Rational use of antibiotics

Dr. Sanjana Tarannum Intern, MU X

Antibiotics
Definition
Antibiotics are substances that kill or inhibit the growth of microorganisms. Bacteriostatic (Tetracycline, Chloramphenicol) Bactericidal (Beta lactams, Aminoglycosides)

Misuse of Antibiotics:
Overuse and inappropriate use of antibiotics has fueled a major increase in prevalence of multidrug -resistant pathogens leading some to speculate that we are nearing the end of antibiotic era. Development of novel drugs has slowed unfortunately. It seems likely that over the next decade we will have to rely on currently available families of drugs. So, it is extremely important that we prescribe antibiotics rationally in appropriate dosage and in appropriate routes.

Classification of antibiotics
Based on their mechanism of action, antibiotics can be divided into the following classes:

Inhibitors of Cell Wall synthesis Inhibitors of Protein synthesis Inhibitors of Nucleic Acid synthesis

Inhibitors of Cell Wall Synthesis

This class includes: Penicillins Cephalosporins Carbapenems Monobactams Vancomycin Beta lactamase inhibitors

Beta Lactams
Penicillins:
a.
b. c.

d.
e. f. g.

h.

Narrow spectrum (natural) : benzylpenicillin, phenoxymethylpenicillin Antistaphylococcal: Cloxacillin, flucloxacillin Broad spectrum: Ampicillin, amoxicillin Mecillinam: pivmecillinam Monobactam: Aztreonam Antipseudomonal: Piperacillin, ticarcillin Carbapenems: Meropenem, Imipenem-cilastatin Penicillin-beta lactamase inhibitor combinations: co-amoxiclav, piperacillin-tazobactam

Spectrum of action of Penicillins

Natural Penicillin (narrow

Amoxicillin (broad

spectrum)

spectrum)

Cephalosporins
Class First generation Examples Cefalexin Cefazolin Routes of administration Oral i.v.

Second generation
Third generation

Cefuroxime Cefoxitin
Cefixime Ceftriaxone Ceftazidime Cefipime

Oral/ i.v.
Oral i.v. i.v. i.v.

Fourth generation

Spectrum of action of Cephalosporins

Cefuroxime (2nd Ceftazidime (3rd

generation)

generation)

Pharmacokinetics and Adverse Effects of Beta lactams

Pharmacokinetics:

Adverse Effects:

Not inhibited by abscess environment (low pH,PMNs) Low CSF levels except in presence of inflammation Safe in pregnancy Dosage needs to be reduced in cases of impaired renal function Delayed excretion with concurrent administration of probenecid Synergistic effect with aminoglycosides

Allergic reactions: itch, rash, fever, angioedema, rarely anaphylactic reaction GI upset and diarrhoea Direct intrathecal injection of a beta lactam is contraindicated ( very high doses cause seizures and encephalopathy) Interstitial nephritis and increased renal damage in combination with aminoglycosides

Inhibitors of Protein Synthesis

This class includes:
Macrolides- erythromycin, clarithromycin,

azithromycin Lincosamides- clindamycin Aminoglycosides- gentamicin, tobramycin, amikacin, netilmicin,neomycin, streptomycin,spectinomycin Tetracyclines- tetracycline, doxycycline,minocycline Chloramphenicol

Mechanism and Spectrum of Action of Macrolides

It binds to the 50S subunit of ribosome and blocks the

translocation and formation of initiation complex, thereby inhibiting protein synthesis.

Pharmacokinetics and Adverse Effects of Macrolides

Pharmacokinetics: Poorly absorbed orally Short half life (except Adverse Effects GI upset Cholestatic jaundice Prolongation of QT

azithromycin) Bacteriostatic Good CSF penetration (erythromycin) Dose adjustment for renal failure is not necessary

interval (erythromycin) Diarrhoea related to Cl. Difficile Theophylline, oral anticoagulants cannot be administered simultaneously

Mechanism and Spectrum of action of Aminoglycosides

Pharmacokinetics and Adverse Effects of Aminoglycosides

Pharmacokinetics Negligible oral Adverse Effects

absorption Negligible CSF and corneal penetration Dose adjustment is critical in renal impairment Post antibiotic effect allows daily once dosing

Ototoxic (permanent) Nephrotoxic ( reversible): not to be given with loop diuretics, vancomycin, amphotericin Neuromuscular blockade after rapid i.v. infusion

Mechanism and Spectrum of action of Tetracyclines

Spectrum of Action of Mechanism of Action:

Tetracyclines: Tetracyclines have a broad spectrum of activity; mostly used against Mycoplasma, Chlamydia and Rickettsia, plus Borrelia and other spirochaetes.

