In this essay we will discuss about antibiotics and its types.
Essay # 1. Meaning of Antibiotics:
Antibiotics (Gk. anti = against, bios = life) constitute the major part of chemotherapeutic agents of modern times that are used for treatment of diseases. They were defined by S.A. Waksman in 1945 as chemical substances produced by microorganisms which can kill or inhibit growth of other microorganisms at a very low concentration.
This definition of an antibiotic is no longer strictly tenable because many antibiotics have been later chemically modified in the laboratory by the addition of extra chemical groups. In the light of this, antibiotics can now be defined as naturally produced microbial products or their derivatives that can kill or inhibit growth of other microorganisms at very low concentration.
The term ‘antibiotic’ was derived from ‘antibiosis’ which refers to the suppression of microorganisms due to secretion of toxic or inhibitory compounds by other microorganisms.
Although antibiosis has been observed by many scientific workers fairly frequently towards the end of the nineteenth century, it was not until the discovery and development of penicillin that a truly wide ranging search for antibiotics was initiated.
The search has resulted in the discovery of an amazing number of antibiotic substances, the majority of which have proved in tests on laboratory animals to be too toxic for them to be of any practical clinical value. But, a number of antibiotic substances have been found useful and entered into clinical use.
The use of antibiotics has saved millions of lives world over and has been the principal way of therapy for last few decades. There are more than 6,000 antibiotics, which have been isolated and purified from a variety of microorganisms, and 100-200 more are discovered every year.
There are about 100 major antibiotics which are in the market and in greater use. Over 100,000 tones of antibiotics are produced worldwide per year, with annual gross sales of about $ 5 billion. This also includes sale of $ 100 million of antibiotics which are used in animal feed and as animal growth promoters.
Essay # 2. Types of Antibiotics:
Antibiotics are soluble compounds that are derived from certain microorganism, and that inhibit the growth of other microorganisms.
Large numbers of chemically unrelated antibiotics are available, and they can be grouped under following heads:
a. β lactum group
b. Aminoglycosides
c. Tetracycline’s
d. Chloramphenicol
e. Macrolides
f. Miscellaneous antibiotics
a. β Lactum Antibiotics:
The β lactum antibiotics are the most commonly used antimicrobial agents because of their high potency, low incidence of serious adverse reactions, and proven effectiveness. The β lactum antibiotics contain a β lactum ring, which is the key structural feature essential for their antibacterial activity. The β lactum includes penicillin’s, cephalosporin’s and other β lactum antibiotics.
Penicillins:
The penicillin’s are bactericidal. They inhibit the synthesis of the bacterial cell wall by causing lysis of the bacterial cell membrane.
Pharmacokinetics:
Natural penicillin (benzylpenicilin) is broken down by the gastric acid, and is not effective orally. It is rapidly excreted by renal tubular secretion and the bactericidal levels are maintained for 4-6 hours after parenteral administration. Penicillin’s diffuse well into body tissues and fluids, but penetration in cerebrospinal fluid is poor except, when meninges are inflamed. They are excreted in urine in therapeutic concentrations. Probenecid blocks the renal tubular excretion of the penicillin, producing higher and more prolonged concentrations.
Antibacterial Spectrum:
Benzyl penicillin (penicillin G) is effective against a fairly wide range of organisms, the most common amongst which include spirochetes (Treponema pallidum, Borrelia and Leptospira), streptococci (groups A and B, viridans, and Streptococcus pneumoniae), enterococci, Neisseria spp. (gonococci, meningococci), Actinomyces, Clostridium spp. (C. perfringens, C. tetani) and a few staphylococci. However, penicillin G resistance is widespread among staphylococci; is increasing rapidly among gonococci, enterococci and pneumococci; and is emerging among meningococci, and viridans streptococci.
Therapeutic Uses:
Penicillin G remains among the drugs of choice for streptococcal infections (such as endocarditis, dental infections, throat infections, and erysipelas), meningococcal meningitis, syphilis, anthrax, actinomycosis and Listeria infections. It is also useful in pneumonia, gas gangrene, tetanus, yaws, leptospirosis, and for prophylaxis in rheumatic fever and in limb amputation. Penicillin G is generally given in doses of 1.2 g daily in 4 divided doses (2.4 g or more in severe cases) by intramuscular route or by intravenous infusion. It is contraindicated in penicillin hypersensitivity.
Adverse Effects:
The most important side effect of the penicillin is hypersensitivity, which causes rashes and anaphylaxis and can be fatal. Penicillin allergic patients occasionally have allergic reactions to cephalosporin. Penicillin, rarely, may cause encephalopathy due to cerebral irritation when very high doses are given or in patients with renal failure. This is the reason penicillin should not be given by intrathecal injection. Oral penicillin frequently causes diarrhea. Penicillin reduces the efficacy of oral contraceptives. The only contraindication to the use of penicillin is penicillin hypersensitivity.
