Cefaclor
Cephamandole
Ceftriaxone
Cefpodoxime
Cefsulodin
Cephalexin
Cephalexin is active against most Gram-positive cocci, except fecal streptococci and MRSA. It is also moderately active against some enterobacteria (including Escherichia coli). It has negligible activity against Haemophilus influenzae.
Cephalexin is stable to gastric acid and almost completely absorbed when given by mouth, and 10% is protein-bound. There is reasonable penetration into bone and purulent sputum. It is almost entirely excreted in the urine, with a half-life of 50 minutes.
Cephalexin occasionally causes hypersensitivity, diarrhoea and abdominal discomfort, and rarely Stevens–Johnson syndrome.
Cefuroxime
Cefuroxime is more active than cephalexin against most of the Enterobacteriaceae, and has useful activity against Haemophilus influenzae. It is similar to cephalexin against Gram-positive cocci. It is not absorbed from the intestinal tract and is usually administered intravenously. It is well distributed, but cerebrospinal fluid levels are not sufficient to treat bacterial meningitis. It is excreted unchanged in the urine, one-half being the result of tubular secretion, with a half-life of 80 minutes.
Cefuroxime is used in the treatment of urinary, soft-tissue, bone, intra-abdominal and pulmonary infections and septicaemia. It is ineffective against faecal streptococci and most anaerobes. Its use in surgical prophylaxis has been discouraged in recent years because of the association between cephalosporins and C. difficile-associated diarrhoea.
Cefotaxime
Cefotaxime is similar to cefuroxime but with much greater activity against many Gram-negative bacteria (e.g. coliforms and Gram-negative cocci including β-lactamase-producing strains). It is usually active against penicillin-resistant strains of Streptococcus pneumoniae. It has only moderate activity against Listeria monocytogenes (amoxicillin must be added if meningitis or septicaemia with this organism is suspected) and limited efficacy against anaerobes (requiring the addition of metronidazole if polymicrobial sepsis is considered likely). It has minimal activity against Pseudomonas aeruginosa.
Cefotaxime is administered intravenously. Unlike other cephalosporins, it is metabolised in the body to desacetyl-cefotaxime, and both the parent compound and metabolite are renally excreted. It has an elimination half-life of 80 minutes.
Cefotaxime has a very wide range of indications, including lower respiratory infections, septicaemia, meningitis, intra-abdominal sepsis, osteomyelitis, pyelonephritis, neonatal sepsis and gonorrhoea.
Ceftriaxone
Ceftriaxone is almost identical to cefotaxime in terms of its spectrum of activity and is prescribed for similar infections. However, it has a much longer serum half-life, allowing for once- or twice-daily dosing schedules. Because of this it is often used in the outpatient and home intravenous therapy setting for the management of difficult skin/soft-tissue infections.
Cefixime
Cefixime is an oral third-generation cephalosporin. Intestinal absorption remains relatively poor and it has a limited role in the hospital setting.
Ceftazidime
Ceftazidime is similar to cefotaxime but much more active against Pseudomonas aeruginosa. It is less active against Gram-positive cocci than other cephalosporins.
It is 17% protein-bound. Distribution of the drug around the body is similar to cefotaxime. It is mainly excreted renally, with a half-life of 2 hours.
It tends to be reserved for use as an anti-pseudomonal agent.
Cefpirome
Cefpirome is a fourth-generation cephalosporin similar to ceftazidime utilised for Gram-negative bacteria including Pseudomonas aeruginosa. 10% is protein bound and 80% is renally excreted with a half-life of 2 hours.
Ceftaroline
Ceftaroline is a fifth-generation cephalosporin active against MRSA and Gram-positive bacteria.
Carbapenems
Examples – ertapenem, imipenem, meropenem
Carbapenems are bicyclic β-lactam compounds with a carbapenem nucleus. Their mechanism of action is similar to that of other β-lactam antibiotics but they seem to have a greater affinity for penicillin-binding protein 2 (PBP-2). This results in faster bacterial death and, in theory, less endotoxin release. They are extremely broad-spectrum antibiotics, because they are resistant to most β-lactamases (including the newer ESBLs). They are, however, susceptible to the recently described metallo-β-lactamases, which are beginning to threaten their efficacy in several parts of the world including India and the Middle East.