Pharmacokinetics and Adverse Effects of Tetracyclines

Pharmacokinetics
Bacteriostatic Best oral absorption in Adverse Effects

fasting state CSF level increases in chronic inflammation

Contraindicated in renal failure (except doxycycline and minocycline) Nausea, diarrhoea Binds to metallic ions in bones and teeth (to be avoided in children and in pregnancy) Phototoxic skin reactions Hypernatremia

Inhibitors of Nucleic Acid synthesis

This group includes: Sulphonamides: Sulfamethoxazole, sulfadoxine Trimethoprim Quinolones: Ciprofloxacin, levofloxacin, pefloxacin, ofloxacin, norfloxacin, gatifloxacin, moxifloxacin, sparfloxacin Rifampicin Azoles: This group includes Antibacterial- Metronidazole, secnidazole, tinidazole, Antifungal- Ketoconazole, fluconazole, Isoconazole, Itraconazole, Clotrimazole Antihelminth- Albendazole, Mebendazole, thiabendazole

Mechanism of action of Sulphonamides and Trimethoprim

Pharmacokinetics and Adverse Effects of Sulphonamides and Trimethoprim

Pharmacokinetics
Well absorbed orally

Adverse Effects
Fatal marrow dysplasia

with good bioavailability Sulphonamides are well distributed in ECF Trimethoprim is lipophilic with high tissue concentrations Dose reduction necessary in renal failure

and haemolysis in G6PD deficiency Skin and mucocutaneous reactions: StevensJohnson syndrome Contraindicated in pregnancy

Mechanism of Action of Quinolones

Spectrum of Action of Quinolones

Pharmacokinetics and Adverse Effects of Quinolones

Pharmacokinetics

Adverse Effects

Well absorbed after oral administration but delayed by food, antacids, ferrous sulphate and multivitamins. Wide volume of distribution. Dose adjustment required in renal impairment (except moxifloxacin and trovafloxacin) These two drugs are contraindicated in hepatic failure

GI side effects CNS effects such as confusion and seizures in the elderly Rare skin reactions Should be avoided in pregnancy Not routinely recommended for use in patients under 18 years of age

Mechanism and Spectrum of Action of Azoles (antibacterial)

Spectrum of action:

It is bacteriostatic. It acts mainly against anaerobic bacteria and retains significant antiprotozoal activity.

Mechanism of action of Azoles (antifungal)

Pharmacokinetics and Adverse Effects of Azoles

Pharmacokinetics Almost completely absorbed after oral administration (60% after rectal administration). Well distributed, especially brain and CSF. Safe in pregnancy. Adverse Effects

Metallic taste Severe vomiting if taken with alcohol

Classification on the basis of the organisms

Antivirals

Antibacterials
Antifungals Antiparasites:

-Antiprotozoals -Antihelminths

Common viral diseases

CNS-Viral meningitis, viral encephalitis

Childhood exanthems- Measles, Mumps,

Rubella, Chicken pox etc. Systemic- Infectious mononucleosis, Influenza, CMV, Dengue, viral haemorrhagic fevers etc. GIT & HBS- Rotavirus; Viral hepatitis Respiratory- Adenovirus

Viral Encephalitis
Aetiology: HSV, Arbovirus, Japanese B

encephalitis
Management:

In case of HSV: Aciclovir 10mg/kg i.v. 8 hourly for 2-3 weeks (early to all patients suspected of suffering from viral encephalitis). Initiation of treatment should not await microbiological diagnosis.

Viral Hepatitis
a. b. c.