Procaine Benzylpenicillin:
Procaine penicillin is a sparingly soluble salt of benzylpenicillin. It is used by intramuscular route and provides therapeutic blood levels up to 24 hours. It is the drug of choice for treatment of yaws and syphilis in doses of 2 ml (procaine benzylpenicillin 900 mg and benzylpenicillin sodium 180 mg) daily for 10-14 days in combination with probenecid.
Benzathine Penicillin:
Benzathine penicillin is a long acting IM repository form of penicillin G. The serum concentration of benzathine penicillin is so low that this preparation is used only for highly susceptible organisms, as with syphilis, streptococcal pharyngitis, and for prophylaxis against rheumatic fever.
In early latent syphilis one dose and in late latent syphilis three doses of 2.4 million units are given by deep intramuscular route. It is occasionally given for group A streptococcal pharyngitis and prophylaxis after acute rheumatic fever or post-streptococcal glomerulonephritis.
Benzyl penicillin has a narrow antibacterial spectrum, is orally ineffective and certain organisms develop resistance to its antibacterial action due to production of an enzyme penicillinase, which inactivates penicillin by hydrolysis of the β lactum ring. To overcome the disadvantages of natural penicillin G, a number of semisynthetic penicillins have been produced.
The available penicillins are:
i. Oral penicillin
ii. Penicillinase resistant penicillin
iii. Broad-spectrum penicillins
iv. Extended-spectrum penicillins (ureidopenicillins)
Oral Penicillin:
Phenoxymethyl penicillin (penicillin V) is less potent than penicillin G, but is gastric acid stable. It is used orally (250-500 mg 4 times a day) principally for group A streptococcal pharyngitis in children and for prophylaxis against rheumatic fever. It should not be used for severe infections.
Penicillinase Resistant Penicillins:
These are synthetic penicillins that are not inactivated by penicillinase and are used extensively for the treatment of infections caused by Staphylococcus aureus, such as otitis externa, impetigo, cellulitis and staphylococcal endocarditis. Flucloxacillin is not inactivated by penicillinase and is used extensively for treating infections caused by staphylococci, such as otitis externa, impetigo, cellulites, and staphylococcal endocarditis in doses of 250-500 mg every 6 hours orally or by injection.
Strains of staphylococci are emerging, which are even resistant to flucloxacillin. They are named methicillin (now discontinued) resistant Staphylococcus aureus (MRSA) and respond to only vancomycin or teicoplanin. Flucloxacillin, in addition to general side effects of natural penicillin, may cause cholestatic jaundice several weeks after stoppage of the treatment.
Nafcillin and oxacillin (2 g IV 4-6 hourly) are the synthetic penicillinase-resistant penicillins that are the drugs of choice for treating oxacillin-sensitive Staphylococcus (OSSA) infections. These drugs have little activity against enterococci or gram- negative bacteria. Dicloxacillin and cloxacillin are oral (250-500 mg 4 hourly) antibiotics with a spectrum of activity similar to that of naficillin and oxacillin and are typically used in the treatment of localized skin infections.
β Lactamase Inhibitors:
Clavulanic acid, sulbactum and tazobactum are substances that irreversibly bind lactamase (penicillinase) and, thus prevent the breakdown of lactum ring. β lactamase inhibitors have no significant antibacterial activity of their own, but are used in combination with broad spectrum and extended-spectrum penicillins against resistant organisms.
Broad Spectrum Penicillins:
These are amino penicillins and include ampicillin and amoxicillin. These penicillins tend to be active against many gram-negative bacilli and have the same activity as natural penicillin against gram- positive bacteria. They are effective against Salmonella, E. coli, Shigella and H. influenzae but are inactivated by penicillinase. Ampicillin is given orally or by injection. Orally, less than half is absorbed and absorption is further decreased by the presence of food in the gut. It is well excreted in the bile and urine.
Ampicillin (2-3 g IV 4-6 hourly) is the drug of choice for treatment of infections caused by susceptible enterococcus species and L. monocytogenes. Oral ampiciliin (250-500 mg orally 6 hourly) is useful in chronic bronchitis, otitis media, urinary infections and typhoid.
Ampicillin/sulbactum (1.5-3.0 g IV 6 hourly), a combination of ampiciliin and β lactamase inhibitor sulbactum is effective against OSSA, anaerobes and many Enterobacteriaceae. It is effective for the upper and lower respiratory tract, genitourinary tract, abdominal, pelvic, and polymicrobial soft-tissue infections. It is the IV antibiotic of choice for serious cellulites due to human or animal bites.
Amoxicillin is a derivative of ampicillin and has a similar antibacterial spectrum. It is better absorbed and its absorption is not affected by the presence of food in the stomach. It also produces higher plasma and tissue concentrations and is preferred to ampicillin.
Amoxicillin in doses of 250-500 mg orally every 8 hours is commonly used in chronic bronchitis, urinary infections, otitis media, sinusitis, dental infections and typhoid. Amoxicillin is also indicated along with gentamycin in endocarditis caused by enterococci and meningitis caused by Listeria and as an adjuvant for H. pylori eradication.
