Aztreonam Antibacterial Activity Question And Answers

Aztreonam Antibacterial

Question 3. Monobactams/Aztreonam. ½
Answer:

Monobactams/Aztreonam:

Monobactams are monocyclic beta-lactams, i.e. they contain a single ring—the beta-lactam ring.

Aztreonam:

• Aztreonam is a monobactam active against gram-negative bacilli including Pseudomonas aeruginosa. Aztreonam is resistant to beta-lactamases produced by gram-negative bacteria.
• It is highly effective against H. influenzae, gonococci, and Enterobacteriaceae, but it is not effective against gram-positive organisms and anaerobes.

Read And Learn More: Pharmacology Question And Answers

Aztreonam Mechanism of action:

• Aztreonam acts by inhibiting cell wall synthesis like penicillins. It is given parenterally.
• Aztreonam is well-tolerated. The adverse effects include occasional skin rashes, urticaria, bronchospasm, and rarely anaphylaxis.
• Thrombophlebitis on IV use and pain after IM use are reported. Nausea, vomiting, diarrhea, altered taste and raised liver enzymes have been noted.
• Dose: 0.5–2 g q 6–8 hours IM/IV.

Aztreonam Uses:

• Pseudomonas infections especially nosocomial and in other gram-negative infections.
• In patients allergic to penicillins as there is no cross-allergenicity with other β-lactams.

Broad-Spectrum Antibiotics

Tetracyclines:

Tetracyclines are antibiotics with four cyclic rings (hence the name) in their structure obtained from the soil actinomycetes. Chlortetracycline was obtained from ‘Streptomyces aureofaciens’ in 1948 and was named so because the colonies appear golden yellow.

Tetracyclines Classification:

Tetracyclines Mechanism of action:

Tetracyclines are taken up by microorganisms by active transport. Since mammalian cells lack this active transport process, tetracyclines are selectively toxic to microorganisms.

• The bacterial ribosome consists of the 50S and 30S subunits and tetracyclines bind to the 30S subunit.
• The tRNA carries amino acids to the ribosome for protein synthesis.
• The ribosome has three binding sites viz. A, P, and E sites. Tetracyclines bind to the ‘A’ site and prevent the binding of tRNA to this site.
• As a result, amino acids cannot be added to the growing peptide chain. Thus they prevent protein synthesis and are bacteriostatic.

Tetracyclines Antibacterial spectrum:

• Tetracyclines are broad-spectrum antibiotics.
• They inhibit gram-positive and gram-negative bacteria including streptococci, staphylococci, gonococci, meningococci, clostridia, Bacillus anthracis, Listeria, Corynebacteria, Propionibacterium acnes, H. influenzae, Vibrio cholera, Yersinia pestis, H. ducreyi, Campylobacter, Brucella,
• Bordatella, Pasturella and Spirochaetes. Many of the organisms have now become resistant.
• Rickettsiae (highly sensitive), chlamydiae, mycoplasma, actinomycetes, and the protozoa
• Entamoeba histolytica and plasmodia are all inhibited by tetracyclines.

Tetracyclines Resistance: Bacteria become resistant by

• Decreased uptake or efflux of the antibiotic from the bacterium.
• Producing enzymes that inactivate tetracyclines.
• Cross-resistance among different tetracyclines is also noted.

Tetracyclines Pharmacokinetics:

• Older tetracyclines are incompletely absorbed from the gut.
• Bioavailability 30–70% but newer ones: Doxycycline ~95% and minocycline is 100%.
• Tetracyclines chelate calcium and other metals which reduce their absorption. Hence, tetracyclines should not be given with milk and milk products, iron preparations, zinc supplements and antacids.
• Tetracyclines undergo enterohepatic circulation → remain in the body for a long time.
• Tetracyclines are widely distributed in the body and accumulate in organs, bone and teeth.
• They attain a good concentration in CSF, sinuses, synovial fluid, urine, prostate and in milk.
• They also cross the placenta.
• All tetracyclines except doxycycline and minocycline are excreted through the kidneys.
• Doxycycline and minocycline are excreted through the gut even when given parenterally and are therefore, safe in renal insufficiency.
• IM injection of tetracyclines should be avoided because:
• They can cause irritation.
• Absorption is poor and unreliable.
• Doxycycline and minocycline are the only tetracyclines that are suitable for IV use because other tetracyclines cause thrombophlebitis.

Tetracyclines Adverse Effects:

• GIT: Gastrointestinal irritation, leading to epigastric burning, oesophageal ulcers, nausea, vomiting, and diarrhea can occur—tetracyclines are given with food to avoid these.
• Hepatotoxicity: Hepatotoxicity on using large doses of tetracyclines → may result in jaundice. Acute hepatic necrosis may occur in pregnant women but is rare.
• Renal toxicity: Renal failure may be aggravated because of increased levels of nitrogen due to the antianabolic effects of tetracyclines. Outdated tetracyclines cause a syndrome like
  • Fanconi’s syndrome: Fanconi’s syndrome with vomiting, polyuria, proteinuria, glycosuria, and acidosis due to the metabolites of outdated tetracyclines.

