ANTIMICROBIAL THERAPY

Principles of Drug Management;

Antimicrobial prescription consideration;

Patient factors Organism Drug

Documentation of infection Culture / absorption
Factors altering kinetics; identification Tissue distribution
Age, renal / hepatic function Adverse drug Route of
Previous drug sensitivity reaction elimination
General health (resistance to Drug interaction
infection) Antimicrobial
pregnancy susceptibility
 Patient factors;
Documentation of infection;
Whenever possible, the clinical suspicion of infection should be supported by
laboratory diagnosis. The appropriate specimens e.g. sputum, urine, pus, blood
etc. should be obtained before treatment is commenced.
Age;
odrug kinetics are influenced by age dependent pathways of elimination.
Clinically important examples involving antimicrobial agents include;
orelative deficiency of hepatic glucuronyl transferase in neonates leading
to accumulation of chloramphenicol.
oPhysiological decrease in renal function with age leading to an
accumulation of aminoglycosides in the elderly with a likelihood of
toxicity. Dose modification is necessary.
oTetracyclines in growing children (tooth discoloration)
Renal and hepatic function;
oMany commonly used antimicrobials are eliminated by the kidneys while a
few undergo hepatic metabolism.
oDose modification is necessary in renal function impairment

Drug sensitivity;
Always ask about previous exposure to drugs.
Sulphonamides, penicillins and cephalosporins are the antimicrobials most
Frequently associated with drug sensitivity reactions.
There is a 5 – 10% cross-sensitivity between penicillin and cephalosporins
because they both contain beta-lactam ring.
Minor reactions to penicillins such as rash should not prevent prescription
of
cephalosporins, but life threatening allergic reaction to penicillins should be
an absolute contraindication to the use of cephalosporins.
Diminished resistance to infection;
• Patients with cancers on chemotherapy are susceptible to infections with
commensal bacteria as well as less common organisms e.g. some viruses,
yeast, fungi and protozoa.
• In particular granulocytopenia (less than 500 x 106 / l) is accompanied by
high risk of septicaemia. Fever in such patients should be assumed to be
infective in aetiology and should be treated aggressively before a definitive
bacteriological diagnosis is made.
Pregnancy;
•Penicillins and cephalosporins are not harmful to the fetus.
•Fetal damage has been associated definitely with streptomycin and the
tetracyclines.
•Possible adverse effects have been ascribed to gentamycin, Kanamycin
and cotrimoxazole.
•In general there is little data on possible teratogenic effects of
newer agents.
 Resistance;
The two major mechanisms by which resistance is produced are gene mutation
and DNA exchange between bacteria. Resistance may take three main forms;
An alteration in the bacterial component on which the drug acts.
Inactivation of the drugs as in case of penicillin inactivation by the
beta-lactamases produced by resistant bacteria.
Reduction of the cell membrane permeability as in resistance to
tetracyclines.
Development of resistance can be reduced if antimicrobials are not given
indiscriminately. The use of combination therapy also limit the appearance of
resistance organism e.g. tuberculosis where prolonged treatment is necessary.
 Drug factor;
Absorption
oCertain antimicrobials e.g. aminoglycosides can only be given parenterally
because absorption from the gastrointestinal tract is negligible.
oWhere a choice exists between oral and parenteral drug administration,
decision
should be based on severity of illness and the need to achieve high tissue
concentration.
oIn case of severely ill patients, absorption from the gut may be unreliable
necessitating use of intravenous preparation. However when patient recovers,
switch over to oral preparation which are generally cheaper and also to reduce
the risk of catheter associated infection.
Tissue distribution

Antimicrobials penetrate different tissues differently. Inflammation generally tends

to improve tissue penetration but not always. Different body fluids attain
preferentially high concentration of specific drugs as shown below;

CSF Bile Urine

Chloramphenicol Penicillin Penicillins
Erythromycin Cephalosporins Cephalosporins
Isoniazid Erythromycin Aminoglycosides
Pyrazinamide Sulphonamides
Rifampicin Nitrofurantoin
flucytosine Nalidixic acid
Ethambutol
Flucytosine

Route of elimination
This is usually renal or hepatic route
Adverse effects;
These are of two general types;
1) Dose-independent hypersensitivity reactions that are either immediate or
delayed.
oThese are idiosyncratic reactions that are not related to the dose of
the
drug
oImmediate reactions cause anaphylaxis whereas delayed tends to be
associated with skin reactions.
oThey are usually seen with penicillins, cephalosporins and
Sulphonamides.

