12 Antibacterial drugs SYNOPSIS The range of antibacterial drugs is wide and affords the clinician scope to select with knowledge of the likely or proved pathogen(s) and of factors relevant to the patient, e.g. allergy, renal disease.Antibacterial drugs are here discussed in groups primarily by their site of antibacterial action and secondly by molecular structure, because members of each structural group are usually handled by the body in a similar way and have the same range of adverse effects. Table I I. I (p. 21 I) is a general reference for this chapter. Classification INHIBITION OF CELL WALL SYNTHESIS (3-lactams, the structure of which contains a (3- lactam ring. The major subdivisions are: (a) penicillins whose official names usually include or end in 'cillin' (b) cephalosporins and cephamycins which are recog- nised by the inclusion of 'cef' or 'ceph' in their official names. In the UK recently all these names have been standardised to begin with 'cef'. Lesser categories of (3-lactams include — carbapenems (e.g. meropenem) — monobactams (e.g. aztreonam) and — p-lactamase inhibitors (e.g. clavulanic acid). Other inhibitors of cell wall synthesis include vancomycin and teicoplanin. INHIBITION OF PROTEIN SYNTHESIS Aminoglycosid.es. The names of those that are derived from streptomyces end in 'mycin', e.g. tobramycin. Others include gentamicin (from Micro- monospora purpurea which is not a fungus, hence the spelling as 'micin') and semisynthetic drugs, e.g. amikacin. Tetracyclines as the name suggests are four-ringed structures and their names end in '-cycline'. Macrolides: e.g. erythromycin. Clindamycin, struc- turally a lincosamide, has a similar action and overlapping antibacterial activity. Other drugs that act by inhibiting protein syn- thesis include quinupristin-dalfopristin, linezolid, chloramphenicol and sodium fusidate. INHIBITION OF NUCLEIC ACID SYNTHESIS Sulphonamides. Usually their names contain 'sulpha' or 'sulfa'. These drugs, and trimethoprim, 215 12 ANTIBACTERIAL DRUGS with which they may be combined, inhibit synthesis of nucleic acid precursors. Quinolones are structurally related to nalidixic acid; the names of the most recently introduced members of the group end in '-oxacin', e.g. cipro- floxacin. They act by preventing DNA replication. Azoles all contain an azole ring and the names end in '-azole', e.g. metronidazole. They act by the production of short-lived intermediate compounds which are toxic to DNA of sensitive organisms. Rifampicin inhibits bacterial DNA-dependent RNA polymerase. Antimicrobials that are restricted to certain speci- fic uses, i.e. tuberculosis, urinary tract infections, are described with the treatment of these conditions in Chapter 13. Inhibition of cell wall synthesis (3-lactams PENICILLINS Benzylpenicillin (1942) is produced by growing one of the penicillium moulds in deep tanks. In 1957 the penicillin nucleus (6-amino-penicillanic acid) was synthesised and it became possible to add various side-chains and so to make semisynthetic penicil- lins with different properties. It is important to recognise that not all penicillins have the same antibacterial spectrum and that it is necessary to choose between a number of penicillins just as it is between antimicrobials of different structural groups, as is shown below. A general account of the penicillins follows and then of the individual drugs in so far as they differ. Mode of action. Penicillins act by inhibiting the enzymes (Penicillin Binding Proteins, PBPs) in- volved in the crosslinking of the peptidoglycan layer of the cell wall which protects the bacterium from its environment; incapable of withstanding the osmotic gradient between its interior and its environment the cell swells and ruptures. Penicillins are thus bactericidal and are effective only against multiplying organisms because resting organisms are not making new cell wall. The main defence of bacteria against penicillins is to produce enzymes, (Mactamases, which open the (3-lactam ring and terminate their activity. Other mechanisms that have been described include modifications to PBPs to render them unable to bind pMactams, reduced permeability of the outer cell membrane of Gram- negative bacteria, and possession of pumps in the outer membrane which remove |3-lactam molecules that manage to enter. Some particularly resistant bacteria may possess several mechanisms that act in concert. The remarkable safety and high therapeu- tic index of the penicillins is due to the fact that human cells, while bounded by a cell membrane, lack a cell wall. They exhibit time-dependent bacterial killing (see p. 203). Narrow spectrum (natural penicillins) Antistaphylococcal penicillins ((3-lactamase resistant) Broad spectrum Mecillinam Monobactam (active only against Gram-negative bacteria) Antipseudomonal Carboxypenidllin Ureidopenicillin Penicillin-p-lactamase inhibitor combinations Carbapenems benzylpenicillin, phenoxymethylpenicillin cloxacillin, flucloxacillin ampicillin, amoxicillin, bacampicillin. pivmecillinam aztreonam' ticarcillin piperacillin co-amoxiclav, piperacillin-tazobactam, ticarcillin-clavulanate meropenem, imipenem-cilastatin Pharmacokinetics. Benzylpenicillin is destroyed by gastric acid and is unsuitable for oral use. Others, e.g. phenoxymethylpenicillin, resist acid and are absorbed in the upper small bowel. The plasma t 1 /, of penicillins is usually < 2 h. They are distributed mainly in the body water and enter well into the 1 While not strictly a penicillin, it has a similar spectrum of action including some antipseudomonal activity. 