimicrobial Activity.

Imipenem, like other β-lactam antibiotics, binds to PBPs, disrupts bacterial cell
wall synthesis, and causes death of susceptible microorganisms. It is very resistant
to hydrolysis by most β-lactamases. The activity of imipenem is excellent in vitro
for a wide variety of aerobic and anaerobic microorganisms. Streptococci
(including penicillin-resistant S. pneumoniae), Enterococci (excluding E.
faecium and non-β-lactamase-producing penicillin-resistant strains),
Staphylococci (including penicillinase-producing strains), and Listeria all are
susceptible. Some strains of methicillin-resistant staphylococci are susceptible:
many strains are not. Activity was excellent against the Enterobacteriaceae until
the emergence of KPC carbapenemase-producing strains. Most strains of
Pseudomonas and Acinetobacter are inhibited. Anaerobes, including B. fragilis, are
highly susceptible.

Pharmacokinetics and Adverse Reactions.

Imipenem is not absorbed orally. The drug is hydrolyzed rapidly by a dipeptidase

found in the brush border of the proximal tubule. To prolong drug activity,
imipenem is combined with cilastatin, an inhibitor of the dehydropeptidase; the
combined preparation is available as PRIMAXIN.
Both imipenem and cilastatin have a t1/2 of ~1 h. When administered concurrently
with cilastatin, ~70% of administered imipenem is recovered in the urine as the
active drug.

Dosage should be modified for patients with renal insufficiency. Nausea and
vomiting are the most common adverse reactions (1-20%). Seizures have been
noted in up to 1.5% of patients, especially when high doses are given to patients
with CNS lesions and to those with renal insufficiency. Patients who are allergic to
other β-lactam antibiotics may have hypersensitivity reactions when given
imipenem.

Therapeutic Uses.

Imipenem–cilastatin is effective for a wide variety of infections, including urinary

tract and lower respiratory infections; intra-abdominal and gynaecological
infections; and skin, soft tissue, bone, and joint infections. The drug
combination appears to be especially useful for the treatment of infections caused
by cephalosporin-resistant nosocomial bacteria. It is prudent to use imipenem for
empirical treatment of serious infections in hospitalized patients who have
recently received other β-lactam antibiotics. Imipenem should not be used as
monotherapy for infections owing to P. aeruginosa because of the risk of
resistance developing during therapy.

MEROPENEM.

Meropenem is a derivative of thienamycin. It does not require co administration

with cilastatin because it is not sensitive to renal dipeptidase. Its toxicity is similar
to that of imipenem except that it may be less likely to cause seizures.

DORIPENEM.

Doripenem has a spectrum of activity that is similar to that of imipenem and

meropenem, with greater activity against some resistant isolates of Pseudomonas.

ERTAPENEM.

Ertapenem differs from imipenem and meropenem by having a longer t1/2 that
allows once-daily dosing and by having inferior activity against P.
aeruginosa and Acinetobacter spp. Its activity against gram-positive organisms,
Enterobacteriaceae, and anaerobes makes it useful in intra-abdominal and pelvic
infections.

AZTREONAM.

Aztreonam is resistant to many of the β-lactamases elaborated by most gram-

negative bacteria, including the metallo-β-lactamases but not the KPC β-
lactamases.

The antimicrobial activity of aztreonam differs from those of other β-lactam

antibiotics and more closely resembles that of an aminoglycoside.
Aztreonam has activity only against gram-negative bacteria; it has no activity
against gram-positive bacteria and anaerobic organisms. Activity against
Enterobacteriaceae is excellent, as is that against P. aeruginosa. It is also highly
active in vitro against H. influenza and gonococci. Aztreonam is administered
either intramuscularly or intravenously. The t1/2 for elimination is 1.7 h; most of
the drug is recovered unaltered in the urine. The t1/2 is prolonged to ~6 h in
anephric patients.

The usual dose of aztreonam for severe infections is 2 g every 6-8 h (reduced in
patients with renal insufficiency). A notable feature is little allergic cross-
reactivity with β-lactam antibiotics, with the possible exception of ceftazidime
with which it has considerable structural similarity.

Aztreonam is therefore useful for treating gram-negative infections that normally

would be treated with a β-lactam antibiotic were it not for a prior allergic
reaction. Aztreonam generally is well tolerated.
Aminoglycosides
Are aminocyclitol derivative antibiotics. Spectinomycin is the pure aminocyclitol
which does not contain amino sugars
Antimicrobial activity of different aminoglycosides:
1. Neomycin and Paromomycin:
 Neomycin is limited only for topical application

 Paromomycin is used in the treatment of systemic infection caused

by Entamoeba histolytica and Leishmania.
2. Streptomycin:
 Streptomycin has activity against Gram negative, certain gram Positive as
well as Staphylococci.
 It is used treatment of Tuberculosis