2) Dose-dependent reaction;
oThese include aminoglycoside toxicity
 Drug interaction;
These can either be;
1)Kinetic e.g. enzyme induction or inhibition
2)Dynamic e.g. two drugs adversely affecting the same organ.
Examples include the following;
Aminoglycoside and frusemide have an additive nephrotic effect.
Rifampicin induces the same enzyme that metabolizes contraceptive pill
and can cause failure of contraception.
Sulphonamides inhibit the enzymes that metabolize phenytoin and can
cause phenytoin toxicity.
Tetracyclines form insoluble complexes in the gut lumen with both antacids
and iron leading to treatment failure.
Quinolones may trigger side effects of theophylline as a result of
decreased
elimination.
Amphotericin B and aminoglycosides or Vancomycin display increased
nephrotoxicity and ototoxicity.
Antimicrobial prophylaxis
Antimicrobial agents are sometimes given to people who do not have an infection
but who are considered to be at risk from a specific organism.
Examples include;
oUse of rifampicin or ciprofloxacin in close contacts of patients with
meningococcal meningitis
oPenicillin administration before and following dental procedures in people at
risk of endocarditis.
oPerioperative prophylaxis in certain types of surgery where risk of infection
is
high e.g. colorectal surgery and open heart surgery.
 ANTIBACTERIAL DRUGS
PENICILLINS
Mechanism of action;
Penicillins have bactericidal action
They inhibit cell wall synthesis by preventing the formation of peptidoglycan
cross-bridges in actively multiplying bacteria
Examples include;
oBenzylpenicillin
oPhenoxymethylpenicillin
oAmpicillin
oAmoxicillin
oCarbenicillin
oTicarcillin
oAzlocillin
oFlucloxacillin
oAmoxiclav
Pharmacokinetics;
Oral absorption;
oNot absorbed; carbenicillin, ticarcillin
oModerately absorbed; benzyl penicillin (penicillin G), ampicillin
oWell absorbed; phenoxypenicillin, amoxicillin, flucloxacillin
Even relatively well absorbed penicillins are destroyed to some extent by the
gastric acid and should therefore be given at least 30-minutes before meals.

Distribution;
Penicillins have good penetration to most tissues but poor entry to CSF; however
meningeal inflammation increases CSF penetration allowing use of these agents
in the treatment of meningitis.
Giving large doses when treating meningitis also increases CSF delivery.
Elimination;
Penicillins undergo enteroheptaic circulation i.e. drug is excreted via bile
and reabsorbed.
The major route of elimination after reabsorption is active secretion in the
renal tubules. This tubular secretion can be blocked by probenecid with
doubling of penicillin blood levels. Dose modification is necessary with
severe renal failure.

Adverse effects;
Immediate hypersensitivity;
oUrticaria
oWheeze
oLife threatening anaphylaxis response
Delayed hypersensitivity;
oRashes
oHaemolytic anaemia
oInterstitial nephritis
oleucopenia
Toxicity;
oConvulsions in large intrathecal or intravenous doses of penicillin
or in renal insufficiency.
oDiarrhoea especially with ampicillin
oInterstitial nephritis has been reported with Methicillin than with
any other penicillin.
Antibacterial spectrum;
oThe major factor limiting efficacy is the production by certain organisms of
enzymes (ß-lactamases or penicillinases) that destroy the ß-lactam ring of
the penicillin molecule. This structure is essential to the antibacterial action
of the penicillins.
oSeveral synthetic penicillins incorporate side chains that protect the
ß-lactam ring against these enzymes.
oAn alternative approach has been to combine amoxicillin with clavulanic
acid which itself has very little antibacterial activity but inhibits
ß-lactamases activity i.e. co-amoxiclav like augmentin.
oPenicillinases-sensitive penicillins;
Benzylpenicillin and phenoxypenicillins activity include;
Streptococci
Pneumococci
Gonococci
Meningococci
Treponema pallidum
Actinomyces israelii
Ampicillin has a broader spectrum including;
Some strains of Escherichia coli
Proteus mirabilis
Shigella
Salmonella
Haemophilus influenza

