ANTIMICROBIALS

ANTIMICROBIALS PART 1

ANTIMICROBIALS (CLASSIFICATION AND CONCENTRATION AND TIME-DEPENDENT ACTION)

Concentration v/s Time-dependent killing (effect):

CDK TDK
Effect increases as concentration Effect increases as time spent above MIC
above MIC increases increases
Usually seen with – Rapidly acting Usually seen with – slowly acting drugs
drugs
Examples: Examples:
• AG • Beta lactams
• FQ • Vancomycin
• Azithromycin
Most important PK measure: Most important PK measure:
Cmax / MIC T > MIC
Usually given as – Large doses less Usually given as – Small doses more
frequently frequently or as a continuous infusion
PAE prolonged PAE negligible

Time-dependent concentration-enhanced action:

• Effect increases with both conc and time > MIC

• Most important PK measure: AUC / MIC
• Examples: Clindamycin and Macrolides
• PAE prolonged

Classification into bactericidal and bacteriostatic agents:

Bactericidal Bacteriostatic
• Cell wall synthesis inhibitors • Protein synthesis inhibitors
▪ β-lactams except Aminoglycosides and
▪ Glycopeptides Rifampicin
• Aminoglycosides • All antimetabolites except
• Rifampicin Cotrimoxazole
• DNA gyrase inhibitors
• Cotrimoxazole

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Antimicrobials not requiring dose reduction in renal failure:

1. Ceftriaxone
2. Cefoperazone
3. Doxycycline
4. Erythromycin
5. Quinupristin / Dalfepristin
6. Rifampicin
7. Amphotericin B
8. Tigecycline
9. Tedizolid

ANTIMICROBIALS (PENICILLINS AND CEPHALOSPORINS)

Orally active (acid-resistant Penicillins): (Mnemonic: VODKAA)

• Penicillin V (Phenoxymethyl Penicillin)

• Oxacillin
• Dicloxacillin
• K(C)loxacillin
• Amoxicillin
• Ampicillin

Indications of cephalosporins:

Generation Primary indication

1st Surgical prophylaxis
2nd Anaerobic infections
3rd Gram negative bacterial infections
4 and 5
th th
Nosocomial infections
5th Reserve drugs for MRSA (except
Ceftolozane – for Ps aueruginosa)

Adverse effects of cephalosporins:

1. Diarrhea
2. Hypersensitivity reactions
3. Nephrotoxicity
4. Bleeding
5. Hypoprothrombinemia
6. Autoimmune neutropenia and thrombocytopenia

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ANTIMICROBIALS (CARBAPENEMS AND AMINOGLYCOSIDES)

Reason for adding cilastatin to imipenem:

• Imipenem is rapidly hydrolyzed by dipeptidase enzyme in brush border of PCT

• This reduces plasma availability of the drug
• Cilastatin is a dipeptidase inhibitor; hence, prevents metabolism of imipenem in the renal
tubules

Ertapenem is not effective against:

• P. aeruginosa
• Acinetobacter
• Enterococcus
Anaerobes are inherently resistant to – Aminoglycosides (as penetration of aminoglycosides
into bacterial cells is an aerobic energy-dependent process)

Aminoglycosides:

• Least nephrotoxic aminoglycoside – Streptomycin

• Most nephrotoxic aminoglycoside – Neomycin
• Least ototoxic aminoglycoside – Netilmicin
• Most vestibulotoxic aminoglycoside – Streptomycin

ANTIMICROBIALS (TETRACYCLINES AND OXAZOLIDINONES)

Adverse effects of tetracyclines:

1. GI symptoms
➢ Nausea
➢ Vomiting
➢ Abdominal pain
➢ Epigastric burning
2. Esophagitis and esophageal ulcers
3. Photosensitivity
4. Skin pigmentation
5. Nail pigmentation
6. Hepatotoxicity
7. Ototoxicity & Vestibulotoxicity (Minocycline)
8. Nephrotoxicity (except Doxycycline)
9. Fanconi’s syndrome (outdated tetracyclines)
10. Diabetes insipidus (Demeclocycline)

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11. Adverse effects in children –
➢ Pseudotumor cerebri
➢ Growth retardation
➢ Teeth discolouration
12. Superinfections
13. Teratogenicity

Contraindications to tetracyclines:

1. Pregnancy
2. Children < 8 years

Tigecycline:

• Glycylcycline – derivative of tetracyclines

• Active against most Gm +ve and Gm –ve cocci and anaerobes
• Reserve drug for resistant infections
• Dose: 100 mg loading dose f/b 50 mg 12 hrly IV infusion over 30-60 min
• Primarily eliminated in bile – dosage adjustment not needed for renal insufficiency