216 P-LACTAMS _12 CSF if the meninges are inflamed. Penicillins are organic acids and their rapid clearance from plasma is due to secretion into renal tubular fluid by the anion transport mechanism in the kidney. Renal clearance therefore greatly exceeds the glomerular filtration rate (127 ml/min). The excretion of penicillin can be usefully delayed by concurrently giving probenecid which competes successfully for the transport mechanism. Dosage of penicillins may should be reduced for patients with severely impaired renal function. Adverse effects. The main hazard with the penicil- lins is allergic reactions. These include itching, rashes (eczematous or urticarial), fever and angioedema. Rarely (about 1 in 10 000) there is anaphylactic shock which can be fatal (about 1 in 50 000-100 000 treatment courses). Allergies are least likely when penicillins are given orally and most likely with local application. Metabolic opening of the f5-lactam ring creates a highly reactive penicilloyl group which polymerises and binds with tissue proteins to form the major antigenic determinant. The anaphylactic reaction involves specific IgE anti- bodies which can be detected in the plasma of susceptible persons. There is cross-allergy between all the various forms of penicillin, probably due in part to their common structure, and in part to the degradation products common to them all. Partial cross-allergy exists between penicillins and cephalosporins (a maximum of 10%) which is of particular concern when the reaction to either group of antimicrobials has been angioedema or anaphylactic shock. Carba- penems (meropenem and imipenem-cilastatin) and the monobactam aztreonam apparently have a much lower risk of cross-reactivity. When attempting to predict whether a patient will have an allergic reaction, a reliable history of a previous adverse response to penicillin is valuable. Immediate-type reactions such as urticaria, angio- oedema and anaphylactic shock can be taken to indicate allergy, but interpretation of maculopapu- lar rashes is more difficult. Since an alternative drug can usually be found, a penicillin is best avoided if there is suspicion of allergy, although the condi- tion is undoubtedly overdiagnosed and may be transient (see below). When the history of allergy is not clear-cut and it is necessary to prescribe a penicillin, the presence of IgE antibodies in serum is a useful indicator of reactions mediated by these antibodies, i.e. imme- diate (type 1) reactions. Additionally, an intradermal test for allergy may be performed using standard amounts of a mixture of a major determinant (meta- bolite) (benzylpenicilloyl polylysine) and minor determinants (such as benzylpenicillin), of the allergic reaction; appearance of a flare and weal reaction indicates a positive response. The fact that only about 10% of patients with a history of 'peni- cillin allergy' respond suggests that many who are so labelled are not, or are no longer, allergic to penicillin. Other (nonallergic) adverse effects include dia- rrhoea due to alteration in normal intestinal flora which may progress to Clostridium difficile-associated diarrhoea. Neutropenia is a risk if penicillins (or other (3-lactam antibiotics) are used in high dose and usually for a period of longer than 10 days. Rarely the penicillins cause anaemia, sometimes haemolytic, and thrombocytopenia or interstitial nephritis. Penicillins are presented as their sodium or potassium salts which are inevitably taken in significant amounts if high dose of antimicrobial is used. Physicians should be aware of this un- expected source of sodium or potassium, especially in patients with renal or cardiac disease. Extremely high plasma penicillin concentrations cause convul- sions. Co-amoxiclav and flucloxacillin given in high doses for prolonged periods in the elderly may cause hepatic toxicity. NARROW SPECTRUM PENICILLINS Benzylpenicillin (penicillin G) Benzylpenicillin (i l / 2 0.5 h) is used when high plasma concentrations are required. The short t 1 ,/ means that reasonably spaced doses have to be large to maintain a therapeutic concentration. Fortunately, the unusually large therapeutic ratio of penicillin allows the resulting fluctuations to be tolerable. 2 Benzylpenicillin is eliminated by the 2 Is it surprise at the answer that reduces most classes of students to silence when asked the trough:peak ratio for a drug given 6-hourly with a t 1 ^ of 0.5 h? (answer: 2 12 = 4096). 