 Amoxicillin is better absorbed and has same antibacterial spectrum as

ampicillin.
 Carbenicillin, ticarcillin and azlocillin are all given parenterally and are active
against;
Pseudomonas aeruginosa
Proteus sp.
Penicillinase-resistant penicillins;
These are indicated in infections caused by penicillinase-producing
staphylococci and include;
Cloxacillin
Flucloxacillin
Methicillin
 Tazocin;
This is a combination of piperacillin and tazobactum and its indication include;
Impaired host defence mechanism e.g. following bone marrow
transplantation
Suspected infection with ß-lactamase producing coliforms.
Severely ill patients in intensive care units.
 Carbapenems;
These are penicillin-like drugs which include imipenem and meronem.
Imipenem;
oThis ß-lactam is a carbapenem with a very broad spectrum of
activity
against many gram-negative, gram-positive and anaerobic
organisms.
oIt is partially inactivated within the kidney and is thus formulated
with
cilastatin which blocks this renal metabolism.
oIt is indicated in severe infection, particularly those that are
resistant
to other antibiotics.
oIn addition to the side effects of all penicillin like drugs, imipenem
does lower seizure threshold.
Meropenem;
This is closely related to imipenem in all aspect except for less adverse effect
of lowering seizure threshold therefore preferred in patients with epilepsy.
 CEPHALOSPORINS
Cephalosporin compounds were first isolated from cultures of Cephalosporium
acremonium from a sewer in Sardinia in 1948 by Italian scientist. He noticed that
these cultures produced substances that were effective against Salmonella typhi.

Mechanism of action;
Cephalosporins are bactericidal.
They contain a ß-lactam ring and their mechanism of action is similar to that
of
Penicillins but less susceptible to penicillinase.
•1st generation
First-generation cephalosporins are moderate spectrum agents, with a spectrum
of activity of bacteria that includes penicillinase-producing, methicillin-susceptible
staphylococci and streptococci,
Examples include;
•Cefacetrile (cephacetrile)
•Cefadroxil (cefadroxyl; Duracef)
•Cephalexin (cephalexin; Keflex)
•Cefaloglycin (cephaloglycin)
•Cefalonium (cephalonium)
•Cefaloridine (cephaloradine)
•Cefalotin (cephalothin; Keflin)
•Cefapirin (cephapirin; Cefadryl)
•Cefazolin (cephazolin; Ancef, Kefzol)
•Cefradine (cephradine; Velosef)
2nd generation
The second-generation cephalosporins have a greater Gram-negative
spectrum while retaining some activity against Gram-positive cocci.
Examples include;
•Cefaclor (Ceclor, Distaclor, Keflor, Raniclor)
• Cefamandole
•Cefonicid (Monocid)
•Cefprozil (cefproxil; Cefzil)
•Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym)
•Cefuzonam
Second generation cephalosporins with antianaerobe activity
(Cephamycins);
•Cefmetazole
•Cefotetan
•Cefoxitin
3rd generation;
•Third-generation cephalosporins have a broad spectrum of activity and further
increased activity against Gram-negative organisms.
•Some members of this group (in particular, those available in an oral
formulation, and those with anti-pseudomonal activity) have decreased activity
against Gram-positive organisms.
•They may be particularly useful in treating hospital-acquired infections. They
are also able to penetrate the CNS, making them useful against meningitis
caused by pneumococci, meningococci, H. influenzae, and susceptible E. coli,
Klebsiella, and penicillin-resistant N. gonorrhoeae. Examples include;
oCeftriaxone (Rocephin)
oCeftazidime (Fortum)
oCefotaxime
oCefixime
oCefpodoxime
oCefdinir
Fourth generation;
•Fourth-generation cephalosporins are extended-spectrum agents with similar
activity against Gram-positive organisms as first-generation cephalosporins.
•They also have a greater resistance to beta-lactamases than the
third-generation cephalosporins.
• Many can cross the blood-brain barrier and are effective in meningitis. They are
also used against Pseudomonas aeruginosa.
•Example include;
•Cefclidine
•Cefepime (Maxipime)
•Cefluprenam
•Cefoselis
•Cefozopran
•Cefpirome(Cefrom)
•Cefquinome
Pharmacokinetics;
1st and 2nd generation cephalosporins are all available in oral preparation and
are well absorbed orally. Intravenous Cefuroxime (2nd Gen) is also available.
3rd generation cephalosporins are all intravenous preparation except for
cefixime, cefpodoxime and cefdinir.
4th generation cephalosporin Cefepime is only available in intravenous form.
They are widely distributed.
The intravenous preparations have long half-life therefore enabling once daily
dosing.
The drugs are eliminated unchanged through renal route by glomerular
filtration and partly by tubular secretion; contribution of each route vary with
individual cephalosporin.
 Adverse effects;
Hypersensitivity reaction. This is the main adverse effect with around
10% cross-sensitivity with penicillin-sensitive patients.
Renal tubular necrosis especially in high doses.
 Several cephalosporins are associated with hypoprothrombinemia causing
occasional bleeding due to reduction of prothrombin concentration.
Disulfiram-like reaction with ethanol.
False positive glycosuria on urinalysis in patients taking cephalosporins.