3. Kanamycin and Amikacin:

 Kanamycin and Amikacin are 2nd line drug for Mycobacterium
 Gentamycin, Tobramycin, Netilmicin and Amiacin also offer activity
against Pseudomonas. These antibiotics are recommended in the
treatment of serious systemic infection and endocarditis caused by
Streptococci along with broad spectrum β-lactam antibiotics.
Mode of Action of Aminoglycosides:
 Aminoglycosides block the initiation step of protein synthesis in bacteria.
The antibiotics aminoglycodie binds to the P-site in 30S ribosome
preventing binding of IF3
 Streptomycin distorts the shape of A-site and therefore interferes with
the correct positioning of the incoming aminoacyl-tRNA and thus leads to
the misreading of the polypeptide chain in bacteria.
 Streptomycin also causes dissociation of polysomes into monosomes in
bacteria
Mechanism of Resistance to Aminoglycosides:
 Anaerobes are inherently resistant to aminoglycosides. Aminoglycosides
requires an active transport system (oxygen dependent) for the uptake of
drugs inside bacterial cell. This type of oxygen dependent transport
system is absent in anaerobes.
 Mutation in the gene responsible for deletion or alteration of the receptor
protein can also leads to development of resistance towards
aminoglycosides.
  Alteration of cell surface that interfere with penetration or uptake of drug
in bacteria can also leads to resistance.
 Production of enzyme such as aminoglycoside acetyltransferase,
aminoglycoside phosphoryltransferase, aminoglycoside
adenyltransferase etc by resistant bacteria that inactivates the
aminoglycoside either by phosphorylation or adenylation or acetylation.
This can also cause resistance to aminoglycosides.
Pharmacological Properties of Aminoglycosides:
 Aminoglycosides are not suitable for oral administration because they
are very poorly absorbed from GI tract.
 None of the aminoglycoside can cross blood brain barrier.

 These drugs are nephrotoxic and ototoxic

 The aminoglycosides are effective primarily against aerobic gram-negative

organisms and, in combination with other classes of antibiotics, are most
often used in the treatment of bacteremia and sepsis. They are ineffective
against anaerobic organisms, and because of their toxicity they are used less
commonly for many gram-negative infections other than bacteremia and
sepsis. Because the therapeutic index of the aminoglycosides is narrow and
toxicity can be serious, close attention must be paid to the
pharmacokinetics of these drugs in individual patients. Renal function must
be assessed, and monitoring of plasma concentrations is recommended.
 Another ribosome-binding agent, Spectinomycin, is related to the
aminoglycosides because it is also an aminocyclitol, but it lacks amino
sugars, and its actions are different. In addition, the aminoglycosides are
bactericidal, whereas spectinomycin is bacteriostatic.
 The ribosome-binding sites for Macrolides such as Erythromycin,
Azithromycin, Clarithromycin, And Clindamycin are on the same 50S
subunit (S represents the sedimentation parameter), but the structures of
the drugs and the spectrum of activities differ considerably.

Erythromycin, one of the first macrolides developed, is relatively safe and widely
used, especially for the treatment of infections in children (Because of the success
of macrolides in the treatment of pulmonary infections, these drugs continue to
be used in the treatment of respiratory tract infections in adults.
The primary differences among Erythromycin,
Clarithromycin, and Azithromycin are related to relative activities against
certain bacterial species such as Mycobacterium, gastrointestinal (GI) tolerability,
and pharmacokinetics. Clindamycin displays antimicrobial activity somewhat
similar to that of erythromycin. However, the two differ structurally, and
clindamycin displays extensive anaerobic activity while having no activity for
atypical respiratory pathogens.

Chloramphenicol is another antibiotic that binds to the 50S ribosomal subunit.

Although widely used at one time, its serious side effects and the availability of
many other antimicrobial drugs have limited the applications for which this drug
is used in the United States.
The ketolides represent a new class of antibiotics within the macrolide-
lincosamide-streptogramin B family. Ketolides are semi synthetic derivatives of
erythromycin that inhibit protein synthesis via interaction with the 50S ribosomal
subunit. Activity against macrolide-resistant respiratory tract pathogens is
maintained in ketolides, which also demonstrate excellent activity against atypical
respiratory pathogens. Therefore ketolides may provide an additional treatment
option for lower respiratory tract infections.
The Tetracyclines and Synthetic Glycylcycline analogs bind to the 30S
ribosomal subunit and are effective against aerobic and anaerobic gram-positive
and gram-negative organisms. Given their wide spectrum of activity, these agents
remain widely used for treatment of Bacterial, Chlamydial, Rickettsial, and
Mycoplasmal infections, although the development of bacterial resistance has
reduced their efficacy against some pathogens
The Streptogramins and Oxazolidinones are newer classes of antibiotics that
were developed primarily for the treatment of gram-positive organisms and often
have activity against organisms that are resistant to β-lactams and glycopeptides.
Both classes inhibit protein synthesis, but their structures and mechanisms of
action differ.
 Therapeutic Overview
Aminoglycosides
Inhibit gram-negative aerobes
Narrow therapeutic index
Renal and otic toxicities can be serious
Pharmacokinetics are important considerations
Plasmid-mediated resistance is a problem
Macrolides
Inhibit Mycoplasma, Chlamydia, Legionella
Inhibit gram-positive organisms
Clindamycin
Inhibits gram-positive cocci and anaerobic species
Active against clostridium difficile-associated diarrhea and colitis
Chloramphenicol
Kills major meningitis pathogens
Serious toxicity
Ketolides
Inhibit respiratory pathogens
Active against penicillin and macrolide-resistant S. pneumoniae
Tetracyclines
Inhibit broad spectrum of organisms
Streptogramins
Inhibit gram-positive organisms
Active against VRE
Oxazolidinones
Inhibit gram-positive organisms
Active against VRE
These drugs represent important agents for the treatment of multidrug-resistant
gram-positive infections, but prudent use will be important to prevent the
development of resistance to these agents.