217 12 ANTIBACTERIAL DRUGS kidney, with about 80% being actively secreted by the renal tubule and this can be blocked by probe- necid, e.g. to reduce the frequency of injection for small children or for single dose therapy as in gonorrhoea. Uses (see Table 11.1, p. 211). Benzylpenicillin is highly active against Streptococcus pneumoniae and the Lancefield group A, (3-haemolytic streptococcus (Streptococcus pyogenes). Viridans streptococci are usually sensitive unless the patient has recently received penicillin. Enterococcus faecalis is less sus- ceptible and, especially for endocarditis, penicillin should be combined with an aminoglycoside, usually gentamicin. This combination is synergistic unless the enterococcus is highly resistant to the aminoglycoside; such strains are becoming more frequent in hospital patients and present major difficulties in therapy. Benzylpenicillin used to be active against most strains of Staphylococcus aureus, but now over 90% are resistant in hospital and domiciliary practice. Benzylpenicillin is the drug of choice for infections due to Neisseria meningitidis (meningococcal meningitis and septicaemia), Baci- llus anthracis (anthrax), Clostridium perfringens (gas gangrene) and tetani (tetanus), Con/nebacterium diphtheriae (diphtheria), Treponema pallidum (syphilis), Leptospira spp. (leptospirosis) and Actinomyces israelii (actinomycosis). It is also the drug of choice for Borrelia burgdorferi (Lyme disease) in children. The sensitivity of Neisseria gonorrhoeae varies in different parts of the world and, in some, resistance is rife. Adverse effects are in general uncommon, apart from allergy (above). It is salutary to reflect that the first clinically useful true antibiotic (1942) is still in use and is also amongst the least toxic. Only in patients with bacterial endocarditis, where the requirement for high doses can co-exist with reduced clearance due to immune complex glomeruloneph- ritis, does a risk of dose related toxicity (convulsions) arise. Preparations and dosage for injection. Benzyl- penicillin may be given i.m. or i.v. (by bolus injection or by continuous infusion). For a sensitive infection, benzylpenicillin 3 600 mg 6-hourly is enough. This is obviously inconvenient in domi- ciliary practice where a mixture of benzylpenicillin and one of its long-acting variants may be preferred (see below). For relatively insensitive infections and where sensitive organisms are sequestered within avascular tissue (e.g. infective endocarditis) 7.2 g are given daily i.v. in divided doses. When an infection is controlled, a change may be made to the oral route using phenoxymethylpenicillin, or amoxicillin which is more reliably absorbed in adults. Procaine penicillin, given i.m. only, is a stable salt and liberates benzylpenicillin over 12-24 h, accord- ing to the dose administered. Usually this is 360 mg 12-24-hourly. There is no general agreement on its place in therapy, and it is no longer available in a number of countries. It is best to use benzyl- penicillin in the most severe infections, especially at the outset, as procaine penicillin will not give therapeutic blood concentrations for some hours after injection and peak concentrations are much lower. Preparations and dosage for oral use. Phenoxy- methylpenicillin (penicillin V), is resistant to gastric acid and so reaches the small intestine intact where it is moderately well absorbed, sometimes erratically in adults. It is less active than benzyl- penicillin against Neisseria gonorrhoeae and meningi- tidis, and so is unsuitable for use in gonorrhoea and meningococcal meningitis. It is a satisfactory substitute for benzylpenicillin against Streptococcus pneumoniae and Streptococcus pyogenes, especially after the acute infection has been brought under initial control by intravenous therapy. The dose is 500 mg 6-hourly. All oral penicillins are best given on an empty stomach to avoid the absorption delay caused by food. Antistaphylococcal penicillins Certain bacteria produce (Mactamases which open the (Mactam ring that is common to all penicillins, and thus terminate the antibacterial activity. (3- lactamases vary in their activity against different (3-lactams, with side chains attached to the p-lactam 3 600 mg = 1 000 000 units, 1 mega-unit. 218 p-LACTAMS _12 ring being responsible for most of these effects by stearic hindrance of access of the drug to the enzymes' active sites. Drugs that resist the action of staphylococcal p-lactamase do so by possession of an acyl side-chain. The drugs do have activity against other bacteria for which penicillin is indi- cated, but benzylpenicillin is substantially more active against these organisms — up to 20 times more so in the cases of pneumococci, (3-haemolytic streptococci and Neisseria. Hence, when infection is mixed, it may be preferable to give benzylpenicillin as well as a (3-lactamase-resistant drug in severe cases. Examples of these agents include: Fludoxacillin (t l / 2 1 h) is better absorbed and so gives higher blood concentrations than does cloxa- cillin. It may cause cholestatic jaundice, particularly when used for more than 2 weeks or to patients > 55 years. Cloxacillin (t l / 2 0.5 h) resists degradation by gastric acid and is absorbed from the gut, but food markedly interferes with absorption. Recently it has been withdrawn from the market in some countries, including the UK. Methidllin and oxacillin: their use is now con- fined to laboratory