• Phototoxicity: Skin reactions and dermatitis on exposure to sun—more likely with doxycycline and demeclocycline.
• Effect on teeth and bones: Tetracyclines chelate calcium. The calcium-tetracyclineorthophosphate complexes get deposited in the developing teeth and bones. The deformities depend on the time of tetracycline administration.

Onycholysis and pigmentation of the nails may also develop. Tetracyclines are thus teratogenic.

• Suprainfections: Intestinal flora are extensively suppressed → suprainfections common.
• Hypersensitivity: Hypersensitivity reactions are not very common.
• Local: IV injections can cause thrombophlebitis due to their irritant effects.
• Pseudotumor cerebri: Tetracyclines may increase intracranial pressure specially in infants.’

This results in the bulging of the anterior fontanelle in infants giving a false impression of the tumor.

• Antianabolic effect: Large doses used for long periods → ↑ ↑ Urinary excretion of nitrogen.
• Long-term use: May cause leukocytosis, formation of atypical lymphocytes, and thrombocytopenic purpura.
• Nephrogenic diabetes insipidus: Democlocycline ↓ ↓ Action of ADH in the kidney. Demeclocycline → Inhibits action of ADH in kidney → Nephrogenic DI

Tetracyclines Uses:

• Tetracyclines were earlier used as empirical therapy for all infections.
• As several organisms have lost sensitivity to them, and also because better and safer antibiotic combinations can be used (penicillin + an aminoglycoside), tetracyclines are not preferred for empirical therapy.

Tetracyclines are the drugs of choice in:

•  Rickettsial infections:  All rickettsial infections including tick typhus, Q fever, Rocky
  • Mountain spotted fever responds to tetracyclines—fever subsides and clinical improvement is seen in 48 hours. Hence, tetracyclines the drugs of choice in rickettsial infections.
  • Dose: 2 g 6 hourly initially and then reduced to 1 g 6 hourly.
• Chlamydial infections:
  • Lymphogranuloma venereum: Tetracyclines are given for 2 weeks.
  • Trachoma: Both topical and oral tetracyclines are needed. Tetracycline ointment 3–4 times a day continued up to 40 days.
  • Inclusion conjunctivitis: Tetracycline ointment for 2–3 weeks 4 times/day.
  • Urethritis/cervicitis due to chlamydiae is treated with tetracyclines.
  • Chlamydia pneumoniae: Pneumonia due to Chlamydia pneumoniae responds.
  • Psittacosis: Tetracycline—2 g/day for 2 weeks used.
• Atypical pneumonia: Pneumonia due to Mycoplasma pneumoniae.
• Granuloma inguinale: Granuloma inguinale caused by Calymmate bacterium granulomatis responds to tetracyclines given for 3 weeks.
• Cholera:
  • Tetracyclines reduce the duration of illness (adjuvant value) but the treatment of dehydration is life-saving in cholera as there is loss of electrolytes particularly sodium.
  • The Vibrio cholerae are killed by single dose of 200 mg doxycycline or 2 g tetracycline.
• Brucellosis: Doxycycline 200 mg + rifampicin 600 mg daily for 6 weeks—treatment of choice.
• Plague: Tetracyclines with an aminoglycoside → Highly effective in both types of plague.

2. Tetracyclines are useful in other infections like:

• Traveler’s diarrhea: Doxycycline reduces the incidence of traveler’s diarrhea.
• Sexually transmitted diseases: Diseases like syphilis, gonorrhea, and chancroid respond to tetracyclines—but are not preferred.
• Acne: The propioni bacteria in the sebaceous follicles metabolize lipids in the sebum into irritating free fatty acids.
  • These cause irritation of the sebacious gland causing inflammation and forming a comedones (black head).
  • This triggers the development of acne. Tetracyclines inhibit the propionic bacteria. Low doses are given for a long time (250 mg BD for 4 weeks).

• Tularemia: Tetracycline + aminoglycoside used.
• Other infections: Treatment of Lyme disease, relapsing fever, leptospirosis and postexposure prophylaxis of anthrax (doxycycline for 60 days).
• Protozoal infections:
  • Amoebiasis: Useful in chronic intestinal amoebiasis.
  • Malaria: Doxycycline + quinine in multidrug-resistant malaria.
  • Inappropriate secretion of ADH: Demeclocycline is used because it inhibits the action of ADH in the kidney.
  • Topical use: Tetracycline ophthalmic solution is used for eye infections.