Pharmacokinetics
Carbapenems are administered intravenously. Excretion is predominantly by glomerular filtration. Carbapenems exhibit a phenomenon known as the post-antibiotic effect. This is a prolonged inhibition of bacterial growth for a period of time after the concentration of antibiotic has fallen below the accepted minimum inhibitory concentration (MIC). Therefore 6-, 8- and even 12-hourly dose regimes can be effective.
Adverse effects
Adverse effects are similar to those of other β-lactams. Neutropenia is a rare complication and is reversible on stopping the drug. Neurotoxicity appears to be more of a problem than with other β-lactam antibiotics but is primarily seen in patients with renal insufficiency and on high doses, particularly neonates and the elderly.
Imipenem
Imipenem is chemically unstable in its natural form and is supplied in crystalline form. It is highly active against virtually all Gram-positive and Gram-negative pathogenic bacteria, including anaerobes. Poor intracellular penetration of eukaryotic cells prevents its use against intracellular infections such as Legionella. It is rapidly bactericidal against a majority of organisms but is only bacteriostatic against faecal streptococci. MRSA is not susceptible, and Pseudomonas aeruginosa can rapidly develop resistance.
Imipenem is rapidly destroyed by dehydropeptidase 1 in renal tubules. It is administered with cilastatin, a selective competitive inhibitor of this enzyme. Cilastatin has similar pharmacokinetic properties to imipenem, and inhibition of dehydropeptidase has no apparent adverse physiological consequences.
Meropenem
Meropenem is similar to imipenem but is stable to human renal dehydropeptidase, rendering the addition of cilastatin unnecessary. It is more active than imipenem against some Gram-negatives but less active against Gram-positives. The main benefit is that it is less neurotoxic than imipenem.
Monobactams
Example – aztreonam
Monobactams have only a single β-lactam ring, while penicillins, cephalosporins and carbapenems all have two. Note that only Gram-negative aerobic bacteria are sensitive. Aztreonam is highly active against most of the Enterobacteriaceae, Haemophilus influenzae and Neisseria, and has some activity against Pseudomonas aeruginosa.
Pharmacokinetics
Intestinal absorption is poor, so aztreonam is given by intravenous or intramuscular injection. Distribution in the body is similar to that of other β-lactams. Elimination is renal, by a combination of glomerular filtration and tubular secretion. Aztreonam has a half-life of 2 hours.
Adverse effects
Aztreonam is similar to other β-lactams. However, as a monobactam, there appears to be very little cross-hypersensitivity with penicillins or cephalosporins. Aztreonam should still be used with caution in patients with severe penicillin allergy. Aztreonam does not seem to interfere with platelet function, unlike some cephalosporins and penicillins.
Glycopeptides and lipopeptides
Examples – teicoplanin, vancomycin (glycopeptides); daptomycin (lipopeptide)
The glycopeptides are a group of complex, high-molecular-weight compounds that are usually slowly bactericidal and prevent bacterial cell wall synthesis at the substrate level. Glycopeptides are active against most Gram-positive bacteria but they do not penetrate the outer membrane of Gram-negative organisms because they are large polar molecules.
Acquired resistance
Acquired resistance is uncommon. Gene mutations occur, which alter cell-wall precursors. These precursors are called Van-A (which produces resistance to both vancomycin and teicoplanin and is inducible and present on plasmids – allowing transfer between strains), Van-B and Van-C (which produce resistance to vancomycin only and are present on bacterial chromosomes – less easy to transfer to other species). Resistance has been reported principally in various Enterococcus species, which have been named vancomycin-resistant enterococci (VRE). The mechanism of resistance is not entirely clear.
The presence of mucopolysaccharide slime reduces the susceptibility of coagulase-negative staphylococci. This is often present when there are microcolonies on the surfaces of joint and heart valve prostheses or on intravenous and peritoneal dialysis cannulae.