sensitivity tests. Identification of methicillin-resistant Staphylococcus aureus (MRSA) in patients indicates the organisms are resistant to flucloxacillin and cloxacillin, all other (3-lactam anti- biotics and often to other antibacterial drugs, and demands special infection-control measures. BROAD SPECTRUM PENICILLINS The activity of these semisynthetic penicillins extends beyond the Gram-positive and Gram-negative cocci which are susceptible to benzylpenicillin, and includes many Gram-negative bacilli. They do not resist (3-lactamases and their usefulness has reduced markedly in recent years because of the increased prevalence of organisms that produce these enzymes. As a general rule these agents are rather less active than benzylpenicillin against Gram-positive cocci, but more active than the (3-lactamase-resistant penicillins (above). They have useful activity against Enterococcus faecalis and many strains of Haemo- philus influenzae. Enterobacteriaceae are variably sen- sitive and laboratory testing for sensitivity is important. The differences between the members of this group are pharmacological rather than bacteriological. Amoxicillin (i l / 2 I h; previously known as amoxy- cillin) is a structural analogue of ampicillin (below) and is better absorbed from the gut (especially after food), and for the same dose achieves approxi- mately double the plasma concentration. Diarrhoea is less frequent with amoxicillin than with ampi- cillin. The oral dose is 250 mg 8-hourly; a parenteral form is available but offers no advantage over ampicillin. For oral use, however, amoxicillin is preferred because of its greater bioavailability and fewer adverse effects. Co-amoxiclav (Augmentin). Clavulanic acid is a p-lactam molecule which has little intrinsic anti- bacterial activity but binds irreversibly to (3-lactamases. Thereby it competitively protects the penicillin, so potentiating it against bacteria which owe their resistance to production of p-lactamases, i.e. clavu- lanic acid acts as a 'suicide' inhibitor. It is formulated in tablets as its potassium salt (equivalent to 125 mg of clavulanic acid) in combination with amoxicillin (250 or 500 mg), as co-amoxiclav, and is a satisfac- tory oral treatment for infections due to (3-lactamase- producing organisms, notably in the respiratory or urogenital tracts. It should be used when (3- lactamase-producing amoxicillin resistant organisms are either suspected or proven by culture. These include many strains of Staphylococcus aureus, many strains of Escherichia coll and an increasing number of strains of Haemophilus influenzae. It also has use- ful activity against [3-lactamase-producing Bacteroides spp. The t 1 /, is 1 h and the dose one tablet 8-hourly. Ampicillin (t 1 // 1 h) is acid-stable and is moderately well absorbed when swallowed. The oral dose is 250 mg-1 g 6-8-hourly; or i.m. or i.v. 500 mg 4-6-hourly. Approximately one-third of a dose appears unchanged in the urine. The drug is concentrated in the bile. Adverse effects. Ampicillin may cause diarrhoea but the incidence (12%) is less with amoxicillin. Ampicillin and amoxicillin are the commonest antibiotics to be associated with Clostridium difficile diarrhoea, although this is related to the frequency 219 12 ANTIBACTERIAL DRUGS of their use rather than to their innate risk of causing the disease (this is probably highest for the injectable cephalosporins). Ampicillin and its analogues have a peculiar capacity to cause a macular rash resembling measles or rubella, usually un- accompanied by other signs of allergy. These rashes are very common in patients with disease of the lymphoid system, notably infectious mononudeosis and lymphoid leukaemia. A macular rash should not be taken to imply allergy to other penicillins which tend to cause a true urticarial reaction. Patients with renal failure and those taking allopurinol for hyperuricaemia also seem more prone to ampicillin rashes. Cholestatic jaundice has been associated with use of co-amoxiclav even up to 6 weeks after cessation of the drug; the clavulanic acid may be responsible. MECILLINAM Pivmecillinam (i l / 2 I h) is an oral agent closely related to the broad spectrum penicillins but with differing antibacterial activity by virtue of having a high affinity for penicillin binding protein. It is active against Gram-negative organisms including p-lactamase-producing Enterobacteriaceae but is inactive against Pseudomonas aeruginosa and its relatives, and against Gram-positive organisms. Pivmecillinam is hydrolysed in vivo to the active form mecillinam (which is poorly absorbed by mouth). It has been used to treat urinary tract infec- tion. Diarrhoea and abdominal pain may occur. MONOBACTAM Aztreonam (t l / 2 2 h) is the first member of this class of (3-lactam antibiotic. It is active against Gram- negative organisms including Pseudomonas aerugi- nosa, Haemophilus influenzae and Neisseria meningi- tidis and gonorrhoeae. Aztreonam is used to treat septicaemia and complicated urinary tract infec- tions, Gram-negative lower urinary tract infections and gonorrhoea. Adverse effects include reactions at the site of infusion, rashes, gastrointestinal