Tetracyline And Doxycycline:

Tetracyclines Contraindications:

• Tetracyclines are contraindicated in pregnancy, lactation, and in children up to 8 years of age for the following reasons:
• Their effects on teeth and bones.
  • Risk of acute hepatic necrosis in pregnant women.
  • Risk of pseudotumor cerebri in infants.
• Should be used cautiously in renal and hepatic impairment.

Doxycycline and minocycline are semisynthetic tetracyclines:

• Given orally they are 95% and 100% absorbed, respectively.
• Food does not interfere with their absorption.
• Both are highly lipid-soluble.
• Have long t½—can be given once daily.
• Excreted through the gut—hence dose adjustment is not needed in renal impairment.
• Both can be given orally and parenterally (IV).
• Microsomal enzyme inducers like barbiturates, phenytoin, and ethyl alcohol can make the metabolism of doxycycline faster resulting in shorter t½ of doxycycline.
• Minocycline causes vestibular toxicity with vertigo, dizziness, ataxia, nausea, and vomiting.
• Minocycline can be used as an alternative to rifampicin to eradicate the meningococcal carrier state, i.e. to eradicate the meningococci from the nasopharynx of the carriers.
• Doxycycline is preferred for postexposure prophylaxis of anthrax.

Doxycycline and minocycline: Dose 100 mg BD on 1st day. 100 mg OD for the next 6–14 days.

Chloramphenicol

Chloramphenicol is a broad-spectrum antibiotic first obtained from Streptomyces venezuelae.

Chloramphenicol Mechanism of action:

Chloramphenicol is bacteriostatic but to some organisms it is bactericidal. It binds to the 50S ribosomal subunit and inhibits protein synthesis—by inhibiting transpeptidation reaction.

Chloramphenicol Antibacterial spectrum:

• Spectrum is broad—includes gram-negative organisms, some gram-positive organisms, anaerobic bacteria, rickettsiae, and Mycoplasma. Thus H. influenzae, Salmonella,
• Shigella, Bordatella, Brucella, gonococci, meningococci, streptococci, staphylococci,
• Clostridium, E. coli, and Klebsiella—are inhibited apart from Rickettsiae and Mycoplasma.
• Chloramphenicol is bactericidal to Neisseria meningitidis, H. influenzae, and some strains of Bacteroides.

Resistance is plasmid-mediated and may be due to:

• Inactivatng enzymes
• Reduced permeability of the microorganisms to the antibiotic.
• Ribosomal insensitivity.

Chloramphenicol Pharmacokinetics:

• Chloramphenicol is rapidly absorbed from the gut; penetration into tissues is excellent; attains high concentration in CSF—almost as much as in plasma.
• It is metabolized in the liver by reduction and glucuronide conjugation. The metabolites are excreted in the urine.
• Dose: 250–500 mg QID.

Chloramphenicol Adverse Reactions

• Gastrointestinal disturbances: Nausea, vomiting, and diarrhea.
• Bone marrow depression: Chloramphenicol may cause bone marrow depression in two ways:
  • Dose-dependent: Dose-dependent Higher doses cause anemia, leukopenia, and thrombocytopenia due to inhibition of protein synthesis. It is reversible.
  • Idiosyncratic: Idiosyncratic response resulting in aplastic anemia which may be fatal. It may be due to a toxic metabolite. Incidence is 1 in 30,000 patients and occurs in genetically predisposed individuals. This toxicity has limited the use of chloramphenicol.

• Gray baby syndrome:
  • Newborn babies given high doses of chloramphenicol may show ‘gray baby syndrome’ manifested as vomiting, refusal of feeds, hypotonia, hypothermia, abdominal distension, metabolic acidosis, and ashen gray cyanosis. It may be fatal.
  • As the newborn cannot metabolize (due to inadequate hepatic glucuronidation) and excrete chloramphenicol adequately, toxicity results. Higher doses should be avoided.
• Hypersensitivity: Hypersensitivity reactions like rashes and fever are uncommon.
• Superinfection: Superinfection can occur.

Chloramphenicol Drug interactions:

• Chloramphenicol inhibits hepatic microsomal enzymes and thereby prolongs the half-life of drugs metabolized by this system.
• This may result in increased toxicity of some drugs like phenytoin, warfarin, tolbutamide, and dicumarol.