Aetiology: Commonly :Hepatotrophic viruses e.g. Hepatitis A,B,C,D,E Less commonly: CMV, EBV Rarely: HSV, Yellow fever virus Management: No antivirals required for Hep A and E, acute Hep B infection In chronic Hep B infection : Options areInterferon- Low viral load, serum transaminases>twice normal, NO LIVER CIRRHOSIS Lamivudine- Decompensated cirrhosis. Adefovir- C/I- Renal failure Chronic Hep C infection : Pegylated alpha interferon weekly s/c + oral ribavirin

Common Bacterial diseases

CNS: Meningitis, brain abscess etc Respiratory: URTI, Pneumonia, Lung abscess,

Bronchiectasis CVS: Acute rheumatic fever, Infective endocarditis GIT and HBS: Cholera, Bacillary dysentery, Enteric fever, gastroenteritis, peritonitis,liver abscess Genitourinary: UTI, pyelonephritis, STDs Musculoskeletal: Osteomyelitis, Septic arthritis Mycobacterial Infections: Tuberculosis, Leprosy Rickettsial Infections Chlamydial Infections Systemic Infections: Sepsis syndrome

Pyogenic Meningitis (Cause Known)

Age of onset
Common

Neonate

Preschool child
Haemophilus influenzae

Older child and adult

Gram Negative bacilli,Group B Streptococci

1. Neisseria meningitidis 2. Streptococcus pneumoniae

Regimen of choice

Cefotaxime 2 g i.v. 6-hourly or ceftriaxone 2 g i.v. 12-hourly for 10-14 days

1.Benzylpenicillin 2.4 g i.v. 4hourly for 5-7 days 2. Cefotaxime 2 g i.v. 6-hourly or ceftriaxone 2 g i.v. 12-hourly for 10-14 days add vancomycin 1 g i.v. 12hourly or rifampicin 600 mg i.v. 12-hourly(in beta lactam resistant groups)

Pyogenic Meningitis (Cause Unknown)

1. Patients with typical meningococcal rash 2. Adults (18-50) without a typical meningococcal rash Benzylpenicillin 2.4g i.v. 6 hourly Cefotaxime 2 g i.v. 6-hourly or Ceftriaxone 2 g i.v. 12-hourly

3. Suspicion of penicillinresistant pneumococcal infection

As above plusVancomycin 1 g i.v. 12-hourly or Rifampicin 600 mg i.v. 12-hourly

As above plusAmpicillin 2 g i.v. 4-hourly or Co-trimoxazole 50 mg/kg i.v.daily in two divided doses

4. Adults>50 years with suspected L.monocytogenes infection

5. Patients with anaphylaxis to beta Chloramphenicol 25 mg/kg i.v. 6-hourly lactams plus Vancomycin 1 g i.v. 12-hourly

Pneumonia- Community Acquired

Common organisms
S. pneumoniae, C. pneumoniae, M. pneumoniae, L. Pneumophilia

Uncommon organisms
H.Influenzae, S.Aureus, Chlamydia psittaci,Coxiella burnetti,

Severe CAP
Clarithromycin 500 mg 12-hourly i.v. or Erythromycin 500 mg 6-hourly i.v. plus Co-amoxiclav 1.2 g 8-hourly i.v. or Ceftriaxone 1-2 g daily i.v. or Cefuroxime 1.5 g 8-hourly i.v. or Amoxicillin 1 g 6-hourly i.v. plus flucloxacillin 2 g 6-hourly i.v.

Pneumonia-Community Acquired
Uncomplicated CAP
Amoxicillin 500 mg 8-hourly orally If patient is allergic to penicillin Clarithromycin 500 mg 12-hourly orally or Erythromycin 500 mg 6-hourly orally If Staphylococcus is cultured or suspected Flucloxacillin 1-2 g 6-hourly i.v. plus Clarithromycin 500 mg 12-hourly i.v. If Mycoplasma or Legionella is suspected Clarithromycin 500 mg 12-hourly orally or i.v. or Erythromycin 500 mg 6-hourly orally or i.v. plus Rifampicin 600 mg 12-hourly i.v. in severe cases

Pneumonia-Hospital Acquired
Hospital Acquired Pneumonia

Aetiology- Gram Negative bacteria e.g.Escherichia,Pseudomonas,Klebsiella and MRSA

Managementa third-generation cephalosporin (e.g. cefotaxime) plus an aminoglycoside (e.g. gentamicin) or meropenem or a monocyclic -lactam (e.g. aztreonam) plus flucloxacillin.