upset, hepatitis, thrombocytopenia and neutropenia. It appears to have a remarkably low risk of causing (3-lactam allergy, and may be used with caution in some penicillin-allergic patients. ANTIPSEUDOMONAL PENICILLINS Carboxypenicillins These in general have the same antibacterial spectrum as ampicillin (and are susceptible to (3- lactamases), but have the additional capacity to destroy Pseudomonas aeruginosa and indole-positive Proteus spp. Ticarcillin (t 1 // 1 h) is presented in combination with clavulanic acid (as Timentin), so to provide greater activity against (3-lactamase-producing organisms. It is given by i.m. or slow i.v. injection or by rapid i.v. infusion. Note that ticarcillin is presented as its disodium salt and each 1 g delivers about 5.4 mmol of sodium, which should be borne in mind when treating patients with impaired cardiac or renal function. Carboxypenicillins inactivate aminogly- cosides if both drugs are administered in the same syringe or intravenous infusion system. Ureidopenicillins These are adapted from the ampicillin molecule, with a side-chain derived from urea. Their major advantages over the Carboxypenicillins are higher efficacy against Pseudomonas aeruginosa and the fact that as monosodium salts they deliver on average about 2 mmol of sodium per gram of antimicrobial (see above) and are thus safer where sodium over- load should particularly be avoided. They are degraded by many (3-lactamases. Ureidopenicillins must be administered parenterally and are elimin- ated mainly in the urine. Accumulation in patients with poor renal function is less than with other penicillins as 25% is excreted in the bile. An unusual feature of their kinetics is that, as the dose is increased, the plasma concentration rises dispropor- tionately, i.e. they exhibit saturation (zero-order) kinetics. For pseudomonas septicaemia, a ureidopenicil- lin plus an aminoglycoside provides a synergistic effect but the co-administration in the same fluid results in inactivation of the aminoglycoside (as with Carboxypenicillins, above). Azlocillin (i l / 2 1 h), highly effective against Pseudo- monas aeruginosa infections, is less so than other 220 OTHER P-LACTAM A N T I B A C T E R I A L S 12 ureidopenicillins against other common Gram- negative organisms and has recently been with- drawn from the market in many countries. Piperacillin (tV 2 1 h) has the same or slightly greater activity as azlocillin against Pseudomonas aeruginosa but is more effective against the common Gram-negative organisms. It is also available as a combination with the p-lactamase inhibitor tazo- bactam (as tazocin). Cephalosporins Cephalosporins were first obtained from a filamen- tous fungus Cephalosporium cultured from the sea near a Sardinian sewage outfall in 1945; their molecular structure is closely related to that of penicillin, and many semisynthetic forms have been introduced. They now comprise a group of antibiotics having a wide range of activity and low toxicity. The term Cephalosporins will be used here in a general sense although some are strictly cephamycins, e.g. cefoxitin and cefotetan. Mode of action is that of the (3-lactams, i.e. Cephalosporins impair bacterial cell wall synthesis and hence are bactericidal. They exhibit time- dependent bacterial killing (see p. 203). Addition of various side-chains on the cephalo- sporin molecule confers variety in pharmacokinetic and antibacterial activities. The (3-lactam ring can be protected by such structural manoeuvring, which results in compounds with improved activity against Gram-negative organisms; a common corollary is that such agents lose some anti-Gram-positive activity. The Cephalosporins resist attack by (3-lactamases but bacteria develop resistance to them by other means. Methicillin-resistant Staphylococcus aureus (MRSA) should be considered resistant to all Cephalosporins. Pharmacokinetics. Usually, Cephalosporins are excreted unchanged in the urine, but some, includ- ing cefotaxime, form a desacetyl metabolite which possesses some antibacterial activity. Many are actively secreted by the renal tubule, a process which can be blocked with probenecid. As a rule, the dose of Cephalosporins should be reduced in patients with poor renal function. Cephalosporins in general have a t 1 // of 1-4 h although there are exceptions (e.g. ceftriaxone, t 1 /^, 8 h). Wide distribu- tion in the body allows treatment of infection at most sites, including bone, soft tissue, muscle and (in some cases) CSF. Data on individual Cephalo- sporins appear in Table 12.1. Classification and uses. The Cephalosporins are conventionally categorised by generations having broadly similar antibacterial and pharmacokinetic properties; newer agents have rendered this classi- fication less precise but it retains sufficient useful- ness to be presented in Table 12.1. Adverse effects. Cephalosporins are well tolerated. The most usual unwanted effects are allergic reac- tions of the penicillin type. There is cross-allergy between penicillins and Cephalosporins involving about 7% of patients; if a patient has had a severe or immediate allergic reaction or if serum or skin testing