Mupirocin, which interferes with transfer ribonucleic acid (tRNA) synthesis, is a

topical agent primarily used to treat cutaneous streptococcal and staphylococcal
infections.

Mechanisms of Action
The bacterial ribosomal subunit to which each of these drugs binds and the
bactericidal or bacteriostatic response of susceptible bacteria to the drugs. The
principal steps in bacterial ribosomal synthesis of proteins, as carried out by the
70S ribosomes and relevant RNAs, and the points at which the drugs act,
Bacteriostatic Inhibitors of Protein Synthesis
All the drugs discussed in this chapter inhibit bacterial protein synthesis.
However, unlike the aminoglycosides, which are bactericidal, the drugs
considered here are largely bacteriostatic. That is, they suppress bacterial growth
and replication but do not produce outright kill. In general, the drugs presented
here are second-line agents, used primarily for infections resistant to first-line
agents.
Tetracyclines
The tetracyclines are broad-spectrum antibiotics. Four tetracyclines are available
for systemic therapy.
All four—Tetracycline, Demeclocycline, Doxycycline, And Minocycline
—are similar in structure, antimicrobial actions, and adverse effects.
Principal differences among them are pharmacokinetic. Because the similarities
among these drugs are more pronounced than their differences, we will discuss
the tetracyclines as a group, rather than focusing on a prototype. Unique
properties of individual tetracyclines are indicated as appropriate.
Mechanism of Action
The tetracyclines suppress bacterial growth by inhibiting protein synthesis. These
drugs bind to the 30S ribosomal subunit and thereby inhibit binding of transfer
RNA to the messenger RNA–ribosome complex. As a result, addition of amino
acids to the growing peptide chain is prevented. At the concentrations achieved
clinically, the tetracyclines are bacteriostatic.
Selective toxicity of the tetracyclines results from their poor ability to cross
mammalian cell membranes. To influence protein synthesis, tetracyclines must
first gain access to the cell interior. These drugs enter bacteria by way of an
energy-dependent transport system. Mammalian cells lack this transport system
and hence do not actively accumulate the drug. Consequently, although
tetracyclines are inherently capable of inhibiting protein synthesis in mammalian
cells, their levels within host cells remain too low to be harmful.
Microbial Resistance
Bacterial resistance results from increased drug inactivation, decreased access to
ribosomes (owing to the presence of ribosome protection proteins), and reduced
intracellular accumulation (owing to decreased uptake and increased export).
Antimicrobial Spectrum
The tetracyclines are broad-spectrum antibiotics, active against a wide variety of
gram-positive and gram-negative bacteria. Sensitive organisms include Rickettsia,
spirochetes, Brucella, Chlamydia, Mycoplasma, Helicobacter pylori, Borrelia
burgdorferi, Bacillus anthracis, and Vibrio cholerae.
Therapeutic Uses
Treatment of Infectious Diseases Extensive use of tetracyclines has resulted in
increasing bacterial resistance. Because of resistance, and because antibiotics
with greater selectivity and less toxicity are now available, use of tetracyclines has
declined. Today, tetracyclines are rarely drugs of first choice.
Disorders for which they are first-line drugs include
(1) Rickettsial Diseases (E.G., Rocky Mountain spotted fever, Typhus Fever, Q
Fever);
(2) Infections Caused By Chlamydia Trachomatis (Trachoma, Lymphogranuloma
Venereum, Urethritis, Cervicitis);
(3) Brucellosis;
(4) Cholera;
(5) Pneumonia Caused By Mycoplasma Pneumoniae;
(6) Lyme Disease;
(7) Anthrax; And
(8) Gastric Infection with H. Pylori.

Treatment of Acne
Tetracyclines are used topically and orally for severe acne vulgaris. Beneficial
effects derive from suppressing the growth and metabolic activity of
Propionibacterium acnes, an organism that secretes inflammatory chemicals. Oral
doses for acne are relatively low. As a result, adverse effects are minimal.
Peptic Ulcer Disease
H. pylori, a bacterium that lives in the stomach, is a major contributing factor to
peptic ulcer disease. Tetracyclines, in combination with metronidazole and
bismuth subsalicylate, are a treatment of choice for eradicating this bug.
Periodontal Disease
Two tetracyclines—doxycycline and minocycline—are used for periodontal
disease.
Doxycycline is used orally and topically, whereas minocycline is used only
topically. Oral Therapy Benefits of oral doxycycline result from inhibiting
collagenase, an enzyme that destroys connective tissue in the gums.
The small doses employed —20 mg twice daily—are too low to harm bacteria.
Topical Therapy
Topical minocycline and doxycycline are employed as adjuncts to scaling and root
planing. The objective is to reduce pocket depth and bleeding in adults with
periodontitis. Benefits derive from suppressing bacterial growth. Both products
are applied directly to the site of periodontal disease.
Rheumatoid Arthritis
Minocycline can reduce symptoms in patients with rheumatoid arthritis,
suggesting a possible infectious component to the disease. Pharmacokinetics
Individual tetracyclines differ significantly in their pharmacokinetic properties. Of
particular significance are differences in half-life and route of elimination. Also
important is the degree to which food decreases absorption.