Aspiration Pneumonia Management-

Co-amoxiclav 1.2g 8-hourly plus Metronidazole 500mg 8-hourly

Lung Abscess & Bronchiectasis

Suppurative pneumonia and Lung abscess
Aetiology: Kleb. Pneumoniae, Strep. pneumoniae, Staph. aureus, Strep. pyogenes, H. influenzae and, in some cases, anaerobic bacteria. Management: Amoxicillin 500mg 8-hourly orally. If anaerobic infection is suspected, oral metronidazole 400mg 8hourly orally. Treatment for 4-6 weeks in cases of lung abscess.

Bronchiectasis
Antibiotic therapy should be guided by microbiological results. Frequently used areoral ciprofloxacin (250-750 mg 12-hourly) or ceftazidime by intravenous injection or infusion (1-2 g 8-hourly).

Tuberculosis
Category I Category II

Criteria: New smear positive pulmonary TB, new smear negative pulmonary TB, extrapulmonary TB, concomitant HIV/AIDS Intensive phase: (HRZE) for 2 months Continuation phase: (HR) for 4 months

Criteria: sputum smear positive pulmonary TB with history of treatment more than 1 month, relapse, treatment failure, treatment after default Intensive phase: 2 months (HRZE)S/ 1 month (HRZE) Continuation phase: 5 months (HR)E

Acute Rheumatic Fever

Aetiology: Immunological response after infection by

Group A Streptococci Management:

Acute attack-A single dose of benzyl penicillin 1.2 million U i.m. or oral phenoxymethylpenicillin 250 mg 6-hourly for 10 days. Secondary prevention-Benzyl penicillin 1.2 million U i.m. monthly (if compliance is in doubt) or oral phenoxymethylpenicillin 250 mg 12-hourly. Treatment should be continued for 5 years or till age of the patient is 21 years (whichever is longer). In those with residual heart disease, prophylaxis should continue until 10 years after the last episode or 40 years of age, whichever is longer.

Infective Endocarditis
Acute- By Staph. aureus and coagulase negative staphylococci. Benzylpenicillin (1.2 g 4 hourly) [penicillin sensitive] Flucloxacillin (2g 4 hourly) [penicillin resistant,meticillin sensitive] Vancomycin (1g 12 hourly) and gentamicin (1mg/kg 8 hourly) [penicillin and meticillin resistant] Subacute- By viridans streptococci, enterococci, Gram negative bacilli (HACEK) group and anaerobes Viridans streptococci: Benzylpenicillin and gentamicin Enterococci: Ampicillin (2g 4 hourly) and gentamicin [ampicillin sensitive] Vancomycin (1g 12 hourly) and gentamicin [ampicillin resistant]
Route of administration: Intravenous Duration of treatment: 4 (native valves)- 6 (prosthetic valves) weeks

Gastrointestinal Infections
Cholera: Tetracycline 250 mg 6-hourly for 3 days, Doxycycline 300 mg single dose or Ciprofloxacin 1 g in adults

Bacillary Dysentery: Ciprofloxacin 500 mg 12-hourly for 3 days Helicobacter pylori Infection: Two antibiotics (from amoxicillin, clarithromycin and metronidazole) for 7 days

Enteric Fever
Aetiology: Salmonella typhi and Salmonella paratyphi A and B Drugs of choice: Fluoroquinolones (Ciprofloxacin 500 mg 12-hourly) Alternatives: Extended-spectrum cephalosporins, ceftriaxone and cefotaxime Fluoroquinolone resistance: Azithromycin 500 mg once daily Treatment should be continued for 14 days. Chronic carrier: Should be treated for 4 weeks with ciprofloxacin