Drug interactions;
Generally well tolerated drugs.
The Nephrotoxicity of cephaloridine is potentiated by loop diuretics and
aminoglycosides.
 Antibacterial spectrum;
First-generation cephalosporins are predominantly active against Gram-positive
bacteria, and successive generations have increased activity against Gram-negative
bacteria (albeit often with reduced activity against Gram-positive organisms).
1st generation cephalosporins are generally limited to gram-positive antimicrobial
activity.
2nd generation cephalosporins have fairly good activity against gram-positive and
gram-negative bacteria including the ß-lactamases producing bacteria.
3rd generation cephalosporins including Ceftriaxone, Ceftazidime, Cefotaxime and
cefixime have very good activity against gram-negative bacteria with limited
activity against gram-positive bacteria; Ceftazidime (Fortum) also shows very good
activity against P. aeruginosa. Cefpodoxime and cefdinir have limited activity on
gram-negative bacteria.
 AMINOGLYCOSIDES
Mechanism of action;
•An aminoglycoside is a molecule composed of a sugar group and an amino
group.
•Aminoglycosides are bactericidal
•They have several potential antibiotic mechanisms, some as protein
synthesis inhibitors, although their exact mechanism of action is not fully known:
•Possible mechanism of action include;
•Binding to the bacterial 30S ribosomal subunit
(some work by binding to the 50S subunit).
•Disruption of the integrity of bacterial cell membrane.
•Aminoglycoside examples include;
• amikacin
• arbekacin
• gentamicin
• kanamycin
• neomycin
• netilmicin
• paromomycin
• rhodostreptomycin
• streptomycin
• tobramycin
• apramycin.
 Pharmacokinetics;

Oral absorption is negligible. Since they are not absorbed from the gut, they are

administered intravenously and intramuscularly. Some are used in topical

preparations for wounds and ocular infections

They have poor penetration into CSF and only moderate penetration into bile.

Elimination is mainly by glomerular filtration.

Traditionally gentamycin is administered 8-hourly, but recent evidence shows

that

better antimicrobial activity is achieved by administering the drug once daily.

Bacterial eradication is faster the higher the level of gentamycin is in blood,

leading to a more rapid clearance of microbes with once daily dosing and lower

chance of emergence of resistant organisms.