Pharmacokinetic Properties of the Tetracyclines

Duration of Action
The tetracyclines can be divided into three groups: Short Acting, Intermediate
Acting, And Long Acting. These differences are related to differences in lipid
solubility: the only short-acting agent (tetracycline) has relatively low lipid
solubility, whereas the long-acting agents (doxycycline, minocycline) have
relatively high lipid solubility.
Absorption
All of the tetracyclines are orally effective, although the extent of absorption
differs among individual agents.
Absorption of three agents—Tetracycline, Demeclocycline, And Doxycycline—is
reduced by food, whereas absorption of minocycline is not. The tetracyclines form
insoluble chelates with calcium, iron, magnesium, aluminum, and zinc. The result
is decreased absorption.
Distribution
Tetracyclines are widely distributed to most tissues and body fluids. However,
penetration to the cerebrospinal fluid (CSF) is poor, and hence levels in the CSF
are too low to treat meningeal infections. Tetracyclines readily cross the placenta
and enter the fetal circulation.
Elimination
Tetracyclines are eliminated by the kidneys and liver. All tetracyclines are
excreted by the liver into the bile. After the bile enters the intestine, most
tetracyclines are reabsorbed. Ultimate elimination of short- and intermediate-
acting tetracyclines— tetracycline and demeclocycline—is in the urine, largely as
the unchanged drug. Because these agents undergo renal elimination, they can
accumulate to toxic levels if the kidneys fail.
Consequently, tetracycline and demeclocycline should not be given to patients
with significant renal impairment. Long-acting tetracyclines are eliminated by the
liver, primarily as metabolites. Because these agents are excreted by the liver,
their half-lives are unaffected by kidney dysfunction.
Accordingly, the long-acting agents (doxycycline and minocycline) are drugs of
choice for tetracycline-responsive infections in patients with renal impairment.
Adverse Effects
Gastrointestinal Irritation
Tetracyclines irritate the gastrointestinal (GI) tract. As a result, oral therapy is
frequently associated with epigastric burning, cramps, nausea, vomiting, and
diarrhoea. These reactions can be reduced by giving tetracyclines with meals—
although food may decrease absorption. Occasionally, tetracyclines cause
esophageal ulceration. Risk can be minimized by avoiding dosing at bedtime.
Because diarrhoea may result from superinfection of the bowel (in addition to
nonspecific irritation), it is important that the cause of diarrhoea be determined.
Effects on Bones and Teeth
Tetracyclines bind to calcium in developing teeth, resulting in yellow or brown
discoloration; hypoplasia of the enamel may also occur. The intensity of tooth
discoloration is related to the total cumulative dose: staining is darker with
prolonged and repeated treatment. When taken after the fourth month of
gestation, tetracyclines can cause staining of deciduous teeth of the infant.
However, use during pregnancy will not affect permanent teeth.
Discoloration of permanent teeth occurs when tetracyclines are taken by patients
aged 4 months to 8 years, the interval during which tooth enamel is being formed.
Accordingly, these drugs should be avoided by children younger than 8 years. The
risk for tooth discoloration with doxycycline may be less than with other
tetracyclines. Tetracyclines can suppress long-bone growth in premature infants.
This effect is reversible on discontinuation of treatment.
Superinfection
A superinfection is an overgrowth with drug-resistant microbes, which occurs
secondary to suppression of drug-sensitive organisms. Because the tetracyclines
are broad-spectrum agents and therefore can decrease viability of a wide variety
of microbes, the risk for superinfection is greater than with antibiotics that have a
more narrow spectrum. Superinfection of the bowel with staphylococci or with
Clostridium difficile produces severe diarrhoea and can be life-threatening. The
infection caused by C. difficile is known as C. difficile–associated diarrhoea
(CDAD), also known as antibiotic-associated pseudomembranous colitis. Patients
should notify the prescriber if significant diarrhoea occurs so that the possibility
of bacterial superinfection can be evaluated.
If a diagnosis of superinfection with staphylococci or C. difficile is made,
tetracyclines should be discontinued immediately. Treatment of CDAD consists of
oral vancomycin or metronidazole plus vigorous fluid and electrolyte
replacement.
Overgrowth with fungi (commonly Candida albicans) may occur in the mouth,
pharynx, vagina, and bowel. Symptoms include vaginal or anal itching;
inflammatory lesions of the anogenital region; and a black, furry appearance of
the tongue.
Superinfection with Candida can be managed by discontinuing tetracyclines.
When this is not possible, antifungal therapy is indicated.
Hepatotoxicity
Tetracyclines can cause fatty infiltration of the liver. Hepatotoxicity manifests
clinically as lethargy and jaundice. Rarely, the condition progresses to massive
liver failure. Liver damage is most likely when tetracyclines are administered
intravenously in high doses (greater than 2 g/day). Pregnant and postpartum
women with kidney disease are at especially high risk.
Renal Toxicity
Tetracyclines may exacerbate renal impairment in patients with pre-existing
kidney disease. Because tetracycline and demeclocycline are eliminated by the
kidneys, these agents should not be given to patients with renal impairment. If a
patient with renal impairment requires a tetracycline, either doxycycline or
minocycline should be used because these drugs are eliminated primarily by the
liver.
Other Adverse Effects
Vestibular toxicity
—manifesting as dizziness, light-headedness, and unsteadiness
—has occurred with minocycline.
Rarely, tetracyclines have produced pseudotumor cerebri (a benign elevation in
intracranial pressure). In a few patients, demeclocycline has produced
nephrogenic diabetes insipidus, a syndrome characterized by thirst, increased
frequency of urination, and unusual weakness or tiredness. Because of their
irritant properties, tetracyclines can cause pain at sites of intramuscular (IM)
injection and thrombophlebitis when administered intravenously.
Drug and Food Interactions
As noted, tetracyclines can form nonabsorbable chelates with certain metal ions
(calcium, iron, magnesium, aluminum, zinc). Substances that contain these ions
include milk products, calcium supplements, iron supplements, magnesium-
containing laxatives, and most antacids. If a tetracycline is administered with
these agents, its absorption will be decreased.
To minimize interference with absorption, tetracyclines should be administered
at least 1 hour before or 2 hours after ingestion of chelating agents. Tetracyclines
can also increase digoxin levels through increasing absorption in the GI tract and
increase international normalized ratio (INR) levels by altering the vitamin
K−producing flora in the gut. Patients on digoxin or warfarin should undergo
careful drug level monitoring.