for penicillin allergy is positive (see p. 217), then a cephalosporin should not be used. Pain may be experienced at the sites of i.v. or i.m. injection. If Cephalosporins are continued for more than 2 weeks, thrombocytopenia, haemolytic anaemia, neutropenia, interstitial nephritis or abnormal liver function tests may occur especially at high dosage; these reverse on stopping the drug. The broad spectrum of activity of the third generation Cephalo- sporins may predispose to opportunist infection with resistant bacteria or Candida albicans and to Clostridium difficile diarrhoea. Ceftriaxone achieves high concentrations in bile and, as the calcium salt, may precipitate to cause symptoms resembling cholelithiasis (biliary pseudolithiasis). Cefamandole may cause prothrombin deficiency and a disulfiram- like reaction after ingestion of alcohol. Other (3-lactam antibacterials CARBAPENEMS Members of this group have the widest spectrum of all currently available antimicrobials, being 221 12 ANTIBACTERIAL DRUGS TABLE 1 2. 1 The cephalosporins Drug First generation Parenteral Cefazolin Cefradine (also oral) Oral Cefaclor Cefadroxil Cefalexin Second generation Parenteral Cefoxitin (a cephamycin) (Cefotetan is similar) Cefuroxime (also oral) Cefamandole Third generation Parenteral Cefodizime Cefotaxime Ceftazidime Ceftizoxime Ceftriaxone Oral Cefixime Ceftibuten Cefpodoxime proxetil t'/ 2 (h) 2 1 1 2 1 1 1 1 3 1 2 1 8 4 2 2 Excretion in urine (%) 90 86 86 88 88 90 80 75 80 60 88 90 56 (44 bile) 23 (77 bile) 65 80 Comment May be used for staphylococcal infections but generally have been replaced by the newer cephalosporins. All very similar. Effective against the common respiratory pathogens Streptococcus pneumoniae and Momxella catarrhalis but (excepting cefaclor) have poor activity against Haemophilus influenzae. Also active against Escherichia coli which, increasingly, is demonstrating resistance to amoxicillin and trimethoprim. May be used for uncomplicated upper and lower respiratory tract, urinary tract and soft tissue infections, and also as follow-on treatment once parenteral drugs have brought an infection under control. More resistant to p-lactamases than the first-generation drugs and active against Stopny/ococcus aureus, Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria spp., Haemophilus influenzae and many Enterobacteriaceae. Cefoxitin also kills Boctero/des fragilis and is effective in abdominal and pelvic infections. Cefuroxime may be given for community-acquired pneumonia, commonly due to Strep pneumoniae (not when causal organism is Mycoplasma pneumoniae, Legionella or Ch/amyd/a).The oral form, cefuroxime axetil, is also used for the range of infections listed for the first-generation oral cephalosporins (above) More effective than the second-generation drugs against Gram-negative organisms whilst retaining useful activity against Gram-postive bacteria. Cefotaxime, ceftizoxime and ceftriaxone are used for serious infections such as septicaemia, pneumonia, and for meningitis. Ceftriaxone also used for gonorrhoea and Lyme disease. Active against a range of Gram-positive and Gram-negative organisms including Staphylococcus aureus (excepting cefixime), Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria spp., Haemophilus influenzae and (excepting cefpodoxime) many Enterobacteriaceae. Used to treat urinary, upper and lower respiratory tract infections. bactericidal against most Gram-positive and Gram- negative aerobic and anaerobic pathogenic bacteria. They are resistant to hydrolysis by most P-lactamases. Only occasional pseudomonas relatives are naturally resistant, and acquired resistance is uncommon in all species. Imipenem Imipenem (i l / 2 1 h) is inactivated by metabolism in the kidney to products that are potentially toxic to renal tubules; combining imipenem with cilastatin (as Primaxin), a specific inhibitor of dihydropeptidase—the enzyme responsible for its renal metabolism—prevents both inactivation and toxicity. Imipenem is used to treat septicaemia, parti- cularly of renal origin, intra-abdominal infection and nosocomial pneumonia. In terms of imipenem, 1-2 g/d is given by i.v. infusion in 3-A doses; reduced doses are recommended when renal function is impaired. Adverse effects. It may cause gastrointestinal upset including nausea, blood disorders, allergic reactions, confusion and convulsions. 222 AM I NOG LYCOS IDES 12 Meropenem (t l / 2 1 h) is similar to imipenem but is stable to renal dihydropeptidase and can therefore be given without cilastatin. It penetrates into the CSF and is not associated with nausea or convulsions. Other inhibitors of cell wall synthesis Vancomycin Vancomycin (i l / 2 8h), a 'glycopeptide' or 'pepto- lide', acts on multiplying organisms by inhibiting cell wall formation at a site different from the (3- lactam antibacterials. It is bactericidal against most strains of clostridia (including Clostridium difficile), almost all strains of Staphylococcus aureus (including those that produce (Hactamase and methicillin- resistant strains), coagulase-negative staphylococci, viridans group streptococci and enterococci, i.e. several organisms that cause