Amoxicilin/clavulanic acid (Augmentin) is an oral antibiotic similar to ampicillin/sulbactum and is used in doses of 2000 mg every 12 hourly as a step-down therapy from IV ampiciliin/ sulbactum.
It is useful for treating complicated sinusitis, otitis media, and skin infections and is the oral antibiotic of choice for prophylaxis in human and animal bites after appropriate local treatment. Broad spectrum penicillins give rise to gastrointestinal disorders, rarely antibiotic associated colitis and rashes.
Extended-Spectrum Penicillins (Ureido Penicillins):
The extended spectrum penicillins (ureido penicillin) have the antibacterial spectrum as ampiciliin, but are also effective against Pseudomonas aeruginosa and Proteus morgani. They are, however, inactivated by some β lactamases and are therefore not active against penicillin resistant Staphylococci. In addition they are also not very effective against other gram-positive organisms. They are not absorbed from the gut and must be given by injection.
Azlocillin, piperacillin and ticarcillin (4 g IV 6 hourly) have reasonable antipseudomal activity but generally require co- administration of an aminoglycoside for treatment of serious infections.
Ticarcillin/clavulanic acid combination extends the spectrum to include most Enterobacteriaceae, OSSA, and anaerobes, making it a useful antibiotic for intra-abdominal and complicated soft- tissue infections.
Piperacillin, is more active against P. aeruginosa than ticarcillin. Zosyn is a preparation that combines piperacillin with tazobactum (β lactamse inhibitor).
Extended-spectrum penicillins are reserved for serious infections with pseudomonas or when the causative organisms are not known. As these drugs are excreted via the kidney, the dose should be reduced in renal impairment.
Adverse Reactions of Penicillin’s:
Penicillins are generally free from toxic effects. However, they may cause rarely pain and abscess at the site of injection. More commonly, sensitization rashes occur either as a result of contact with the drug during or after systemic administration. The rash is often urticarial and is sometimes resistant to treatment. Broad spectrum penicillin’s may cause erythematous rash, which may even occur after the drugs have been stopped.
All penicillin’s can cause interstitial nephritis, anemia and leucopenia. Prolonged high dose therapy (>2 weeks) should be monitored with weekly serum creatinine and blood counts. Oxacillin/naficillin can cause jaundice. The most serious complication is an acute anaphylactic reaction with collapse which, though rare, can be fatal. All patients should be asked about penicillin allergy, and penicillin should not be used in patients with a reported serious penicillin allergy without prior skin testing or desensitization, or both.
Cephalosporins:
The cephalosporins are broad-spectrum antibiotics and consist of large group of antibiotics with marked differences in activity, pharmacokinetics and toxicity. Like penicillin, they also contain β lactum ring and are amenable to inactivation by the enzyme β lactamase. All currently available cephalosporins are devoid of activity against enterococci and oxacillin-resistant S. aureus (ORSA).
The first-generation cephalosporins have a spectrum that include penicillinase-producing, methicillin-susceptible Staphylococci and most Streptococci, but are not the drugs of choice for infections with gram-positive bacteria.
They have excellent activity against E. coli, K. pneumoniae, and P. mirabilis and are among the drugs of choice for community-acquired urinary tract infections. Cefazolin (1 -2 g IV/IM 8 hourly) is a parenteral preparation, while cefadroxil, cefalexin, and cefradine are oral preparations, which are given in doses of 500 mg every 6 hourly.
The parenteral second-generation cefalosporins extend the gram-negative spectrum of first generation compounds. No second- generation cephalosporin is active against Pseudomonas and Acinetobacter. The various second-generation agents have different activities and can be divided into above-the-diaphragm and below the-diaphragm agents.
Above the Diaphragm:
Cefuroxime (1.5 g IV/IM 8 hourly) and cefamandole (1-2 g IV/ IM 4-6 hourly) have good activity against gram-positive (Staphylococci and Streptococci) and gram-negative aerobes that include Klebsiella, Proteus, H. influnzae, and serratia and N. gonorrhoeae. They are not effective against B. fragilis.
They are useful in:
i. Skin/soft- tissue infections
ii. Community acquired pneumonia (cefuroxime)
iii. Complicated urinary tract infections
Below the Diaphragm:
Cefoxitin (1-2 g IV 4-8 hourly), cefotetan (1-2 g IV/IM 12 hourly) and cefmetazole (2 g IV every 6-12 hourly) do not have dependable activity against gram-positive organisms, but have an extended spectrum against gram-negative aerobes and anaerobes including B. fragilis.
They are useful for surgical prophylaxis and treatment of:
i. Intra-abdominal prophylaxis and infections
ii. Gynecological prophylaxis and infections
iii. Diverticulitis
iv. Pelvic inflammatory diseases.