 Adverse effects;
There are two major adverse effects both dose related;
1)Nephrotoxicity
2)Ototoxicity
The renal lesion consists of tubular destruction.
8th nerve damage can be mainly vestibular in case of streptomycin and
gentamycin or auditory in case of Kanamycin.
The severity of these reactions is related to aminoglycoside serum
concentration,
which in turn is related to dose and rate of elimination.
Accumulation of drug occurs when glomerular filtration is decreased by renal
disease or at the extreme of ages. Doses must be modified in these situation and
drug concentration monitoring mandatory.
Aminoglycosides cross the placenta and can cause 8th nerve damage in the
fetus.
An uncommon effect of aminoglycoside is neuromuscular blockade occurring
after rapid intravenous injection; this is marked in patients with myasthenia
gravis.
Drug interaction;
Nephrotoxicity is enhanced by co-administration with cephaloridine.
Ototoxicity is enhanced by loop diuretics.
The neuromuscular blockade of curare-like drugs can be prolonged by
aminoglycosides.
Antibacterial spectrum;
Aminoglycosides are popular for the initial management of life threatening
septicaemia of uncertain aetiology. In this situation, aminoglycoside is usually
combined with metronidazole and an extended spectrum penicillin.
Gentamycin;
oGentamycin is the most widely used aminoglycoside and is active
against most gram negative rods including pseudomonas and
proteus spp. and also against staphylococci.
oMost streptococci are resistant because gentamycin cannot
penetrate the cell; however penicillins and aminoglycosides have a
synergistic effect against some streptococci.
oAll anaerobes are resistant to gentamycin
 Amikacin is resistant to most of the bacterial enzymes that inactivate gentamycin,
but is more toxic than gentamycin and is therefore indicated for infection caused by
aerobic gram-negative rods against which gentamycin is no longer effective.
Tobramycin is 2-4 times more active than gentamycin against pseudomonas but
is
Otherwise similar to gentamycin.
Neltimicin has a similar antibacterial spectrum to gentamycin, but is claimed to be
less ototoxic.
Neomycin is given orally to decrease bacterial content of the colon in liver failure
or
before surgery. If there is severe liver, renal failure or inflammatory bowel disease,
sufficient neomycin can be absorbed to cause ototoxicity.
Streptomycin is effective against tubercle bacilli.
 SULPHONAMIDES
Mechanisms;
Sulphonamides drugs are bactericidal.
 Examples include;
Short-acting
Sulfaisodimidine
Sulfanilamides
Intermediate-acting
Sulfadiazine
Sulfamethoxazole (SMX)
Long-acting
Sulfadimethoxine
Sulfamethoxypyridazine (SMP)
Ungrouped
Sulfacetamide
Sulfadoxine
The most commonly used sulphur drug is Co-trimoxazole.
Co-trimoxazole (Septrin) is a combination of sulphamethoxazole and trimethoprim in the
ratio 5:1, i.e. 400mg ; 80mg
The basis of the action of sulphonamide is that bacterial cells are impermeable to folic acid
and so they must synthesize their own from para-aminobenzoic acid with which
Sulphonamides have a strong similarity.
Competitive inhibition of folic acid synthesis occurs. Trimethoprim blocks the next synthetic
step, from folic acid to tetrahydrofolate by inhibiting the enzyme dihydrofolate reductase.
 Pharmacokinetics;
Co-trimoxazole is well absorbed following oral administration and is also
available for intravenous use.
There is wide tissue distribution and elimination is by renal excretion.
Drug interaction;
The sulphonamide component competes for hepatic enzyme-binding sites and
can decrease the clearance of phenytoin, tolbutamide and warfarin. This may cause
phenytoin toxicity, hypoglycaemia and enhanced anticoagulation respectively.
Displacement of methotrexate from protein-binding sites can also lead to
toxicity.
Adverse effects;
Skin rashes; including Stevens-Johnson syndrome
Renal failure
Blood dyscrasias
Gastrointestinal symptoms
Kernicterus in new born babies due to displacement of bilirubin from protein-
binding sites.
Teratogenicity due to trimethoprim
Antibacterial spectrum;
These drugs are broad spectrum. Coverage include;
o Gram-positive cocci,
o Neisseria gonorrhoea
oH. influenzae
oE. coli
oP. mirabilis
oShigella sp.
oSalmonella sp.
oPneumocystis carinii (now named P. jiroveci)
oBrucella sp.

Dose;
Each tablet of Co-trimoxazole contains 400mg sulphamethoxazole and
80mg trimethoprim.
The usual dose of Co-trimoxazole is two tablets twice daily.
Higher doses of up to three tablets thrice daily have been given in
Pneumocystis jiroveci pneumonia a common infection in patients with AIDS
 TETRACYCLINES
Mechanism;
They are obtained from soil streptomyces. Tetracyclines are Bacteriostatic,
though with intravenous injection, weak bactericidal effect can be achieved.
They bind to the 30S ribosomal subunit with consequent misreading of
information needed for protein synthesis.
Pharmacokinetics;
Tetracyclines are adequately absorbed following oral administration.
Dairy products reduce absorption, also antacids and iron preparations due to
chelation to Ca, Fe, Al and an increase in gut pH.
Tissue distribution is good throughout the body.
They are mostly excreted unchanged in urine.
 Examples include;
Short-acting (Half-life is 6-8 hrs)
oTetracycline
oChlortetracycline
oOxytetracycline
Intermediate-acting (Half-life is ~12 hrs)
oDemeclocycline
oMethacycline
Long-acting (Half-life is 16 hrs or more)
oDoxycycline
oMinocycline
oTigecycline
Minocycline and Doxycycline are eliminated mainly unmetabolised through the
biliary route.
The plasma half-life of tetracycline is about 8-hours but this may be increased in
renal failure.
Doxycycline has a long half-life and can be administered once daily.
 Adverse effects;
Impairment of bone growth and discoloration of teeth during active mineralization
(up to 8-years, should not be given until after 12-years). This is caused by binding
of tetracycline to bone and teeth.
Heartburn
Nausea
Diarrhoea
Photosensitivity and skin rash
Teratogenic effect hence contraindication in pregnancy
Hepatic necrosis and renal failure in large doses.
Drug interaction;
Milk, antacids, calcium, magnesium and iron form insoluble complexes with
tetracyclines in the gut lumen leading to treatment failure; with exception of
minocycline.
Antibacterial spectrum;
 The tetracyclines are effective against a wide range of bacteria but resistance is
increasing, and should no longer be considered useful in broad spectrum
antibiotics.
 The importance of tetracyclines is based on their efficacy against;
oChlamydia (e.g. non-specific urethritis, psittacosis)
oRickettsia (e.g. Q-fever, typhus, Rocky mountain spotted fever)
oMycoplasma
oBrucella
oCholera
oPropionibacterium acnes in the acne treatment.