PATIENT-CENTERED CARE ACROSS THE LIFE SPAN Tetracyclines

Dosage and Administration

Administration For systemic therapy, tetracyclines may be administered orally or
intravenously. Oral administration is preferred, and all tetracyclines are available
in oral formulations. As a rule, oral tetracyclines should be taken on an empty
stomach (1 hour before meals or 2 hours after) and with a full glass of water.
An interval of at least 2 hours should separate tetracycline ingestion and ingestion
of products that can chelate these drugs (e.g., milk, calcium or iron supplements,
antacids). Two tetracyclines can be given intravenously but this route should be
employed only when oral therapy cannot be tolerated or has proved inadequate.
Major Precautions
Two tetracyclines—tetracycline and demeclocycline
—are eliminated primarily in the urine and hence will accumulate to toxic levels
in patients with kidney disease. Accordingly, patients with kidney disease should
not use these drugs. Tetracyclines can cause discoloration of deciduous and
permanent teeth. Tooth discoloration can be avoided by withholding these drugs
from pregnant women and from children younger than 8 years. Diarrhoea may
indicate a potentially life-threatening superinfection of the bowel. Advise patients
to notify the prescriber if diarrhoea occurs.
High-dose intravenous (IV) therapy has been associated with severe liver damage,
particularly in pregnant and postpartum women with kidney disease. As a rule,
these women should not receive tetracyclines.
Unique Properties of Individual Tetracyclines
Tetracycline Tetracycline hydrochloride is the least expensive and most widely
used member of the family. When employed systemically, the drug has the
indications, pharmacokinetics, adverse effects, and drug interactions described
for the tetracyclines as a group. Like most tetracyclines, tetracycline
hydrochloride should not be administered with food and is contraindicated for
patients with renal impairment.
Demeclocycline
Demeclocycline shares the actions, indications, and adverse effects described
previously for the tetracyclines as a group. Because of its intermediate duration of
action, demeclocycline can be administered at dosing intervals that are longer
than those used for tetracycline. Like tetracycline, demeclocycline should not be
administered with food.
Demeclocycline is unique among the tetracyclines in that it stimulates urine flow.
This side effect can lead to excessive urination, thirst, and tiredness. Interestingly,
because of its effect on renal function, demeclocycline has been employed
therapeutically to promote urine production in patients suffering from the
syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
Doxycycline
Doxycycline is a long-acting agent that shares the actions and adverse effects
described for the tetracyclines as a group. Because of its extended half-life,
doxycycline can be administered once daily in some situations. Absorption of oral
doxycycline is greater than that of tetracycline. However, food can still reduce the
absorption of doxycycline somewhat, and hence it is best to give this drug on an
empty stomach.
Doxycycline is eliminated primarily by nonrenal mechanisms. As a result, it is safe
for patients with renal failure.
Doxycycline is a first-line drug for Lyme disease, Anthrax, Chlamydial Infections
(Urethritis, Cervicitis, and Lymphogranuloma Venereum), and sexually acquired
proctitis (in combination with ceftriaxone). A topical formulation is used for
periodontal disease, as is a low-dose oral formulation.
Another low-dose oral formulation is used for acne.
Minocycline
Minocycline is a long-acting agent similar to doxycycline. Unlike other
tetracyclines, minocycline can be taken with food. Like doxycycline, and unlike
tetracycline and demeclocycline, minocycline is safe for patients with kidney
disease. Minocycline is unique among the tetracyclines in that it can damage the
vestibular system, causing unsteadiness, light-headedness, and dizziness. This
toxicity limits its use. Minocycline is expensive, costing significantly more than
tetracycline.
In addition to fighting systemic infection, minocycline can reduce symptoms of
arthritis and is available in an extended-release formulation for acne and a topical
formulation for periodontal disease.