Oral second-generation cephalosporin’s include cefuroxime axetil, cefprozil and cefaclor and are given in doses of 250-500 mg twice a day. They have fair activity against gram-positive cocci and H. influenzae and are widely used in outpatient therapy for otitis media, bronchitis, sinusitis, and lower respiratory tract infections, urinary tract infections, local soft-tissue infections and step-down therapy for pneumonia or cellulites responsive to parenteral cephalosporin’s.
Loracarbef is chemically classified as a carbapenem rather than a cephalosporin but is generally used for the same indications as the oral second-generation cephalosporins. The parenteral third-generation cephalosporins have broad coverage against enteric, aerobic gram-negative rods and retain significant activity against streptococci other than enterococci.
They have moderate anaerobic activity but do not reliably cover B. fragilis. Ceftazidine is the only third generation cephalosporin that is useful for treating serious P. aeruginosa infections. Several of these agents have substantial CNS penetration and are useful in treating meningitis.
Third-generation cephalosporins are not reliable for treatment of serious infections caused by organisms producing ampicillin-inducible beta-lactamases regardless of the results of susceptibility testing. These microbes should be treated with cefepime, carbapenems, or quinolones.
Ceftriaxone (1-2 g IV/IM 12-24 hourly), cefotaxime (1-2 g IV/IM 4-12 hourly), ceftazidime (1-2 g IV/IM 6 hourly), ceftizoxime (1-4 g IV/IM 8-12 hourly) and cefoperazone (2-4 g IV 12 hourly) are very similar to one another in spectrum and efficacy. They are used when the causative organism is not known (empiric therapy) or other antibacterial drugs are contraindicated.
Their main indications are:
i. Pyelonephritis, urosepsis and pneumonia (ceiriaxone or cefotaxime)
ii. Intra-abdominal infections in combination with metronidazole
iii. Gonorrhea and meningitis (ceftriaxone and cefotaxime)
iv. Osteomyelitis, septic arthritis, endocarditis and soft-tissue infections, if the organism has been identified.
Oral third-generation cephalosporins include cefpodoxime proxetil (100-400 mg), cefdinir (300 mg), ceftibuten (400 mg), and cefditoren pivoxil (200-400 mg). They are given twice a day for the treatment of bronchitis and complicated sinusitis, otitis media, and urinary tract infections. They can also be used as step- down therapy for pneumonia that is responsive to third-generation parenteral cephalosporins. Cefpodoxime can be used as single- dose therapy for uncomplicated gonorrhea.
The parenteral fourth-generation cephalosporin Cefepime (500 mg-2 g IV/IM 8-12 hourly) is a fourth generation cephalosporin with excellent all-round activity including P. aeruginosa and other bacteria producing β lactamases. It is routinely used for empiric therapy in febrile neutropenic patients. It is used for serious antibiotic-resistant gram-negative bacillary and some polymicrobial infections (involving gram-negatives and gram-positives) in most sites.
Mechanism of Action:
Cephalosporins, like penicillins, inhibit bacterial cell wall synthesis and are bactericidal.
Bacterial Resistance:
Cephalosporins are highly resistant to penicillinase. Some bacteria elaborate a β lactamase called cephalosporinase that acts on cephalosporin nucleus to destroy its antibacterial activity. However, many newer cephalosporins are resistant to cephalosporins.
Adverse Effects:
The principal side effect is hypersensitivity reactions and about 10% of patients, who are allergic to penicillin, will also be allergic to cephalosporins.
Gastrointestinal disorders are seen and rarely may lead to antibiotic associated colitis. Other side effects include blood disorders, hemorrhage due to interference with blood clotting factors and renal and hepatic impairment. Cephalosporins are contraindicated in hypersensitivity and porphyria.
Other β Lactum Antibiotics:
Aztreonam is only effective against gram negative aerobic bacteria including P. aeruginosa, N. meningitides, H. influenzae and N. gonorrhoeae. It has no activity against gram-positive organisms or anaerobes and should not be used for blind therapy. Usual dose is 1-2 g IV every 6-8 hours. It is useful in patients allergic to penicillin or cephalosporin, as no apparent cross reactivity is present. Adverse effects include GIT disorders, skin rashes, jaundice and hepatitis, and blood disorders.
Carbapenems:
Imipenem (500 mg-1 g IV/IM 6-8 hourly) and meropenem (1 g IV 8 hourly) are short acting and ertapenem (1 g IV 24 hourly) is long-acting carbapenem. They are bactericidal and act by interfering with cell wall synthesis.
Carbapenems have a broad antibacterial spectrum of activity, which includes most gram-positive and gram-negative bacteria, anaerobes as well as organisms producing ampicillin/cephalosporin lactamases. Notable bacteria that are resistant include ampicillin- resistant enterococci and oxacillin-resistant Staphylococcus aureus (ORSA).
Carbapenems are generally used for empiric treatment of antibiotic-resistant nosocomial (hospital acquired) infections at most body sites. Some of the common uses of carbapenems include severe polymicrobial infections, gangrene, intra-abdominal catastrophes, and sepsis in compromised patients. Meropenem is the drug of choice for the treatment of CNS infections.