Dose;
 Tetracycline and oxytetracycline; 250-500mg 6-hourly.
 Minocycline; 200mg start, then 100mg 12-hourly
 Doxycline; 200mg start, then 100mg 12-hourly
 Parenteral administration; infusion of tetracycline or oxytetracycline in normal
saline, usually 1-g per day in divided doses.
 MACROLIDES;
The macrolides are a group of drugs (typically antibiotics) whose activity stems from the

presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy

sugars, usually cladinose and desosamine, may be attached.

Common antibiotic macrolides include;

1) Azithromycin

2) Clarithromycin

3) Dirithromycin

4) Erythromycin

5) Roxithromycin (Rulid, Surlid, Roxid)

6) Telithromycin
 Indications

 Antibiotic macrolides are used to treat infections such as respiratory tract and soft

tissue infections.

 The antimicrobial spectrum of macrolides is slightly wider than that of penicillin,

and therefore macrolides are a common substitute for patients with a penicillin

allergy.

 Beta-hemolytic streptococci, pneumococci, staphylococci and enterococci are

usually susceptible to macrolides.

 Unlike penicillin, macrolides have been shown to be effective against Atypical

organisms e.g. mycoplasma, mycobacteria, some rickettsia, and chlamydia

(especially in non-specific urethritis).