Tetracyclines should not be administered together with

(1) Calcium Supplements,
(2) Milk Products (Because They Contain Calcium),
(3) Iron Supplements,
(4) Magnesium-Containing Laxatives, and
(5) Most Antacids (Because They Contain magnesium, aluminum, or both).
Sun Exposure Risk with Tetracyclines
All tetracyclines can increase the sensitivity of the skin to ultraviolet light. The most common result
is exaggerated sunburn. Advice patients to avoid prolonged exposure to sunlight, wear protective
clothing, and apply a sunscreen to exposed skin.
Macrolides
The macrolides are broad-spectrum antibiotics that inhibit bacterial protein
synthesis. They are called macrolides because they are big. Erythromycin is the
oldest member of the family. The newer macrolides—Azithromycin and
Clarithromycin—are derivatives of erythromycin.
Erythromycin
Erythromycin has a relatively broad antimicrobial spectrum and is a preferred or
alternative treatment for a number of infections. The drug is one of our safer
antibiotics and will serve as our prototype for the macrolide family.
Mechanism of Action
Antibacterial effects result from inhibition of protein synthesis: erythromycin
binds to the 50S ribosomal subunit and thereby blocks addition of new amino
acids to the growing peptide chain. The drug is usually bacteriostatic but can be
bactericidal against highly susceptible organisms or when present in high
concentration. Erythromycin is selectively toxic to bacteria because ribosomes in
the cytoplasm of mammalian cells do not bind the drug. Also, in contrast to
chloramphenicol ,erythromycin cannot cross the mitochondrial membrane and
therefore does not inhibit protein synthesis in host mitochondria.
Acquired Resistance
Bacteria can become resistant by two mechanisms:
(1) Production of a pump that exports the drug and
(2) Modification (by methylation) of target ribosomes so that binding of
erythromycin is impaired.
Antimicrobial Spectrum
Erythromycin has an antibacterial spectrum similar to that of penicillin. The drug
is active against most gram-positive bacteria as well as some gram-negative
bacteria. Bacterial sensitivity is determined in large part by the ability of
erythromycin to gain access to the cell interior.
Therapeutic Uses
Erythromycin is a commonly used antibiotic. The drug is a treatment of first
choice for several infections and may be used as an alternative to penicillin G in
patients with penicillin allergy. Erythromycin is considered the drug of first
choice for individuals infected with Bordetella pertussis, the causative agent of
whooping cough. Because symptoms are caused by a toxin produced by B.
pertussis, erythromycin does little to alter the course of the disease. However, by
eliminating B. pertussis from the nasopharynx, treatment does lower infectivity.
Corynebacterium diphtheriae is highly sensitive to erythromycin.
Accordingly, erythromycin is the treatment of choice for acute diphtheria and
eliminating the diphtheria carrier state. Several infections respond equally well to
macrolides and tetracyclines. Both are drugs of first choice for certain chlamydial
infections (urethritis, cervicitis) and for pneumonia caused by M. pneumoniae.
Pharmacokinetics
Absorption and Bioavailability
Erythromycin for oral administration is available in three forms: erythromycin
base and two derivatives of the base: Erythromycin Stearate and Erythromycin
Ethylsuccinate. The base is unstable in stomach acid, and its absorption can be
variable; the derivatives were synthesized to improve bioavailability.
Bioavailability has also been enhanced by formulating tablets with an acid
resistant coating, which protects erythromycin while in the stomach and then
dissolves in the duodenum, permitting absorption from the small intestine.
As a rule, food decreases the absorption of erythromycin base and erythromycin
stearate, whereas absorption of erythromycin ethylsuccinate is not affected. Only
erythromycin base is biologically active; the derivatives must be converted to the
base (either in the intestine or after absorption) in order to work.
When used properly (i.e., when dosage is correct and the effects of food are
accounted for), all of the oral erythromycins produce equivalent responses. In
addition to its oral forms, erythromycin is available as erythromycin lactobionate
for IV use. IV dosing produces drug levels that are higher than those achieved
with oral dosing.