endocarditis. Vancomycin is poorly absorbed from the gut and is given i.v. for systemic infections, as there is no satisfactory i.m. preparation. It distributes effec- tively into body tissues and is eliminated by the kidney. Uses. Vancomycin is effective in cases of antibiotic- associated pseudomembranous colitis (caused by Clostridium difficile or, less commonly, staphylo- cocci) in a dose of 125 mg 6-hourly by mouth (although oral metronidazole is preferred, being as effective and less costly). Combined with an amino- glycoside, it may be given i.v. for streptococcal endocarditis in patients who are allergic to benzyl- penicillin. It may also be used for serious infection with multiply-resistant staphylococci. Dosing is guided by plasma concentration monitoring. Adverse effects. The main disadvantage to vanco- mycin is auditory damage. Tinnitus and deafness may improve if the drug is stopped. Nephrotoxicity and allergic reactions also occur. Rapid i.v. infusion may cause a maculopapular rash possibly due to histamine release (the 'red person' syndrome). Teicoplanin is structurally related to vancomycin and is active against Gram-positive bacteria. The t 1 /^ of 50 h allows once daily i.v. or i.m. adminis- tration. It is used for serious infection with Gram- positive bacteria including endocarditis, and for peritonitis in patients undergoing chronic ambula- tory peritoneal dialysis. It is less likely to cause oto- or nephrotoxicity than vancomycin, but serum monitoring is required for severely ill patients and those with changing renal function to assure adequate serum concentrations are being achieved. A rising prevalence of clinically-significant resist- ance and decrease in susceptibility to vancomycin and teicoplanin has become a serious worry recently with the emergence of vancomycin-resistant entero- cocci (VRE) or glycopeptide-resistant enterococci (GRE) and vancomycin-intermediate resistant Staphy- lococcus aureus (VISA or GISA). Only one naturally occurring strain of vancomycin resistant Staphylo- coccus aureus has been reported, but these will no doubt emerge in time and the appearance of anti- biotics active against multiply resistant Gram- positive bacteria, e.g. quinupristin-dalfopristin and linezolid (see p. 229), is welcome. Cycloserine is used for drug-resistant tuberculosis (see p. 253). Inhibition of protein synthesis Aminoglycosides In the purposeful search that followed the demon- stration of the clinical efficacy of penicillin, strepto- mycin was obtained from Streptomyces griseus in 1944, cultured from a heavily manured field, and also from a chicken's throat. Aminoglycosides resemble each other in their mode of action, and their pharmacokinetic, therapeutic and toxic proper- ties. The main differences in usage reflect variation in their range of antibacterial activity; cross- resistance is variable. Mode of action. The aminoglycosides act inside the cell by binding to the ribosomes in such a way that incorrect amino acid sequences are entered into 223 12 ANTIBACTERIAL DRUGS peptide chains. The abnormal proteins which result are fatal to the microbe, i.e. aminoglycosides are bactericidal and exhibit concentration-dependent bacterial killing (see p. 203). Pharmacokinetics. Aminoglycosides are water- soluble and do not readily cross cell membranes. Poor absorption from the intestine necessitates their administration i.v. or i.m. for systemic use and they distribute mainly to the extracellular fluid; transfer into the cerebrospinal fluid is poor even when the meninges are inflamed. Their t 1 // is 2-5 h. Aminoglycosides are eliminated unchanged mainly by glomerular filtration, and attain high concentrations in the urine. Significant accumula- tion occurs in the renal cortex unless there is severe renal parenchymal disease. Plasma concentration should be measured regularly (and frequently in renally-impaired patients) and it is good practice to monitor approximately twice weekly even if renal function is normal. With prolonged therapy, e.g. endocarditis (gentamicin), monitoring must be meticulous. The dose should be reduced to com- pensate for varying degrees of renal impairment, including that of normal aging. Numerous success- ful legal actions by patients against doctors for negligence in this area have resulted in large compensation payments, especially for ototoxicity. Current practice is to administer aminoglyco- sides as a single daily dose rather than as twice or thrice daily doses. Algorithms are available to guide such dosing according to patients' weight and renal function, and in this case only trough con- centrations need to be assayed. Single daily dose therapy is probably less oto- and nephrotoxic than divided dose regimens, and appears to be as effec- tive. The immediate high plasma concentrations that result from single daily dosing are advanta- geous, e.g. for acutely ill septicaemic patients, as aminoglycosides exhibit concentration-dependent killing (see p. 203). Antibacterial activity. Aminoglycosides are in general active against staphylococci and aerobic Gram-negative organisms including almost all the Enterobacteriaceae; individual differences in activity