Chloramphenicol Uses: Because of the risk of bone marrow toxicity and the availability of safer drugs, chloramphenicol is not generally preferred. Some specific indications are:

• Typhoid fever:
  • Chloramphenicol was earlier the drug of choice in typhoid fever but S. typhi developed resistance to it.
  • For the sensitive strains of Salmonella typhi, chloramphenicol is used as an alternative to fluoroquinolones and cephalosporins.
  • It is given for 14 days (500 mg QID till fever subsides and then 250 mg QID up to the 14th day).
• Bacterial meningitis: In meningococcal and H. influenzae meningitis, chloramphenicol is an alternative to penicillin and cephalosporins.
• Anaerobic infections: Chloramphenicol + penicillin + an aminoglycoside can be used in severe anaerobic infections as an alternative to metronidazole and clindamycin.
• Rickettsial infections: As an alternative when tetracyclines are contraindicated.
• Eye and ear infections: Chloramphenicol eye drops → good penetration into aqueous humor. Ear drops are effective in infections of the external ear.
• Brain abscess: Brain abscess due to anaerobes responds to surgical drainage and a course of chloramphenicol.

Drugs used in the Treatment of Typhoid:

The incidence of typhoid or enteric fever caused by Salmonella typhimurium has been increasing and requires prompt treatment to avoid complications. The choice of antibiotic depends on the susceptibility of the microorganism.

Drugs for empirical treatment:

• Ceftriaxone—1–2 g/day IV for 7–14 days
• Azithromycin—1 g/day oral for 5 days

Other drugs (based on sensitivity report):

• Ciprofloxacin 500 mg BD for 5–7 days
• Amoxicillin—1 g TID oral for 14 days
• Chloramphenicol—25 mg/kg TID oral/IV for 14 days
• Cotrimoxazole (double strength)—BD oral for 7–14 days

Multidrug-resistant:

• Ciprofloxacin—500 mg BD for 5–7 days
• Ceftriaxone—2–3 g/day IV
• Azithromycin—1 g/day oral

Tigecycline

Tigecycline is a derivative of minocycline. It has a broad antibacterial spectrum including many methicillin and vancomycin-resistant strains of staphylococci, streptococci, multidrug-resistant enterococci, S. pneumoniae, anaerobes, Enterobacteriaceae, mycobacteria, rickettsiae, chlamydiae and

• Legionella. Tigecycline is thus effective against many gram-positive and gram-negative aerobes and anaerobes that are resistant to tetracyclines.
• Tigecycline is given IV—initial dose of 100 mg followed by 50 mg twice daily. It has a long t½ of 36 hours. Penetration and distribution into cells and tissues are very good.
• It is excreted through the gut and therefore, does not require dose reduction in renal dysfunction. Tigecycline can cause nausea and vomiting apart from other adverse effects of tetracyclines.

Tigecycline Uses:

As an alternative in life-threatening infections due to drug-resistant microorganisms and nosocomial pathogens including skin and skin structure infections, intra-abdominal infections and pneumonia.

Aminoglycosides

• Aminoglycosides (AGs) are antibiotics with amino sugars joined by glycosidic linkages.
• They are derived from the soil actinomycetes of the genus Streptomyces (streptomycin, kanamycin, tobramycin, neomycin) and the genus  Micromonospora (gentamicin and sisomicin)—hence the difference in spelling.
• Amikacin and netilmicin are semisynthetic products.

Aminoglycosides include:

• Streptomycin, gentamicin, tobramycin, kanamycin, paromomycin.
• Newer ones Amikacin, sisomicin, netilmicin.
• Topical Neomycin, framycetin.

Aminoglycosides Common Properties:

• All aminoglycosides contain amino sugars in glycosidic linkages.
• They are highly water-soluble, polar compounds.
• Not absorbed orally (as they ionize in solution)—all are given parenterally.
• They remain extracellularly and penetration into CSF is very poor.
• They are excreted unchanged by the kidneys.
• They are more active at alkaline pH.
• They are all bactericidal.
• They act by inhibiting bacterial protein synthesis.
• They are mainly effective against gram-negative organisms.
• All causes of ototoxicity and nephrotoxicity but severity varies.

Aminoglycosides Antibacterial spectrum:

• Narrow spectrum effective mainly against aerobic gram-negative bacilli like E. coli, Proteus, Y. pestis, Nocardia, V. cholera, Pseudomonas, Brucella,
• Salmonella, Shigella and Klebsiella.

Aminoglycosides Mechanism of action:

• Aminoglycosides, being water-soluble, penetrate the bacterial cell membrane through aqueous pores and reach the periplasmic spaces.
• They are taken up by an oxygen-dependent active transport into the cytoplasm.
• Inside the cell, aminoglycosides bind to 30S ribosomes and inhibit bacterial protein synthesis—block initiation of protein synthesis, cause termination of protein synthesis and cause the addition of wrong amino acids resulting in the synthesis of abnormal proteins. Aminoglycosides are bactericidal.

Aminoglycosides produce:

• Concentration-dependent killing: The higher the concentration in plasma, the greater is the bacterial effect.
• Postantibiotic effect: Remains even after the plasma levels of aminoglycosides fall. Hence, even though they have a short t½, they can be given once a day and avoid multiple injections.