Carbapenems should be avoided in patients with CNS pathology or renal insufficiency, as they may cause convulsions. Ideally, they are used unless no reasonable therapy is available. Cross-hypersensitivity is present with penicillin and like cephalosporin; carbapenems have been associated with anaphylaxis, nephritis, and blood disorders.
b. Aminoglycosides:
Streptomycin, kanamycin, neomycin, gentamycin, and tobramycin are naturally occurring aminoglycosides, whereas amikacin and netilmicin are semisynthetic derivatives developed for their activity against resistant strains. The aminoglycosides are active primarily against aerobic gram-negative bacilli. Tobramycin is the most active against/ aeruginosa whereas amikacin shows the least resistance.
Despite their potential for toxicity, they are used in combination with broad spectrum β lactum antibiotics in serious gram-negative bacillary infections. With β lactum antibiotics, gentamycin and streptomycin exhibit synergism against Staphylococci, Streptococci and Enterococci and such a combination therapy has proved to be highly effective in the treatment of endocarditis and bacterimia.
They have a number of common properties:
i. They are bactericidal and are generally used as a component of combination therapy
ii. They are not orally absorbed and have to be given by injection for systemic effects
iii. They are excreted by kidneys and accumulation may occur with impaired renal function
iv. They have potential ototoxicity and nephrotoxicity, especially in elderly and patients with renal failure
v. They impair neuromuscular transmission.
Antibacterial Spectrum:
Aminoglycosides are effective against a wide range of gram- positive and gram-negative organisms. Susceptible organisms include S. aureus, S. viridans, Enterococci, H. influenzae, Brucella abortis, E. coli, Proteus, Pseudomonas, and Klebsiella. Streptomycin is also effective against Mycobacterium tuberculosis (all forms of tuberculosis).
Aminoglycosides are not particularly effective against Streptococcus pneumoniae or Streptococcus pyogenes. Aminoglycosides are not effective against anaerobes and their activity is impaired in low pH/low oxygen environment of abscesses.
Mechanism of Action:
Aminoglycosides inhibit protein biosynthesis and are bactericidal. In normal cell RNA is bound to ribosomes, which are essential for protein synthesis. Aminoglycosides bind onto ribosomes, excluding the RNA and thus protein synthesis is inhibited. They also disrupt the bacterial cytoplasm membrane.
Bacterial Resistance:
Bacteria produce several enzymes that inactivate the aminoglycoside molecule. Amikacin and netilmicin are not affected by most aminoglycoside inactivating enzymes that cause bacterial resistance in some species.
Pharmacokinetics:
Aminoglycosides are not absorbed from the gut. They are distributed in all extracellular fluids, but tissue concentrations are low except in the kidney and ear. Penetration in the cerebrospinal fluid is poor unless the meninges are inflamed. Excretion is principally by glomerular filtration and accumulation occurs in renal impairment. All the aminoglycosides are more active in alkaline environment.
Gentamycin is the most widely used aminoglycoside. It is the drug of choice and used in:
i. Peritonitis and biliary tract cephalosporin resistant infections (with ampicillin)
ii. Endocarditis caused by Strept. viridans or Strep, faecalis and hospital acquired pneumonia (with penicillin)
iii. Meningitis caused by listeria (with amoxicillin)
iv. Acute pyelonephritis or prostatitis (with ampicillin)
v. Septicemia community or hospital acquired (with amoxicilin)
vi. Plague
vii. Purulent conjunctivitis – gentamycin eye drops.
It is given by intramuscular or intravenous and intrathecal injection or as eye/ear drops. Excretion is fairly rapid so that it is usually given three times daily.
Tobramycin is the most effective aminoglycoside against P. aeruginosa and can be used as an inhalational agent for adjunctive therapy for patients with cystic fibrosis or bronchiectasis complicated by P. aeruginosa infection.
Amikacin has the advantage over gentamycin in that it is less amenable to be inactivated by aminoglycoside inactivating enzymes and is principally indicated for the treatment of serious infections caused by gram-negative bacilli resistant to gentamycin. Amikacin has an additional unique role in Mycobacterial and Nocardia infections.
Netilmicin may cause less ototoxicity in those needing treatment for longer than 10 days and is also active against a number of gentamycin-resistant gram-negative bacilli.
Neomycin is too toxic for parenteral administration and can only be used topically for infections of the skin or mucous membranes or orally to reduce the bacterial population of the colon prior to bowel surgery or in hepatic failure.
Streptomycin is most commonly used for treating drug-resistant tuberculosis. Other indications for streptomycin (tularemia, brucellosis, plague) have largely been supplanted by gentamycin or other antibiotics.
Spectinomycin, which is not an aminoglycoside but does contain an aminocyclitol ring, is only occasionally used to treat gonorrhea, especially β lactamase -producing strains.