 Mechanism of action
 Macrolides are protein synthesis inhibitors. Most commonly used are
erythromycin and azythromycin.
 Absorption of macrolides following oral administration is variable. Erythromycin is
poorly absorbed whereas Azithromycin is well absorbed following oral
administration.
 Macrolides exhibit enterohepatic recycling; that is the drug is absorbed in the gut
and sent to the liver, only to be excreted into the duodenum in bile from the liver.
This can lead to a build up of the product in the system.
 Azithromycin has extremely long half-life of 68-hours allowing once daily dosing
and short courses of treatment. It has a broader spectrum of activity than
erythromycin including enhanced activity against H. influenzae. a common
pathogen in infectious exacerbations of chronic pulmonary disease.
 The mechanism of action of macrolides is inhibition of bacterial protein
biosynthesis,
 Macrolide antibiotics do so by binding reversibly to the subunit 50S of the
bacterial ribosome.
 This action is mainly bacteriostatic, but can also be bactericidal in high
concentrations. Macrolides tend to accumulate within leukocytes, and are
therefore actually transported into the site of infection.
 Side effects
 Nausea & vomiting especially with erythromycin and clarithromycin.
 Combination of macrolides and statins (used for lowering cholesterol) is not
advisable and can lead to debilitating myopathy. This is because macrolides are
potent inhibitors of the cytochrome P450 system, particularly of CYP3A4.
 Macrolides, mainly erythromycin and clarithromycin, also have a class effect of
QT prolongation which can lead to torsade de pointes.
Doses;
 Erythromycin;
 Oral; 250-500mg 6-hourly in adults and, 125-250mg 6-hourly in
children
 Intravenous; 300mg i.v. infusion 6-hourly in adults, 30-50mg/kg
daily in divided doses 6-hourly for children.
 Clarithromycin;
Oral or intravenously; 500mg 12-hourly
 Azythromycin;
500mg once daily for 3-days orally and intravenously.
 NITRO-IMIDAZOLES
4-Nitroimidazole is an imidazole derivative which contains a nitro group.
Several derivatives of nitroimidazole constitute the class of nitroimidazole
antibiotics which have been used to combat anaerobic bacterial and parasitic
Infections e.g. amoebiasis, giardiasis and trichomoniasis.
Perhaps the most common example is metronidazole (Flagyl).
Nitroimidazoles include:
oMetronidazole (Flagyl)
oTinidazole
oNimorazole
oSecnidazole (Flagentyl)
oSatranidazole
oOrnidazole
Pharmacokinetics;
Following oral administration, metronidazole is well absorbed, with peak plasma
concentrations occurring between one and two hours after administration.
Disposition of metronidazole in the body is similar for both oral and intravenous
dosage forms, with an average elimination half-life in healthy humans of eight
hours.
Metronidazole appears in cerebrospinal fluid, saliva, and human milk in
concentrations similar to those found in plasma.
 The major route of elimination of metronidazole and its metabolites is via the
urine (60 to 80% of the dose), with fecal excretion accounting for 6 to 15% of
the dose.
 It is metabolized in the liver, with unchanged metronidazole accounting for
approximately 20% of the total.
 Decreased renal function does not alter the single-dose pharmacokinetics of
metronidazole. However, plasma clearance of metronidazole is decreased in
patients with decreased liver function.
 Bactericidal concentrations of metronidazole have also been detected in pus
from hepatic abscesses.
Indications;
Trichomoniasis (Trichomonas vaginalis)
 Amebiasis
Intra-abdominal infections;
including peritonitis, intra-abdominal abscess, and liver
abscess, caused by Bacteroides species including the B. fragilis
group (B. fragilis, B. distasonis,B. ovatus, B. thetaiotaomicron, B.
vulgatus), Clostridium species, Eubacterium species,
Peptococcus niger, and Peptostreptococcus species.
Skin and skin structure infections;
Caused by Bacteroides species including the B. fragilis group,
Clostridium species, Peptococcus niger, Peptostreptococcus
species,and Fusobacterium species.
Gynecologic infections;
Including endometritis, endomyometritis, tubo-ovarian abscess,

and postsurgical vaginal cuff infection; caused by Bacteroides

species including the B. fragilis group, Clostridium species,
Peptococcus niger, and Pepto-streptococcus species.
Bacterial septicemia;
Caused by Bacteroides species including the B. fragilis group,

and Clostridium species.

Bone and joint infections;

As adjunctive therapy, caused by Bacteroides species including

the B. fragilis group.

Central Nervous System (CNS) infections;
Including meningitis and brain abscess, caused by Bacteroides
species including the B.fragilis group.
Lower respiratory tract infections;
Including pneumonia, empyema, and lung abscess, caused by
Bacteroides species including the B. fragilis group.
Endocarditis;
Caused by Bacteroides species including the B.fragilis group.
 Side effects;
Serious adverse reactions reported in patients treated with Flagyl (metronidazole)
include;
 Convulsive seizures
 Headache, dizziness, vertigo, incoordination, ataxia, confusion, irritability,
depression, weakness, and insomnia.
 Peripheral neuropathy characterized mainly by numbness or paresthesia of
an extremity.
Gastrointestinal tract;
oAnorexia / sharp metallic taste
oNausea reported by about 12% of patient
oVomiting
oEpigastric distress
oDiarrhoea
oAbdominal cramping
oConstipation has also been reported.

Other side effects include;

Hypersensitivity: Urticaria, erythematous rash, flushing, nasal congestion
Flagyl is contraindicated during the first trimester of pregnancy due to
possible teratogenic effect.
Drug Interactions
Metronidazole has been reported to potentiate the anticoagulant effect of
warfarin and other oral coumarin anticoagulants, resulting in a prolongation
of prothrombin time.This possible drug interaction should be considered
when Flagyl (metronidazole) is prescribed for patients on this type of
anticoagulant therapy
Alcoholic beverages should not be consumed during Flagyl therapy and for
at least one day afterward because abdominal cramps, nausea, vomiting,
headaches, and flushing may occur. (Disulfiram-like reaction).
Dose;
For metronidazole, the usual adult intravenous dosage is 7.5 mg/kg every
eight hours (approx. 500 mg for a 70-kg adult). Oral treatment dose is 400 mg
three times daily for seven consecutive days.
Other nitroimidazoles are only available in oral preparation form;
oTinidazole;
oAmoebiasis 2gm OD x 3-days
oTrichomoniasis 2gm start
oChildren 50-75mg/kg start
oSatranidazole;
oAmoebiasis 300mg BD x 3-5 days
oTrichomoniasis 600mg start
oSecnidazole (Flagentyl);
oThe usual dose for amoebiasis and Trichomonas is
2gm start
oOrnidazole;
oThe usual dose is 500mg BD x 5-7days
oNimorazole
 QUINOLONES
The quinolones also referred to as fluoroquinolones are a family of synthetic

