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hydrolysed to the active chloramphenicol and there is much individual variation in the capacity to perform this reaction. Chloramphenicol is inactivated by conjugation with glucuronic acid in the liver (t'/2 5 h in adults). In the neonate, the process of glucuronidation is slow, and plasma concentrations are extremely variable especially in premature neonates (see below). Monitoring of plasma concentration is therefore essential if it is ever used in the neonate and infant, and in the adult with serious infection. Chloramphenicol penetrates well into all tissues, including the CSF and brain, even in the absence of meningeal inflammation.

Uses. The decision to use chloramphenicol for systemic infection is influenced by its rare but serious toxic effects (see below). Its role in meningitis and brain abscess has largely been superseded by broad-spectrum cephalosporins such as cefotaxime and ceftriaxone, but it is a second-line agent for these indications, and for haemophilus epiglottitis in children. Chloramphenicol may be used for salmonella infections (typhoid fever, salmonella septicaemia) but ciprofloxacin is now preferred. Topical administration is effective for bacterial conjunctivitis.

Adverse effects include gastrointestinal upset which tends to be mild. Optic and peripheral neuritis occur with prolonged use (which should be avoided) but are uncommon. The systemic use of chloramphenicol is dominated by the fact that it can cause rare (between 1:18 000-100 000 courses) though serious bone marrow damage. This is of two types:

1. a dose-dependent, reversible depression of erythrocyte, platelet and leucocyte formation that occurs early in treatment (type A adverse drug reaction);

2. an idiosyncratic (probably genetically determined), non-dose-related, and usually fatal aplastic anaemia which tends to develop during, or even weeks after, prolonged treatment, and sometimes on re-exposure to the drug ('type B' adverse reaction) (hence avoid repeated courses); this has also occurred, rarely, with eye drops.

Marrow depression may be detected at an early and recoverable stage by frequent checking of the full blood count.

The 'grey baby' syndrome occurs in neonates as circulatory collapse in which the skin develops a cyanotic grey colour. It is caused by high chloramphenicol plasma concentration due to failure of the liver to conjugate, and of the kidney to excrete the drug.

Sodium fusidate

Sodium fusidate is a steroid antimicrobial which is used almost exclusively against (^-lactamase producing staphylococci; it has little useful activity against Gram-negative bacteria. Because staphylococci may rapidly become resistant via a one-step genetic mutation, the drug should be combined with another antistaphylococcal drug, e.g. flucloxa-cillin. Sodium fusidate is readily absorbed from the gut and distributes widely in body tissues including bone. It is metabolised and very little is excreted unchanged in the urine; the t]/2 is 5 h.

Uses. Sodium fusidate is a valuable drug for treating severe staphylococcal infections, including osteomyelitis and is available as i.v. and oral preparations. In an ointment or gel, sodium fusidate is used topically for staphylococcal skin infection and as a cream is applied to eradicate the staphylococcal nasal carrier state. Another gel preparation is used for topical application to the eye: this contains such a high fusidic acid concentration that it possesses useful activity against most bacteria that cause conjunctivitis, not only staphylococci.

Adverse effects. It is well tolerated, but mild gastrointestinal upset is frequent. Jaundice may develop, particularly with high doses given intravenously, and liver function should be monitored.

Resistance to antimicrobials: quinupristin-dalfopristin and linezolid

These novel antibiotics were developed in response to the emergence of multiply resistant Gram-positive pathogens during the 1990s. Both have clinically useful activity against MRSA (including vancomycin intermediate resistant strains), vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae. They are currently reserved for treatment of infections caused by such bacteria and for use in patients who are allergic to more established antibiotics. Difficult decisions are being faced about how such novel but expensive antimicrobial agents should be used:

'No antibiotic should be used recklessly, however difficult it appears to be to select for resistance in vitro. On the other hand, the attitude that "All new antibiotics should be locked away" risks stifling innovation whilst denying life-saving treatments ... Debates on the use of new antiGram-positive agents are sure to intensify ... and it is vital that they take place on a basis of science not knee-jerk restrictions or over-zealous marketing.'4

They are inactive against most Gram-negative bacteria.

Quinupristin-dalfopristin is a combination of two streptogramin molecules: the dalfopristin component binds first to the 50S bacterial ribosome, inducing a conformational change which allows the additional binding of quinupristin. The combination results in inhibition of both aminoacyl-tRNA attachment and the peptidyl transferase elongation step of protein synthesis resulting in premature release of polypeptide chains from the ribosome. The summative effect is bactericidal. Acquired resistance is currently rare, but a variety of possible mechanisms of resistance have been reported including methylation of the 23S RNA molecule (also involved in erythromycin resistance), enzymatic hydrolysis and phosphorylation and efflux pumps. Most strains of Enterococcus faecalis are naturally resistant, but E. faecium strains are susceptible. Most Gram-negative bacteria have impermeable membranes and hence are resistant, but the respiratory pathogens Legionella pneumophila and Mycoplasma pneumoniae are susceptible.

4 Livermore D M. Quinupristin/dalfopristin and linezolid: where, when, which and whether to use? Journal of Antimicrobial Chemotherapy 2000 46: 347-350.

The t'/2 is 1.5 h. Quinupristin-dalfopristin is available for administration only by i.v. injection; the usual dose is 7.5 mg/kg x 8 h.

It is licensed in the UK for Enterococcus faecium infections, skin and soft tissue infection, and in hospital-acquired pneumonia.

Injection to peripheral veins frequently causes phlebitis, so a central line is required. Arthralgia and myalgia are seen in about 10% patients.

Linezolid, a synthetic oxazolinidone, is the first member of the first totally new class of antibacterial agents to be released to the market for 20 years. It has a unique mode of action, binding to the 50S ribosomal subunit and inhibiting formation of the initiation complex between transfer-RNA, messenger RNA and the ribosomal subunits at the first stage of protein synthesis. It is bacteriostatic against most Gram-positive bacteria, including staphylococci, streptococci and enterococci resistant to other antimicrobial agents, but is bactericidal against pneumococci.

Resistance has been reported so far in only a few enterococci isolated from immunocompromised patients treated with linezolid for long periods. The resistant isolates appeared to possess modified ribosomal RNA genes. Cross-resistance to other antibiotics has not yet been seen. Most Gram-negative bacteria are resistant by virtue of possessing membrane efflux pumps, but many obligate anaerobes are susceptible.

It is eliminated via both renal and hepatic routes (t'/2 6h) with 30-55% excreted in the urine as the active drug. Oral and parenteral formulations are available, and doses range from 400 to 600 mg 12-hourly by both routes; absorption after oral administration is rapid, little affected by food, and approaches 100%.

Linezolid is licensed in the UK for skin, soft tissue and respiratory tract infections, and it is usually restricted on grounds of cost to those caused by multiply resistant pathogens. The oral formulation may prove useful for follow-on therapy of severe and chronic infections caused by bacteria resistant to other agents, e.g. MRSA osteomyelitis.

Adverse effects include nausea, vomiting and headache with much the same frequency as with penicillin and macrolide therapy; marrow suppression may occur especially where there is pre

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