Adverse Effects:
Nephrotoxicity is the major adverse effect of aminoglycosides. It is reversible when detected early but can be permanent, especially in patients with tenuous renal function due to other medical conditions.
Ototoxicity (vestibular or cochlear) is also possible, if the treatment is prolonged for more than 14 days. Streptomycin is unique in that it causes more ototoxicity with a lower risk of nephrotoxicity. Aminoglycosides should be avoided during pregnancy, as they are ototoxic to the fetus.
c. Tetracyclines:
Tetracyclines have similar pharmacological properties. They are chlortetracycline, oxytetracycline, tetracycline, doxycycline and minocycline.
Mechanism of Action:
Tetracyclines are primarily bacteriostatic. They inhibit protein synthesis by binding to ribosomes.
Antibacterial Spectrum:
Tetracyclines are broad spectrum antibiotics. They inhibit not only the bacteria, but also some of the large viruses. The important organisms, which respond to tetracyclines include H. influenzae, Strep, pneumoniae, Mycoplasma, Chlamydia, Rickettsia, Nocardia, Brucella abortus, Treponema pallidum. However, their general use is limited because of widespread resistance among most common bacterial pathogens.
Pharmacokinetics:
Tetracyclines are well absorbed from the GIT, particularly from the stomach and upper small intestine. Blood levels are maintained with 6-hourly doses. Absorption is decreased by milk, antacids and calcium, iron and magnesium salts. They are widely distributed into body fluids. The penetration, across the meningeal barrier into CSF is variable (about 20%), unless the meninges are inflamed. They undergo enterohepatic circulation and are primarily excreted via the kidneys, although there is some fecal excretion. Tetracyclines are deposited in growing bones and teeth, causing staining and dental hyperplasia.
Doxycycline and minocycline are slowly excreted, so that only one dose is required daily. Unlike, other tetracyclines, doxycycline and minocycline absorption is not affected by food and calcium. Doxycycline does not exacerbate renal failure and can be used when renal function is impaired.
Therapeutic Uses:
Tetracycline and oxytetracycline are given in doses of 250-500 mg every 6 hours, while doxycycline and minocycline are given in doses of 100-200 mg once a day. Chlortetracycline is only available as eye drops or as an ointment.
Tetracyclines, because of their broad spectrum bacteriostatic activity, which includes not only bacteria but also some of the larger viruses and some other groups of organisms, are widely used in a variety of community-acquired infections. However, with some bacteria, resistant strains have emerged, which limit their use.
The main uses for the tetracyclines at present are chronic bronchitis, sexually transmitted diseases such as non-gonococcal urethritis, granuloma inguinale, and lymphogranuloma venereum, and for rickettsial infections, Lyme disease, and brucellosis (with streptomycin or rifampicin). The tetracyclines are also used in penicillin-allergy patients for the treatment of leptospirosis, syphilis, actinomycosis, and skin and soft-tissue infections caused by gram-positive cocci.
Doxycycline is the most commonly used tetracycline and is standard therapy for C. trachomatis, Rocky Mountain spotted fever, ehrlichiosis, and psittacosis. It has also a role for malaria prophylaxis and for treatment of community-acquired pneumonia.
Minocycline is similar to doxycycline in its spectrum of activity and clinical indications. It is second-line therapy for pulmonary nocardiosis and cervicofacial actinomycosis.
Adverse Effects:
The most common side effect of tetracyclines is super-infection due to their broad antibacterial spectrum, which causes considerable changes in the bacterial flora in the intestine and elsewhere. This may result in antibiotic associated colitis, due to multiplication of resistant organisms, usually a Staphylococcus. Candida is the other troublesome organism, which may emerge causing “thrush” in the mouth or vaginal candidiasis.
Tetracyclines damage and colour developing teeth and depress bone growth and should be avoided from the fourth month of pregnancy until the child is 12 years old.
Other toxic effects include exacerbation of renal failure, rarely skin rashes and drug sensitisation.
Doxycycline can be used in renal impairment.
d. Chloramphenicol:
Chloramphenicol (Chloromycetin) is a bacteriostatic broad spectrum antibiotic, closely related in its action to tetracyclines. It is given orally. Unlike tetracyclines, it crosses the meningeal barrier and diffuses widely into the CSF. It is excreted via the kidneys.
Chloramphenicol has the antibacterial spectrum like tetracyclines, with the important addition of Salmonella and Paratyphoid organisms.
Therapeutic Uses:
Chloamphenicol is a reserved antibiotic, and is exclusively used in life threatening vancomycin-resistant E. faecium infections. It is also used in meningitis caused by susceptible organisms in penicillin-allergic patients, because of its excellent CNS penetration.
Ciprofloxacin is the preferred antibacterial drug, because lack of serious toxic effects and emergence of chloamphenicol resistant organisms. Chloramphenicol is commonly used in superficial eye infections and otitis externa as drops.