Liver Abscess
Aetiology (pyogenic): E.coli, various streptococci

esp. Strep. Milleri; anaerobes like streptococcus and Bacteroides (amoebic): Entamoeba histolytica Management: Pyogenic: Combination of antibiotics e.g. ampicillin, gentamicin and metronidazole Amoebic: Metronidazole (800 mg 8-hourly for 5 days) or tinidazole (2 g daily for 3 days) Luminal amoebicide-diloxanide furoate (500 mg 8hourly for 10 days)

Sepsis and Spontaneous bacterial peritonitis

Sepsis: Broad spectrum antibiotics covering

both Gram positive and Gram negative organisms should be given after sending blood and other specimens for culture. Spontaneous bacterial peritonitis: In CLD with ascites: mostly caused by E.coli. Treatment should be with broad spectrum antibiotics e.g. cefotaxime.Recurrence may be reduced by quinolones e.g.norfloxacin or ciprofloxacin.

UTI & Pyelonephritis

Aetiology: E.coli, Proteus, Pseudomonas, streptococci,
Staph. Epidermidis
Choice of antibiotics: Trimethoprim, Nitrofurantoin,

Ciprofloxacin, Norfloxacin, Co-amoxiclav,Cefuroxime, Cefalexin

Duration of Treatment:

For UTI - 3days For Pyelonephritis - 7-14 days Severe cases require intravenous therapy, with a cephalosporin, quinolone or gentamicin

Leprosy
Type of Leprosy Monthly supervised drug treatment
600 mg

Daily selfDuration administered of drug treatment treatment

Dapsone 100 mg Clofazimine 50 mg Dapsone 100 mg 6 months 12 months

Paucibacillary Rifampicin Multibacillary

Rifampicin 600 mg Clofazimine 300 mg

Paucibacillary single lesion is to be treated with a single

dose of Ofloxacin 400 mg, Rifampicin 600 mg and Minocycline 100 mg

STDs : Syphilis, Gonorrhoea, Chlamydial infections

Syphilis: Penicillin is the drug of choice. Doxycycline (in

penicilin allergy) and azithromycin are also advocated. Chlamydia:

Azithromycin 1 g orally as a single dose or Doxycycline 100 mg 12-hourly orally for 7 days

Gonorrhoea:
Cefixime 400 mg stat or Ciprofloxacin 500 mg orally stat or Ofloxacin 400 mg orally stat or Amoxicillin 3 g plus probenecid 1 g orally stat

Common fungal diseases

Candidiasis
Caused by Candida albicans
Treatment: Systemic- Amphotericin B, Fluconazole, Voriconazole Topical (oral or vaginal thrush)Nystatin, fluconazole etc.

Dermatophytes (ring

worms):
Microsporum Trichophyton Epidermophyton Clinical forms includeTinea corporis, tinea cruris, tinea capitis Treatment: TopicalTerbinafine,miconazole Systemic-Terbinafine, griseofulvin or itraconazole

Anti Protozoals
Amoebiasis & Giardiasis

Malaria
Kala-azar

Malaria
Uncomplicated Malaria Uncomplicated Malaria

Confirmed: Tab. Co-artem 24 tablets in 6 divided doses Tab Quinine for 7 days

Alternative regimen: Quinine for 7 days + Tetracycline (250 mg 6 hourly) for 7 days Quinine for 7 days + Doxycycline (100 mg 12 hourly) for 7 days

Presumptive: Cholorquine Tab. 150 mg base Day 1: 4 tabs Day 2: 4 tabs Day 3: 2 tabs

Malaria
Severe Malaria:
Loading dose: Quinine dihydrochloride 20mg salt/kg body wt by infusion in 5% D/A over 4 hours Maintenance dose: 8 hours after loading dose, maintenance 10mg/kg body wt in 5% D/A over 4 hours. This should be repeated 8 hourly upto 6 doses (including loading dose). Then the quinine dose will be reduced to 5-7 mg salt/kg body wt until the patient can take oral medication. If patient can take orally properly: Oral quinine sulphate 10mg salt/kg 8 hourly to complete a 7 day course of treatment

Vivax Malaria:
Chloroquine 3 days + Primaquine 14 days

Kala-azar
Treatment Plan A Treatment Plan C

Miltefosine 2.5mg/kg body wt in 2 divided doses, orally, in morning and evening after meal for 28 days. Treatment Plan B If miltefosine is not available or in kala-azar treatment failure, sodium antimony gluconate 20 mg/kg body wt. i.m. or i.v. for 30 days is to be given.