Vancomycin
Vancomycin is used to treat difficult Gram-positive bacterial infections including MRSA, staphylococcal or streptococcal infective endocarditis, coagulase-negative staphylococci on indwelling materials and antibiotic-associated colitis (Clostridium difficile).
Spectrum of activity
Vancomycin is effective against Gram-positive cocci (including MRSA), coagulase-negative staphylococci (e.g. Staphylococcus epidermidis), streptococci, enterococci, bacilli, corynebacteria, Listeria monocytogenes (moderate), and Gram-positive anaerobes (Clostridium perfringens and other Clostridia spp. including C. difficile). Resistance is sometimes encountered in enterococci (VRE strains), which can cause line-associated bacteraemias.
Pharmacokinetics
Vancomycin is administered intravenously, because intestinal tract absorption is poor and intramuscular injection causes pain and necrosis. Protocols for continuous infusion are available but there seems to be little difference in efficacy between twice-daily short-duration infusions (1–2 hours depending on dose) and continued infusion therapy.
It is widely distributed, reaching most body compartments except the cerebrospinal fluid. It may also be administered into CSF shunts and into the peritoneum, and for antibiotic-associated colitis it is given orally. It is occasionally administered by intravitreal injection for difficult eye infections.
When given by the oral route it remains mainly in the intestinal tract. It is an effective oral treatment for C. difficile-associated colitis.
Vancomycin is 55% protein-bound. It is excreted, unchanged, mainly by glomerular filtration, with a half-life of 6–8 hours. Plasma monitoring is normally performed on pre-dose serum but is required mainly in those with renal impairment or on prolonged high-dose regimes. Note that it is not removed effectively by either haemodialysis or haemofiltration. When it is given orally for C. difficile infection, monitoring of blood levels is not normally required unless given in high doses for an extended period to patients with severe renal impairment.
Adverse effects
Adverse effects include hypersensitivity, nephrotoxicity, ototoxicity and occasionally neutropenia. Chemical thrombophlebitis is relatively common when vancomycin is administered via a peripheral vein. Vancomycin-induced histamine release with rapid infusion produces the ‘red man syndrome’. This comprises itching, flushing, angio-oedema, hypotension and tachycardia. Bronchospasm does not occur. It normally resolves within 1 hour of the infusion stopping. It is prevented by antihistamines. The hypotensive effect may be severe. Nephrotoxicity and ototoxicity may be related to impurities in earlier preparations, and are now rare.
Teicoplanin
Teicoplanin has slightly greater activity against some streptococci and slightly less activity against staphylococci than vancomycin. It is distributed similarly to vancomycin but is more protein-bound (> 90%). The serum half-life is considerably longer (47 hours) than that of vancomycin, partly because of the protein binding. It may be given by rapid IV infusion or intramuscularly. It is less toxic than vancomycin but, for difficult-to-treat infections, periodic serum levels (pre-dose) are advised to ensure adequate concentrations are being achieved.
Daptomycin
Daptomycin is a cyclic lipopeptide. It is generally more active than glycopeptides against a range of Gram-positive bacteria, including some vancomycin-resistant enterococci (VRE). Most significantly, it is more rapidly bactericidal than either vancomycin or teicoplanin. It does not have activity against Gram-negative bacteria.
Aminoglycosides
Examples – amikacin, gentamicin, netilmycin, streptomycin, tobramycin
Aminoglycosides are naturally occurring or semisynthetic polycationic compounds with aminosugars glycosidically linked to aminocyclitols.
Mechanism of action
Aminoglycosides bind to the 30S subunit of the bacterial ribosome, causing inhibition of protein synthesis. It is not known why aminoglycosides are usually rapidly bactericidal, whereas other inhibitors of protein synthesis are bacteriostatic. Aminoglycosides cause cell-membrane leakiness and consequent cell death. In general, aminoglycosides are active against Staphylococcus aureus, a majority of the coagulase-negative staphylococci, the Enterobacteriaceae, and most are effective against Pseudomonas aeruginosa and other Pseudomonas spp.
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