Adverse Effects:
The most serious toxic effect of chloramphenicol is bone marrow depression. Aplastic anemia, though rare, is always fatal. In premature neonates and infants, chloramphenicol can cause a dose related “grey syndrome” that is characterised by cyanosis, hypotension, and death and results from an inability of the newborn to metabolise the drug. These potentially serious toxicities and the availability of newer drugs have substantially reduced the indications for chloramphenicol.
e. Macrolides:
This group of antibiotics consists of erythromycin, azithromycin, clarithromycin, and dirithromycin.
Mechanism of Action:
The macrolides inhibit bacterial protein synthesis by binding to ribosomes of sensitive microorganisms. They are bacteriostatic, but can be bactericidal in some situation.
Pharmacokinetics:
Erythromycin is absorbed rather erratically and diffuses into most body tissues except cerebrospinal fluid. It is concentrated in the liver and is excreted primarily in bile and faeces.
Antibacterial Spectrum:
Erythromycin has an antibacterial spectrum that is similar but not identical to penicillin. It is effective against some strains of S. aureus that are penicillin G resistant, Strep. pyogenes, Strep. pneumoniae, Strep. viridans, M. catarrhalis, Legionella, Mycoplasma pneumoniae, Chlamydia and atypical Mycobacteria.
It is, however, not always effective against H. influenza, a common cause of respiratory infection. Bacteria readily become resistant to erythromycin, but do not show cross-resistance to other antibiotics.
Therapeutic Uses:
Erythromycin (250-500 mg orally or 0.5-1.0 g IV every 6 hours) possesses activity against gram-positive cocci (except enterococci) and can be used to treat bronchitis, pharyngitis, sinusitis, otitis media, and skin-soft tissue infections in penicillin allergic patients. It is effective for treatment of atypical respiratory tract infections.
It is, however, not always effective against H. influenzae, a common cause of the respiratory infection. Erythromycin is also used for treatment of Chlamydia trachomatis infections (500 mg orally every 6 hours for 7 days) and as an alternate therapy for syphilis in penicillin allergic patients.
Clarithromycin (250-500 mg oral twice daily) has the same antibacterial activity as erythromycin, but a higher concentration is found in the tissues and has enhanced activity against H. influenza species than erythromycin. It has the same uses against infections caused by gram-positive cocci as erythromycin.
Clarithromycin has a unique role in the treatment and prophylaxis of Mycobacterium avium complex infections in HIV patients and is an important component of regimens used to eradicate H. pylori infections in peptic ulcer.
Azithromycin (500 mg) appears to be similar to clarithromycin; but with a long half-life; one oral daily dose is adequate. It is also commonly used to treat C. trachomatis infection (1 g single dose). Another advantage of azithromycin is that it does not have the numerous drug interactions seen with erythromycin and clarithromycin.
Dirithromycin (500 mg) has a similar spectrum of activity and clinical application as erythromycin with the convenience of oral once-a-day dosing. Like azithromycin, it also does not have the numerous drug interactions.
Adverse Effects:
Marolides are well tolerated, but can cause vomiting and diarrhea and rarely jaundice (particularly erythromycin), if injected. Intravenous administration is liable to cause thrombophlebitis.
Drug Interactions:
Erythromycin and clarithromycin inhibit the hepatic metabolism of a large number of drugs, resulting in an increase in their plasma concentrations and consequent toxicity. Some of the drugs whose plasma concentration is increased by these macrolides include analgesics (alfentanil), anticoagulants (warfarin), antiepileptics (carbamzepine), antihistamines (terfenadine), anxiolytics and hypnotics (midazolum and zopiclone), calcium antagonists, cardiac glycosides, cisapride, ergotamine, and theophylline.
f. Miscellaneous Antibiotics:
Clindamycin (150-450 mg orally 4 times or 600-900 mg IV 8 hourly) is effective against many gram-positive organisms similar to that of erythromycin. Unlike macrolides, clindamycin is active against most anaerobes, including B. fragilis. It inhibits bacterial protein synthesis and essentially has a bacteriostatic action. Clindamycin has excellent oral bioavailability and appears to penetrate into bone and abscesses.
The important indications of clindamycin are:
i. Aspiration pneumonia and lung abscesses
ii. ORSA and streptococal infections
iii. Osteomyelitis
iv. Anaerobic infections (peritosillar/retropharyngeal abscesses, necrotising fascitis). For intra-abdominal infections, metronidazole is preferred because of its more reliable activity against B. fragilis.
v. Toxoplasmosis (with pyrimethamine)
vi. Pneumocystis crainii (with primaquine)
Side effects are not common; diarrhea may be a problem and rarely takes the form of a serious colitis (pseudomembranous colitis). Clindamycin enhances the actions of non-depolarising muscle relaxants and antagonises the effect of neostigmine and pyrodostigmine.
Sodium fusidate, the salt of fusidic acid, is a narrow spectrum antibiotic active against penicillin resistant Staphylococci. It is given orally in doses.of 0.5-1 g every 8 hours in osteomyelitis and Staphylococcal endocarditis.