are given below. Bacterial resistance to aminoglyco- sides is an increasing but patchily-distributed problem, notably by acquisition of plasmids (see p. 209) which carry genes coding for the formation of drug-destroying enzymes. Gentamicin resistance is rare in community-acquired pathogens in many hospitals in the UK. Uses include: • Gram-negative baciUary infection, particularly septicaemia, renal, pelvic and abdominal sepsis. Gentamicin remains the drug of choice but tobramycin may be preferred for infections caused by Pseudomonas aeruginosa. Amikacin has the widest antibacterial spectrum of the aminoglycosides but is best reserved for infection caused by gentamicin-resistant organisms. As long as local resistance rates are low, an aminoglycoside may be included in the initial best-guess regimen for treatment of serious septicaemia before the causative organism(s) is identified. A potentially less toxic antibiotic may be substituted when culture results are known (48-72 h), and toxicity is very rare after such a short course. • Bacterial endocarditis. An aminoglycoside, usually gentamicin, should comprise part of the antimicrobial combination for enterococcal, streptococcal or staphylococcal infection of the heart valves, and for the therapy of clinical endocarditis which fails to yield a positive blood culture. • Other infections: tuberculosis, tularaemia, plague, brucellosis. • Topical uses. Neomycin and framycetin, whilst too toxic for systemic use, are effective for topical treatment of infections of the conjunctiva or external ear. They are sometimes used in antimicrobial combinations selectively to decontaminate the bowel of patients who are to receive intense immunosuppressive therapy. Tobramycin is given by inhalation for therapy of infective exacerbations of cystic fibrosis. Sufficient systemic absorption may occur to recommend assay of serum concentrations in such patients. Adverse effects. Aminoglycoside toxicity is a risk when the dose administered is high or of long duration, and the risk is higher if renal clearance is inefficient (because of disease or age), other poten- tially nephrotoxic drugs are co-administered (e.g. 224 [...]... formed in the fetus are of less clinical importance because pigmentation has no cosmetic disadvantage and a short exposure to tetracycline is unlikely significantly to delay growth Since tetracyclines act by inhibiting bacterial protein synthesis, the same effect occurring in man causes blood urea to rise (the antianabolic effect) The increased nitrogen load can be clinically important in renal failure... macrolides: erythromycin, clarithromycin, and azithromycin Mayo Clinic Proceedings 74: 613-634 AZOLES Chambers H F 1997 Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications Clinical Microbiology Reviews 10: 781-791 Diekema D J, Jones R N 2001 Oxazolidine antibiotics Lancet 358:1975-1982 Fisman D N, Kaye K M 2000 Once-daily dosing of aminoglycoside antibiotics Infectious... and in toxicity Streptomycin, superseded as a first-line choice for tuberculosis, may be used to kill resistant strains of the organism Spectinomycin is active against Gram-negative organisms but its clinical use is confined to gonorrhoea in patients allergic to penicillin, or to infection with gonococci that are (3-lactam drug resistant The steady growth of resistant gonococci, particularly p-lactamase-producing... quinupristin-dalfopristin and linezolid These novel antibiotics were developed in response to the emergence of multiply resistant Gram-positive 229 12 A N T I B A C T E R I A L DRUGS 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... eliminated in the urine, partly unchanged and partly as metabolites The t1/, is 8 h 233 12 ANTIBACTERIAL DRUGS Uses Metronidazole is active against a wide range of anaerobic bacteria and also protozoa Its clinical indications are: • Treatment of sepsis to which anaerobic organisms, e.g Bacteroides spp and anaerobic cocci, are contributing, notably postsurgical infection, intra-abdominal infection and septicaemia,... with impaired renal function Uses Tetracyclines are active against nearly all Gram-positive and Gram-negative pathogenic bacteria, but increasing bacterial resistance and low innate activity limit their clinical use They remain drugs of first choice for infection with chlamydiae (psittacosis, trachoma, pelvic inflammatory disease, lymphogranuloma venereum), mycoplasma (pneumonia), rickettsiae (Q fever,... addition to the antimicrobial arsenal Lancet 354: 2012-2013 Kelkar P S, Li J T-C 2001 Cephalosporin allergy New England Journal of Medicine 345: 804-809 Moellering R C 1998 Vancomycin-resistant enterococci Clinical Infectious Diseases 26: 1196-1199 Piddock L J 1994 New quinolones and Gram-positive bacteria Antimicrobial Agents & Chemotherapy 38:163-169 Walker R C 1999 The fluoroquinolones Mayo Clinic Proceedings . apart from allergy (above). It is salutary to reflect that the first clinically useful true antibiotic (1942) is still in use and is also amongst . assure adequate serum concentrations are being achieved. A rising prevalence of clinically-significant resist- ance and decrease in susceptibility to