Distribution
Erythromycin readily distributes to most tissues and body fluids. Penetration to
the CSF, however, is poor. Erythromycin crosses the placenta, but adverse effects
on the fetus have not been observed.
Elimination
Erythromycin is eliminated primarily by hepatic mechanisms, including
metabolism by CYP3A4 (the 3A4 isoenzyme of cytochrome P450). Erythromycin
is concentrated in the liver and then excreted in the bile. A small amount (10%–
15%) is excreted unchanged in the urine.
Adverse Effects
Erythromycin is generally free of serious toxicity and is considered one of our
safest antibiotics. However, the drug does carry a very small risk for sudden
cardiac death from QT prolongation. Gastrointestinal Effects Gastrointestinal
disturbances (epigastric pain, nausea, vomiting, and diarrhoea) are the most
common side effects. These can be reduced by administering erythromycin with
meals. However, this should be done only when using erythromycin products
whose absorption is unaffected by food (erythromycin ethylsuccinate, certain
enteric-coated formulations of erythromycin base).
Patients who experience persistent or severe GI reactions should notify the
prescriber.
QT Prolongation and Sudden Cardiac Death
A study published in 2004 raised concerns about cardiotoxicity, especially when
erythromycin is combined with drugs that can raise its plasma level. When
present in high concentrations, erythromycin can prolong the QT interval, thereby
posing a risk for torsades de pointes, a potentially fatal ventricular dysrhythmia.
Sudden death can result.
The study revealed that, when erythromycin is combined with a CYP3A4
inhibitor, there is a fivefold increase in the risk for sudden cardiac death—or 6
extra deaths for every 100,000 patients using the drug. To minimize risk,
erythromycin should be avoided by patients with congenital QT prolongation and
by those taking class IA or class III antidysrhythmic drugs. Also, the drug should
be avoided by patients taking CYP3A4 inhibitors, including certain calcium
channel blockers (Verapamil And Diltiazem), Azole Antifungal Drugs (e.g.,
Ketoconazole, Itraconazole), HIV protease inhibitors (e.g., Ritonavir, Saquinavir),
and Nefazodone (an antidepressant).
Other Adverse Effects
By killing off sensitive gut flora, erythromycin can promote superinfection of the
bowel. Thrombophlebitis can occur with IV administration; this reaction can be
minimized by infusing the drug slowly in dilute solution. Transient hearing loss
occurs rarely with high-dose therapy. There is evidence that erythromycin may
cause hypertrophic pyloric stenosis in infants, especially those younger than 2
weeks.
Drug Interactions
Erythromycin can increase the plasma levels and half-lives of several drugs,
thereby posing a risk for toxicity. The mechanism is inhibition of hepatic
cytochrome P450 drug-metabolizing enzymes. Elevated levels are a concern with
theophylline (used for asthma), carbamazepine (used for seizures and bipolar
disorder), and warfarin (an anticoagulant).
Accordingly, when these agents are combined with erythromycin, the patient
should be monitored closely for signs of toxicity. Erythromycin prevents binding
of chloramphenicol and clindamycin to bacterial ribosomes, thereby antagonizing
their antibacterial effects.
Accordingly, concurrent use of erythromycin with these two drugs is not
recommended. As noted, erythromycin should not be combined with drugs that
can inhibit erythromycin metabolism. Among these are verapamil, diltiazem, HIV
protease inhibitors, and azole antifungal drugs.
Clarithromycin
Actions and Therapeutic Uses
Like erythromycin, clarithromycin binds the 50S subunit of bacterial ribosomes,
causing inhibition of protein synthesis. The drug is approved for respiratory tract
infections, uncomplicated infections of the skin and skin structures, and
prevention of disseminated Mycobacterium avium complex infections in patients
with advanced HIV infection. It is also used for H. pylori infection and as a
substitute for penicillin G in penicillin-allergic patients.
Pharmacokinetics
Clarithromycin is available in three oral formulations: immediate-release (IR)
tablets, extended-release (ER) tablets, and granules for solution. The IR tablets
and granules are well absorbed, in the presence and absence of food. In contrast,
the ER tablets are absorbed poorly if food is absent. After absorption,
clarithromycin is widely distributed and readily penetrates cells.
Elimination is by hepatic metabolism and renal excretion. A reduction in dosage
may be needed for patients with severe renal impairment.
Adverse Effects and Interactions
Clarithromycin is well tolerated and does not produce the intense nausea seen
with erythromycin. The most common reactions (3%) have been diarrhoea,
nausea, and distorted taste—all described as mild to moderate. In clinical trials,
only 3% of patients withdrew because of side effects, compared with 20% of
those taking erythromycin. High doses of clarithromycin have caused fetal
abnormalities in laboratory animals; possible effects on the human fetus are
unknown. Like erythromycin, clarithromycin may prolong the QT interval and
hence may pose a risk for serious dysrhythmias. Like erythromycin,
clarithromycin can inhibit hepatic metabolism of other drugs and can thereby
elevate their levels. Affected drugs include warfarin, carbamazepine, and
theophylline. Dosages of these drugs may need to be reduced.
Azithromycin
Actions and Therapeutic Uses
Like erythromycin, azithromycin binds the 50S subunit of bacterial ribosomes,
causing inhibition of protein synthesis. The drug is used for respiratory tract
infections, cholera, chancroid, otitis media, uncomplicated infections of the skin
and skin structures, disseminated M. avium complex disease, and infections