A second antistaphylococcal antibiotic (flucloxacillin) is usually combined to prevent emergence of resistance. Sodium fusidate is relatively free of side effects, though high doses may cause jaundice, which recovers when the treatment is stopped.
Vancomycin is bactericidal for most aerobic and anaerobic gram-positive bacteria, particularly Staphylococci and Streptococci and bacteriostatic for Enterococci. It is not effective orally for systemic infections and is given by slow intravenous infusion in doses of 1 g every 12 hours.
The most serious problem with vanomycin is the emergence of vacomycin-resistant E. faecium and vancomycin-resistant Staphylococcus aureus. To avoid it, vancomycin should not be used routinely for surgical prophylaxis, empiric therapy for nonspecific neutropenic fever, minor localized infections (e.g. cellulitis, carbuncle) and in topical application or irrigation.
The main indications for its use include:
i. Serious infections caused by oxicillin-resistant Staphylococcus aureus
ii. Serious infections caused by ampicillin-resistant Enterococci
iii. Serious infections caused by gram-positive bacteria in patients allergic to all other antibacterial drugs
iv. Oral treatment of pseudomembranous colitis that has not responded to metronidazole
v. Empirically in suspected gram-positive meningitis along with third generation cephalosporins
vi. ORSA endocarditis
Adverse Effects:
Vancomycin is ototoxic and nephrotoxic, and is often given slowly (lasting for at least 1 hour) into a central vein as it can cause venous thrombosis. Rapid IV infusion of vancomycin can cause “red-man syndrome”, which is a histamine-mediated reaction that is typically manifested by flushing and redness of the upper body.
Drug Interactions:
Anaesthetics with concomitant vancomycin infusion can cause hypersensitivity-like reactions. Aminoglycosides, capreomycin and loop diuretics increase the risk of ototoxicity and nephrotoxicity.
Teicoplanin is very similar to vancomycin, but has a longer duration of action, can also be given by intramuscular injection and has considerably less adverse effects. It is used for potentially serious infections such as Staph, aureus, for dialysis-associated peritonitis and in orthopedic surgery where there is a risk of infection with gram-positive organisms.
Adverse Effects:
Teicoplanin may cause angioedema, anaphyiaxis, blood disorders, hearing loss and injection abscesses. It is contraindicated in pregnancy, breast-feeding, and renal impairment and in patients with adverse effects with vancomycin.
Polymyxin is effective against a wide range of gram-negative organisms including P. aeruginosa. It is not absorbed by mouth and is rarely used for systemic effects, because of its toxicity. It is particularly useful in topical applications for the eye and ear infections.
Colistin is active against gram-negative bacteria such as P. aeruginosa. It is not absorbed orally, and is only used with antifungal nystatin for bowel sterilisation in neutropenic patients.
Quinupristin and dalfopristin. This is a mixture of two antibiotics. The antibacterial spectrum consists of antibiotic resistant gram-positive organisms, especially vancomycin-resistant E. faecum and S. aureus. ORSA and antibiotic resistant strains of Strept. pneumoniae. It is ineffective against E. faecalis.
Quinupristin/dalfopristin is used via an IV infusion into central vein in serious infections caused by gram-positive organisms resistant to vancomycin as an alternative treatment. Most common side effects are arthralgia and myalgia, which may require discontinuation of therapy. Drug interactions are similar to those with erythromycin.
Linezolid is effective against antibiotic-resistant gram-positive organisms, especially vancomycin-resistant E. faecium and S. aureus. ORS A, and Strep, pneumoniae. Its use should be restricted to serious infections in patients, who are intolerant to vancomycin.
Linezolid is well absorbed orally (bioavailability 90%) and can be given by oral or IV route. Linezolid is well tolerated and its principal side effects are diarrhea, nausea, disturbances of taste and headache. Rarely, it may cause hypertension, tinnitus and various blood disorders.
Linezoid is contraindicated in breast-feeding and with other monoamine oxidase inhibitor drugs.
Daptomycin is available only for IV administration. It has a rapid bactericidal activity against a wide variety of gram-positive organisms including Enterococci, Staphylococci Streptococci. It is effective against the bacteria which have become resistant to oxacillin and vancomycin. Presently, the use of the drug is mainly confined to treatment of complicated skin and soft-tissue infections.
The common side effects include muscle weakness and pain which may necessitate discontinuation of the drug. Fostomycin is bactericidal against most urinary tract pathogens that include P. aeruginosa, Enterobacter spp., and vancomycin- resistant Enterococci. It is used as a single-dose therapy for treatment of uncomplicated lower urinary-tract infections, particularly in women. Diarrhea is the most common side effect.
Mupirocin is available only as a topical antibiotic for use against staphylococci and streptococci. Its major applications are for impetigo and for eradication of the staphylococcal carrier state. It is the drug of choice for the elimination of carriage of both methicillin-susceptible and methicillin-resistant Staphylococci.