In kala-azar treatment failure or in pregnancy, amphotericin B is the drug of choice. Non liposomal (amphotericin B deoxycholate) 1mg/kg body wt. daily i.v. for 20 days in 5% dextrose. Liposomal amphotericin B 3 mg/kg body wt. i.v. daily for 5 days.

Kala-azar
Treatment Plan D

Indication: Post Kala-azar Dermal Leishmaniasis. Drug of choice: Sodium antimony gluconate 20mg/kg body wt i.m. or i.v. for 20 days per cycle; 6 cycles with 10 days interval between the cycles.
Alternative drug: Liposomal amphotericin B 3mg/kg body wt. i.v. for 5days per cycle; or Non liposomal amphotericin B1mg/kg body wt. for 15 days per cycle; 6cycles with 10 days interval between the cycles

Anti helminths
Gastro-Intestinal:

Ancylostoma, Ascaris:

Albendazole 400 mg single dose or Mebendazole 100 mg 12 hourly for 3 days

Tissue parasite: Filariasis: Caused by Wuchereria bancrofti Treatment: Diethylcarbamazine 6 mg/kg body

wt. orally in 3 divided doses for 12 days.

Renal dosing of commonly used antibiotics

Antibiotics
amoxicillin po amoxicillin/ clavulanate po

Usual dosage
250-500mg 8-12h 250/125 to 500/125 8h

Renal dosage
>30:no change 1030:12h <10:24h >30:no change 10-30:12h <10:24h

ceftriaxone iv
cefuroxime po

1-2g 24h
250-500mg 12h

no adjustment
>30:no change 10-29: 12-24h <10: 250mg 24h >/=10:no change <10: 50-75%of dose at same interval

erythromycin po

250-500mg 6-12h

Renal dosing of commonly used antibiotics

Antibiotics
clarithromycin po

Usual dosage
250-500mg 12h

Renal dosage
>/=30:no change <30:500 mgx1, then 250mg 12-24h no adjustment >/= 50: no change 10-50: q12-24h <10: q24h

azithromycin po Tetracycline po ** Avoid if possible due to risk of liver toxicity

500mg x1, then 250mg daily x4days 250-500 6h

doxycycline
ciprofloxacin po

100mg 12h
250-750mg 12h

no renal adjustment
>/=30:no change <30: 24h

Renal dosing of commonly used antibiotics

Antibiotic
Ciprofloxacin iv levofloxacin po/iv

Usual dosage
200-400mg 12h 500mg 12h

Renal dosage
>/=30:no change <30:24h >/= 50: no change 20-49: 500mg x1, then 250mg 24h 10-19: 500mg x 1, then 250m 48h >/= 10: no change <10: 500mg 8-12h no renal adjustment >/=10:no change <10: may give half usual dose

metronidazole po/iv adjust for hepatic failure isoniazid rifampicin po/iv

500mg 6-8h

300mg po daily 600mg 24h

Renal dosing of commonly used antibiotics

Antibiotic
ethambutol

Usual dosage
15-25mg/kg 24h

Renal dosage
>/=10:no change <10:48h >50: no change 30-50: 5-10mg/kg 12h 10-30: 5-10mg/kg 24h <10: 2.5-5mg/kg 24h >50: no change 20-50: 1/2 usual dose 24h <20: 1/4 dose 24h, or 1/2 48h

acyclovir iv

5-10mg/kg 8h

fluconazole po/iv

100-400mg 24h

References
Davidsons Principles and Practices of

Medicine, 20th Ed Clinical Pharmacology, P.N.Bennet, M.J.Brown, 9th Ed Basic and Clinical Pharmacology, Katzung, 11th Ed http://www.globalrph.com/renaldosing2.htm#t op