Antimicrobial with MAO inhibitory property – Linezolid

ANTIMICROBIALS (ANTIMETABOLITES)

MOA of antimetabolite antimicrobials:

Antibacterials Mechanism of action

Sulfonamides Inhibit dihydropteroate synthase
Dapsone
Trimethoprim Inhibit dihydrofolate reductase
Pyrimethamine
Cotrimoxazole Inhibits both the enzymes

Adverse effects of sulfonamides and cotrimoxazole: (Mnemonic: CAR-PHEK)

1. Crystalluria
2. Acute renal failure
3. Rashes
4. Photosensitivity
5. Hypersensitivity reactions (SJS & TEN)
6. Erythema multiforme
7. Kernicterus

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ANTIMICROBIALS (FLUOROQUINOLONES AND ANTIMICROBIAL RESISTANCE)

Adverse effects of fluoroquinolones:

1. Nausea
2. Vomiting
3. Headache
4. Dizziness
5. Rashes
6. Photosensitivity
7. Tendinitis and tendon rupture
8. Arthralgias
9. Pancreatitis (Gatifloxacin)
10. QT prolongation
• Sparfloxacin
• Moxifloxacin
• Gatifloxacin

WHO global priority list of antibiotic-resistant bacteria:

Organism Resistant to
Priority 1: CRITICAL
Acinetobacter baumannii Carbapenems
Pseudomonas aeruginosa Carbapenems
Enterobacteriaceae Carbapenems, 3rd generation cephalosporins
Priority 2: HIGH
Enterococcus faecium Vancomycin
Staphylococcus aureus Methicillin, Vancomycin
Helicobacter pylori Clarithromycin
Campylobacter Fluoroquinolones
Salmonella spp Fluoroquinolones
Neisseria gonorrhoeae 3rd generation cephalosporins,
Fluoroquinolones
Priority 3: MEDIUM
Streptococcus pneumoniae Penicillins
Haemophilus influenzae Ampicillin
Shigella spp Fluoroquinolones

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Mechanisms of resistance to antimicrobials:

1. Decreased penetration of drug into the cell

2. Efflux of the drug from the cell
3. Metabolism of the drug by cleaving enzymes
4. Alteration in the target binding sites
5. Decreased activation of pro-drug
6. Increased production of target sites

ANTIMICROBIALS PART 2

TREATMENT OF BACTERIAL INFECTIONS

Drugs effective against MRSA:

1. Glycopeptides
• Vancomycin
• Teicoplanin
• Telavancin
• Dalbavancin
• Oritavancin
2. Linezolid
3. Streptogramins
• Quinupristin / Dalfepiristin
4. Daptomycin
5. Mupirocin
6. 5th generation cephalosporins
• Ceftobipirole
• Ceftaroline
• Ceftolozane
7. Tigecycline
8. Cotrimoxazole
9. Ciprofloxacin

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Treatment of community-acquired pneumonia (OPD basis):

No co-morbidities and no antibiotics Macrolide OR

received in past 3 months Doxycycline
Co-morbidities present OR received Respiratory fluoroquinolone OR
antibiotics in past 3 months β-lactam + Macrolide

Treatment of community-acquired pneumonia (OPD basis):

Non-ICU setting Respiratory fluoroquinolone OR

β-lactam + Macrolide
ICU setting β-lactam + Macrolide OR respiratory
fluoroquinolone
If CA-MRSA is a Add Linezolid OR Vancomycin
consideration
If Pseudomonas is a Anti-pseudomonal β-lactam + respiratory
consideration fluoroquinolone OR
Anti-pseudomonal β-lactam +
aminoglycoside + azithromycin

Treatment of typhoid fever:

Situation First-line agents

Empirical treatment Ceftriaxone OR Azithromycin

Diagnosed and fully susceptible Ciprofloxacin OR Azithromycin

If quinolone or multi-drug Ceftriaxone OR Azithromycin

resistant

Treatment of Stenotrophomonas maltophila infection:

TMP-SMX (1600/320 mg q12h IV) + Ticarcillin/clavulanate (3.1g q4h IV) x 14 days

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Use of antimicrobials in diarrhea:

Useful only in severe

Regularly useful in cases (but not mild ones) Have no value in
of
• Cholera • Traveller’s diarrhea • Irritable bowel
• Campylobacter jejuni • Enteropathogenic E.. coli syndrome
infection (EPEC) infection • Celiac disease
• Clostridium difficile • Shigella enteritis • Pancreatic enzyme
diarrhea • Non-typhoid Salmonella deficiency
• Diarrhea associated with enteritis • Tropical sprue
bacterial growth in blind • Yersinia enterocolitica (except in case of
loops / diverticulitis infection secondary
• Amebiasis infections)
• Giardiasis • Thyrotoxicosis

ANTIVIRALS (CLASSIFICATION OF ANTIRETROVIRALS)

Classification of antiretrovirals:

1 Nucleoside Competitively inhibit HIV • Zidovudine

reverse reverse transcriptase • Lamivudine
transcriptase enzyme → Interfere with • Stavudine
inhibitors (NRTIs) viral DNA synthesis • Didanosine
• Zalcitabine
• Emtricitabine
• Abacavir
• Festinavir
2 Nucleotide Competitively inhibit HIV • Tenofovir
reverse reverse transcriptase
transcriptase enzyme → Interfere with
inhibitor viral DNA synthesis
3 Non-nucleoside Non-competitively inhibit • Nevirapine
reverse HIV reverse transcriptase • Efavirenz
transcriptase enzyme → Interfere with • Etavirine
inhibitors viral DNA synthesis • Delavirdine
(NNRTIs)

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 4. Protease Inhibit HIV protease • Ritonavir
inhibitors enzyme → Prevent • Saquinavir
proteolysis of viral pro- • Indinavir
proteins • Nelfinavir
• Amprenavir
• Fosamprenavir
• Lopinavir
• Atazanavir
• Tipranavir
• Darunavir
5. Entry inhibitors / Maraviroc: Binds to CCR5 • Maraviroc
Fusion inhibitors → prevents entry of viral • Enfuvirtide
nucleic acid into host cell.
Enfuvirtide: Binds to gp 41
→ Prevents fusion of
viral and host cell
membranes
6. Integrase Inhibit viral integrase • Raltegravir
inhibitors enzyme → Prevent • Elvitegravir
integration of viral • Dolutegravir
nucleic acid into host
genome

ANTIMICROBIALS (INDIVIDUAL ANTIRETROVIRALS AND TREATMENT OF HIV)

Hypersensitivity reactions to abacavir:

• Potentially fatal reaction

• Within 6 weeks of starting therapy
• Requires immediate drug discontinuation
• Risk increased in patients with HLA-B57 polymorphisms

Tenofovir:

• Given as prodrug Tenofovir disoproxil – improves oral bioavailability

• Inhibits HIV reverse transcriptase and HBV DNA polymerase
• Dose: 300 mg once a day oral

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Adverse effects of HIV protease inhibitors:

1. Nausea
2. Vomiting
3. Diarrhea
4. Abdominal pain
5. Metallic taste
6. Lipodystrophy and lipid redistribution
7. Hypertriglyceridemia
8. Hypercholesterolemia
9. Increased risk of atherosclerosis
10. Renal stones – Indinavir

Initiation of antiretroviral therapy:

U.S. Department of Health and Human Services Guidelines (2010): Start ART in –
1. All symptomatic HIV patients
2. Asymptomatic patients with CD4 ≤ 350 / µL
3. HIV + HBV / HCV patients
4. Pregnant HIV +ve women
5. Patients with HIV nephropathy

Post-exposure prophylaxis:

Low risk High risk

Basic regimen: Expanded regimen:
• Zidovudine 300 mg + • Zidovudine 300 mg +
• Lamivudine 150 mg • Lamivudine 150 mg +
• Twice daily x 4 weeks • Twice daily x 4 weeks
• Indinavir 800 mg (or any other PI)
• Thrice daily x 4 weeks

ANTIMICROBIALS (DRUGS FOR INFLUENZA AND HERPES SIMPLEX INFECTIONS)

Dose of Oseltamivir:

• Prophylaxis: 75 mg OD oral x 5 days

• Treatment: 75 mg BD oral x 5 days

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Adverse effects of Foscarnet:

1. Nephrotoxicity (dose-limiting)
2. Interstitial nephritis
3. Symptomatic hypocalcaemia (dose-limiting)
4. Hypokalemia
5. Hypomagnesemia
6. Neurotoxicity
7. Painful genital ulcerations (rare)

ANTIFUNGALS (CLASSIFICATION)

Classification, MOA and examples of antifungals:

Group Mechanism Examples

1. Antibiotics
Polyenes Bind to ergosterol in fungal cell • Amphotericin B
membrane • Nystatin
↓ • Hamycin
Orient themselves within the • Natamycin
membrane to form micropores
↓
Leakage of ions, amino acids and
other substances through the
micropores
↓
Cell death
Echinocandins Inhibit synthesis of β-1,3-D- • Caspofungin
glucan • Micafungin
↓ • Anidulafungin
Reduce structural integrity of
fungal cell wall
↓
Osmotic instability
↓
Cell death
Heterocyclic Binds to β-tubulin in polymerized Griseofulvin
benzofurans microtubules
↓
Disorientation of microtubules

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 ↓
Disruption of mitotic spindle
assembly
↓
Inhibition of mitosis
2. Antimetabolites
Gets metabolized to 5- 5-Flucytosine
Fluorouracil
↓
Activated to mono- and di-
phosphates
↓
Inhibit RNA and DNA synthesis
3. Azoles
Inhibit 14-α-sterol demethylase Imidazoles:
(lanosterol demethylase) • Clotrimazole
involved in ergosterol synthesis • Econazole
↓ • Miconazole
Accumulation of 14-α-sterols in • Oxiconazole
the fungal cells • Butaconazole
↓ • Sertaconazole
Disrupt the close packing of
• Luliconazole
phospholipids and inhibit cell-
• Ketoconazole
membrane bound enzymes
• Triazoles:
↓
Inhibition of fungal growth • Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole
• Isavuconazole
4. Allylamines •
Inhibit squalene epoxidase • Terbinafine
↓ • Butenafine
Reduced ergosterol production • Naftifine
↓
Deficient fungal cell membranes

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ANTIFUNGALS (TREATMENT OF FUNGAL INFECTIONS)

Griseofulvin is not preferred nowadays for treatment of dermatophytosis due to:

• High incidence of s/e

• High incidence of drug-drug interactions
• Long duration of treatment
• Development of resistance

Drugs for Mucormycosis:

• Amphotericin B
• Echinocandins
• Azoles – Posaconazole and Isavuconazole

ANTIMICROBIALS PART 3

ANTITUBERCULAR (CLASSIFICATION AND 1ST LINE ANTITUBERCULAR)

WHO – revised classification of antitubercular:

GROUP EXAMPLES
Group I • Isoniazid (H)
Oral first line agents • Rifampicin (R)
• Pyrazinamide (Z)
• Ethambutol (E)
• Rifabutin
• Rifapentine
Group II • Streptomycin
Injectables • Amikacin
• Capreomycin
• Kanamycin
Group III • Ciprofloxain
Fluoroquinolones • Ofloxacin
• Levofloxacin
• Moxifloxacin

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 GROUP EXAMPLES
Group IV • Ethionamide
Oral second line agents • Protionamide
• Cycloserine
• Terizidone
• PAS
Group V • Linezolid
Drugs with unclear efficacy • Bedaquiline
• Delamanid
• High dose H
• Clarithromycin
• Clofazimine
• Imipenem / Cilastatin
• Meropenem
• Amoxicillin / Clavulanate

Adverse effects of ethambutol:

• Optic neuritis – Decreased visual acuity

• Red-green colour blindness
• Rashes
• Fever
• Pruritus
• Arthralgias

ANTITUBERCULARS (2ND LINE ANTITUBERCULARS AND TREATMENT OF TUBERCULOSIS)

Bedaquiline:

• Approved for MDR-pulmonary TB

• Dose: 400 mg q24h x 2 weeks f/b 200 mg three times a week x 22 weeks
• To be administered with food – oral bioavailability improved with fatty meals
• To be used in severe hepatic failure only if benefit > risk
• Caution to be exercised when combined with –
• Other QT interval prolonging drugs (Increased risk)
• CYP enzyme inhibitors (Metabolism of bedaquiline may be inhibited)

Treatment of tuberculosis in pregnancy:

WHO and British Thoracic Society – 2 HRZE + 4 HR (Avoid S)

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RNTCP – 2 HRE + 7 HR + Pyridoxine 10 -25 mg/d (Avoid Z and S)

Treatment of TB in HIV patients:

1. Substitute rifabutin / rifapentine for rifampicin

2. 3 NRTIs (Zidovudine + Lamivudine + Abacavir instead of 2 NRTI + 1 NNRTI)
3. Efavirenz to be preferred if started on 2 NRTI + 1 NNRTI (Nevirapine to be avoided)

ANTITUBERCULARS (TREATMENT OF RESISTANT TUBERCULOSIS)

Drug-resistant TB:

• MDR-TB: Resistance to H+R

• XDR-TB: Resistance to H+R, any FQ and any of the injectables
• Pre-XDR-TB: Resistance to H+R + Either FQ / injectable
• TDR-TB: Resistance to all available 1st line and 2nd line drugs

Treatment of MDR-TB:

Regimen 1:

IP: 8 months; CP: 12 months

Minimum of 5 drugs –
• Pyrazinamide
• One other drug from Group I
• One drug from Group II (Injectable)
• One drug from Group III (Fluoroquinolone)
• Other drugs from Groups IV

Regimen 2 (Bangladesh regimen):

IP: 4 months (+2 months if still sputum

CP: 5 months
+ve)
• Pyrazinamide • Isoniazid
• Ethambutol • Pyrazinamide
• High dose isoniazid • Moxifloxacin / Gatifloxacin
• Moxifloxacin / Gatifloxacin • Clofazimine
• Kanamycin
• Protionamide
• Clofazimine

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Regimen 3 (RNTCP):

IP (6-9 months) CP (18 months)

• Kanamycin • Ofloxacin or Levofloxacin
• Ofloxacin or Levofloxacin • Ethionamide
• Ethionamide • Cycloserine
• Cycloserine • Ethambutol
• Ethambutol
• Pyrazinamide
+ Pyridoxine (100 mg/d)

Treatment of X-DR TB:

Minimum of 5 drugs –
• Pyrazinamide
• One drug from Group A (Fluoroquinolone)
• One drug from Group B (injectable)
• Other drugs from Group C
If the minimum number cannot be met from the above, one drug from D2 and one or more
from D3 can be selected

Drugs for treatment of XDR-TB:

Group A (in decreasing order of preference)

FQ • Levofloxacin
• Moxifloxacin
• Gatifloxacin
Group B • Amikacin
Injectables • Capreomycin
• Kanamycin
• Streptomycin
Group C (in decreasing order of preference)
Other core second-line agents • Ethionamide
• Protionamide
• Cycloserine
• Terizidone
• Linezolid
• Clofazimine
Group D1 • Z

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 Add-on drugs • E
• High dose H
D2 • Bedaquiline
Add-on drugs • Delamanid
D3 • PAS
Add-on drugs • Imipenem / Cilastatin
• Meropenem
• Amoxicillin / Clavulanate
• Thiacetazone

ANTIMALARIALS

Treatment of malaria:

DOC for In pregnancy

Uncomplicated malaria Chloroquine Chloroquine
Complicated malaria ACT 1st trimester – Quinine
2/3 – ACT
CQ-resistant malaria ACT 1st trimester – Quinine
2/3 – ACT

Situation in India:

• P. vivax – CQ-sensitive
• P. falciparum – CQ-resistant

Chemoprophylaxis of malaria:

DOC for In pregnancy

Travel to CQ-sensitive Chloroquine Chloroquine
area
Travel to CQ-resistant < 6 wks – Doxycycline Mefloquine
area > 6 wks – Mefloquine

Adverse effects of chloroquine:

Immediate –

1. Nausea
2. Vomiting
3. Anorexia
4. Epigastric pain

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5. Uneasiness
6. Uncontrollable itching

Long-term:

1. Retinopathy (Irreversible)
2. Corneal deposits (Reversible)
3. Ototoxicity – Loss of hearing
4. Greying of hair
5. Rashes
6. Photoallergy
7. Mental disturbances
8. Myopathy

OTHER ANTIPROTOZOALS AND ANTHELMINTHICS

Drugs for visceral leishmaniasis (kala-azar):

1. Amphotericin B
2. Sodium stibogluconate
3. Pentamidine
4. Miltefosine
5. Ketoconazole
6. Paromomycin
7. Allopurinol

Indications of albendazole:

1. Ascariasis
2. Hookworm infestation
3. Enterobiasis
4. Trichuriasis
5. Trichinosis
6. Strongyloidiasis
7. Neurocysticercosis
8. Cutaneous larva migrans
9. Visceral larva migrans
10. Hydatid disease
11. Other echinococcal infections
12. Lymphatic filariasis

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13. Microsporidial infections
14. Capillaria phillipinensis infections

Indications of triclabendazole:

1. Ascariasis
2. Fasciola hepatica
3. Fasciola gigantica
4. Paragonimiasis
5. Ectoparasitic infections

Treatment of strongyloidiasis:

• DOC: Ivermectin single dose 150-200 µg/kg

• Second dose recommended after one week
• More efficacious than a 3-day course of albendazole

❑ ❑ ❑

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