broad-spectrum antibiotics.

The term quinolone(s) refers to potent synthetic chemotherapeutic antibacterials.

The first generation of which was derived from an attempt to create a synthetic

form of chloroquine, which was used to treat malaria during World War II.
 Hans Andersag discovered chloroquine, in 1934 at Bayer I.G.

Farbenindustrie A.G. laboratories in Eberfeld, Germany.

The first generation of the quinolones begun with the introduction of nalidixic

acid in1962 for treatment of urinary tract infections in humans

Nalidixic acid was discovered by George Lesher and coworkers in a

distillate

during an attempt at chloroquine synthesis.

Nalidixic acid is considered to be the predecessor of all members of the

quinolone family, including the second, third and fourth generations

commonly known as fluoroquinolones.

 Mechanism of action
Quinolones are synthetic chemotherapeutic agents which have a broad spectrum
antimicrobial activity.
They have a unique mechanism of action resulting in inhibition of bacterial DNA gyrase
and
topoisomerase IV.
Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby
inhibiting DNA replication and transcription.
Quinolones can enter cells easily via porins and therefore are often used to treat
intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae.
For many gram-negative bacteria DNA gyrase is the target, whereas topoisomerase IV is
the target for many gram-positive bacteria.
 Quinolones are well absorbed following oral administration.
They are well distributed in the body tissues and mainly excreted unchanged by the
kidneys. They are also partly excreted by the biliary route.
 QUINOLONE GENERATIONS

1st generation 2nd generation

o cinoxacin o ciprofloxacin
o flumequine o lomefloxacin
o nadifloxacin
o nalidixic acid
o norfloxacin
o oxolinic acid
o ofloxacin
o piromidic acid o pefloxacin
o pipemidic acid o rufloxacin
o rosoxacin
3rd generation 4th generation
obalofloxacin oclinafloxacin
ogatifloxacin ogemifloxacin
olevofloxacin ositafloxacin
omoxifloxacin otrovafloxacin
osparfloxacin oprulifloxacin
otosufloxacin
Aerobic gram-positive microorganisms coverage
(Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes
 Aerobic gram-negative microorganisms coverage

Campylobacter jejuni Proteus mirabilis

Citrobacter Proteus vulgaris
Citrobacter freundii Providencia rettgeri
Enterobacter cloacae Providencia stuartii
Escherichia coli Pseudomonas aeruginosa
Haemophilus influenzae Salmonella typhi
Haemophilus parainfluenzae Serratia marcescens
Klebsiella pneumoniae Shigella boydii
Moraxella catarrhalis Shigella dysenteriae
Morganella morganii Shigella flexneri
Neisseria gonorrhoeae Shigella sonnei
 Indications include

Acute bacterial exacerbation of chronic bronchitis

Uncomplicated cystitis in females caused by E coli

Uncomplicated cystitis caused by K. pneumoniae or P.mirabilis

Fluoroquinolone use for pneumonia is increasing and with it so is bacterial

resistance to fluoroquinolones.

NB
Anaerobes in general are resistant to quinolones.
 Adverse effects
Fluoroquinolones are generally well tolerated with most side effects being mild to
moderate. Occasionally serious adverse effects occur.
Some of the serious adverse effects which occur more commonly with fluoroquinolones
than with other antibiotic drug classes include CNS and tendon toxicity.
The currently marketed quinolones have safety profiles similar to that of other
antimicrobial classes.
These adverse reactions are a class effect of all quinolones, however, certain quinolones
are more strongly associated with increased toxicity to certain organs.
Adverse effects include;
oGastrointestinal disturbances
oQTc interval prolongation and cardiac arrhythmias
o Insomnia, confusion, Convulsions
oTendon rupture
oTorsade de pointes
oHypoglycemia