caused by C. trachomatis, for which it is a drug of choice. It may also be used as a
substitute for penicillin G in penicillin-allergic patients.
Pharmacokinetics
Absorption of azithromycin is decreased by food, and hence dosing should occur
on an empty stomach. After absorption, azithromycin is widely distributed to
tissues and becomes concentrated in cells.
Elimination is through the bile as metabolites and parent drug.
Adverse Effects and Interactions
Like clarithromycin, azithromycin is well tolerated and does not produce the
intense nausea seen with erythromycin. The most common reactions are
diarrhoea, mild nausea, and abdominal pain. In one trial, only 0.7% of patients
withdrew because of side effects. Aluminum- and magnesium-containing antacids
reduce the rate (but not the extent) of absorption. In contrast to erythromycin
and clarithromycin, azithromycin does not inhibit the metabolism of other drugs.
However, there is concern that azithromycin may enhance the effects of warfarin
(an anticoagulant) and may thereby pose a risk for bleeding. In patients taking
both drugs, prothrombin time should be closely monitored to ensure that
anticoagulation remains at a safe level.
QT Prolongation
Like erythromycin, azithromycin has the potential to cause fatal heart
dysrhythmias secondary to prolonging the QT interval. Patients at highest risk
include those with existing QT interval prolongation, low blood levels of
potassium or magnesium, or a slower-than-normal heart rate, and those who use
drugs to treat abnormal heart rhythms.
Other Bacteriostatic Inhibitors of Protein Synthesis
Clindamycin
Clindamycin can promote severe CDAD, a condition that can be fatal. Because of
the risk for CDAD, indications for clindamycin are limited. Currently, systemic use
is indicated only for certain anaerobic infections located outside the central
nervous system (CNS)
Mechanism of Action
Clindamycin binds to the 50S subunit of bacterial ribosomes and thereby inhibits
protein synthesis. The site at which clindamycin binds overlaps the binding sites
for erythromycin and chloramphenicol.
As a result, these agents may antagonize each other's effects. Accordingly, there
are no indications for concurrent use of clindamycin with these other antibiotics.
Antimicrobial Spectrum
Clindamycin is active against most anaerobic bacteria (gram positive and gram
negative) and most gram-positive aerobes. Gram-negative aerobes are generally
resistant. Susceptible anaerobes include Bacteroides fragilis, Fusobacterium
species, Clostridium perfringens, and anaerobic streptococci.
Clindamycin is usually bacteriostatic. However, it can be bactericidal if the target
organism is especially sensitive. Resistance can be a significant problem with B.
fragilis.
Therapeutic Use
Because of its efficacy against gram-positive cocci, clindamycin has been used
widely as an alternative to penicillin. The drug is employed primarily for
anaerobic infections outside the CNS (it doesn't cross the blood-brain barrier).
Clindamycin is the drug of choice for severe group A streptococcal infection and
for gas gangrene (an infection caused by C. perfringens), owing to its ability to
rapidly suppress synthesis of bacterial toxins. In addition, clindamycin is a
preferred drug for abdominal and pelvic infections caused by B. fragilis.
Pharmacokinetics
Absorption and Distribution
Clindamycin may be administered by the oral, IM, or IV route. Absorption from
the GI tract is nearly complete and not affected by food. The drug is widely
distributed to most body fluids and tissues, including synovial fluid and bone.
However, penetration to the CSF is poor.
Elimination
Clindamycin undergoes hepatic metabolism to active and inactive products, which
are later excreted in the urine and bile. Only 10% of the drug is eliminated
unchanged by the kidneys. The half-life is approximately 3 hours. In patients with
substantial reductions in liver function or kidney function, the half-life increases
slightly, but adjustments in dosage are not needed. However, in patients with
combined hepatic and renal disease, the half-life increases significantly and hence
the drug may accumulate to toxic levels if dosage is not reduced.
Adverse Effects
Clostridium Difficile–Associated Diarrhoea
CDAD, formerly known as antibiotic-associated pseudomembranous colitis, is the
most severe toxicity of clindamycin. The cause is superinfection of the bowel with
C. difficile, an anaerobic gram-positive bacillus. CDAD is characterized by profuse,
watery diarrhoea (10–20 watery stools per day), abdominal pain, fever, and
leukocytosis.
Stools often contain mucus and blood. Symptoms usually begin during the first
week of treatment but may develop as long as 4 to 6 weeks after clindamycin
withdrawal. Left untreated, the condition can be fatal. CDAD occurs with
parenteral and oral therapy. Because of the risk for CDAD, patients should be
instructed to report significant diarrhoea (more than five watery stools per day).
If superinfection with C. difficile is diagnosed, clindamycin should be discontinued
and the patient given oral vancomycin or metronidazole, which are drugs of
choice for eliminating C. difficile from the bowel. Diarrhoea usually ceases 3 to 5
days after starting vancomycin. Vigorous replacement therapy with fluids and
electrolytes is usually indicated. Drugs that decrease bowel motility (e.g., opioids,
anticholinergics) may worsen symptoms and should not be used.
Other Adverse Effects
a. Diarrhoea (unrelated to CDAD) is relatively common.
b. Hypersensitivity reactions (especially rashes) occur frequently.
c. Hepatotoxicity and blood dyscrasias (Agranulocytosis, Leukopenia, and
Thrombocytopenia) develop rarely.
d. Rapid IV administration can cause electrocardiographic changes,
hypotension, and cardiac arrest.