NTew Drugs · BRITISH MEDICALJOURNAL VOLUME286 28 MAY 1983 NTew Drugs Antibiotics I: newantibiotics andadvancesin antibiotic treatment CRPENNINGTON, J CROOKS The prescribing of antibiotics

BRITISH MEDICAL JOURNAL VOLUME 286 28 MAY 1983

NTew Drugs

Antibiotics I: new antibiotics and advances inantibiotic treatment

C R PENNINGTON, J CROOKS

The prescribing of antibiotics has been influenced by theincreasing number of available drugs, changing patterns ofbacterial resistance and disease, a changing patient population,and the patient's belief that all infections respond to anti-biotics. In this article we review developments in antibioticprescribing which have followed the introduction of new drugsand the recognition of "new" applications for established ones.

New antibiotics

New antibiotics may conveniently be considered in four maingroups: penicillins, cephalosporins, aminoglycosides, and amiscellaneous group.

PENICILLINS

The introduction of new penicillin analogues and esters, newderivatives of carbenicillin, the acylureido penicillins (azlocillin,mezlocillin, and piperacillin), and mecillinam has provided arange of drugs that share the features of relative safety, occa-sional hypersensitivity, and susceptibility to inactivation bybacterial r-lactamase with the parent compound. One innovationof interest is the combination of the r-lactamase inhibitorclavulanic acid with one member of the group amoxycillin(Augmentin) in order to extend its antibacterial spectrum, anddevelopments of this type might conceivably be applied toother members of the group.

The ampicillins

The insertion of a hydroxyl group in the benzyl side chainof ampicillin resulted in the production ofamoxycillin. Comparedwith ampicillin amoxycillin (Amoxil) has several advantages-namely, improved intestinal absorption with correspondinglygreater tissue concentrations and a considerably more rapidcidal action. Diarrhoea and the selection of resistant organismsoccur less often during treatment with amoxycillin. Theseadvantages together with the fewer daily doses required than

with ampicillin have led to this derivative being increasinglyused.

Ampicillin esters such as talampicillin (Talpen) have noantibacterial activity, but ampicillin is liberated by hydrolysisduring absorption. The lower incidence of diarrhoea and re-duced selection of resistant organisms must be weighed againstthe tendency of these preparations to provoke gastric disturbanceand the knowledge that ampicillin rather than an improvedanalogue is the actual antibiotic. Consequently these derivativeswould appear to confer no advantage.The combination of clavulanic acid with amoxycillin (Aug-

mentin) extends the activity of amoxycillin against organismswhich owe their resistance to the production of r-lactamaseenzymes. These include Staphyloccus aureus, many species ofEnterobacteriaceae, Neisseria gonorrhoeae and resistant forms ofHaemophilus iMfluenzae. Experience with Augmentin is pre-sently limited to infections of the urinary and respiratory tracts.Adverse reactions occur in 12o` of recipients and mainly consistof nausea, vomiting, and diarrhoea. At present it is recommendedthat this drug is reserved for use against respiratory and urinaryinfections caused by organisms known to be resistant to amoxy-cillin alone.

Carfecillin and ticarcillin

Carbenicillin has a predominantly Gram negative spectrumof activity that includes Pseudomonas aeruginosa and some otherbacilli resistant to ampicillin. Large doses are required byintravenous infusion, which creates the potential problem ofsodium overload. Carfecillin (Uticillin) is the phenyl ester ofcarbenicillin which is absorbed after oral administration andhydrolysed by tissue esterases to phenol and carbenicillin.Unfortunately, tissue concentrations of the active drug are lowalthough urinary concentrations are adequate. Carfecillin is,therefore, reserved for use against urinary tract infections,especially those due to Ps aeruginosa.

Ticarcillin (Ticar) resembles carbenicillin in its pharmacologyand range of antimicrobial activity except that it is twice asactive against Ps aeruginosa. It is not, however, active in vivoagainst strains resistant to carbenicillin. Nevertheless, ticar-cillin's greater activity represents an important advantage overcarbenicillin.

Ninewells Hospital and Medical School, Dundee DD1 9SYC R PENNINGTON, MD, MRCP, consultant physician and honorary senior

lecturer in medicineJ CROOKS, MD, FRCP, professor of therapeutics

Correspondence to: Dr C R Pennington.Professor J Crooks died on 3 January 1983.

Azlocillin, mezlocillin, and piperacillin

Azlocillin (Securopen) is a new parenteral acylureido peni-cillin. Against Ps aeruiginosa it is two to four times more activethan ticarcillin or mezlocillin, and it can be active againststrains resistant to other agents. Like carbenicillin and ticar-cillin it is less active than mezlocillin against Escherichia coliand Klebsiella spp. At present it would seem reasonable to

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reserve azlocillin for use against a strain of Ps aerluginosa knownto be resistant to other agents.

Mezlocillin (Baypen) embraces the spectrum of ampicillinand carbenicillin and has a broader spectrum than azlocillin.Although it has been advocated for treating a wide range ofinfections, in vitro studies suggest that bacterial resistance,especially with coliforms and anaerobes, may be a problem.Consequently, it should not be used alone for abdominal sepsis;for this condition combination with an aminoglycoside such asgentamicin or netilmicin is recommended.

Piperacillin (Pipril) is the most recent addition to this group.It is claimed that it combines the potency of azlocillin againstPs aerulginosa with the broad spectrum of mezlocillin. It isactive against some strains of Ps aeruginosa resistant to otheragents and a wide range of micro-organisms, including somestrains of bacteroides. Piperacillin is therapeutically activeagainst organisms producing 3-lactamases, to which it is un-stable in vitro, and clinical studies have shown that it may beeffective in serious infections when used alone. It should,however, be used in conjunction with another antibiotic, suchas an aminoglycoside, as resistance may develop.

Further studies are needed to define more precisely the roleof these drugs. At present they are known to be useful anti-pseudomonal agents and they exhibit synergy with aminogly-cosides, with which they should be combined to treat seriousintra-abdominal infection.

Meci/linam

Mecillinam is a novel derivative with a different mode ofaction on the cell wall and a Gram negative spectrum. Mecilli-nam (Selexidin) is not absorbed; the oral form is the esterpivmecillinam (Selexid). The main role of this drug is inmanaging urinary infections, for which it is safe and effectiveand active against many organisms resistant to amoxycillin.Although it exhibits impressive in vitro activity against Sal-nionella species, results in patients with enteric fever have beendisappointing, and the drug has no established place in themanagement of systemic infections.

CEPHALOSPORINS

The cephalosporins are traditionally classified into three"generations." The first generation includes drugs such ascephalexin, cephradine, cephaloridine, and cefaclor. All drugsin this group lack stability to p-lactamase enzymes elaboratedby Gram negative organisms, and they have no action againstPs aerlugitiosa. They have been available for many years and willbe considered no further. The second generation includescefuroxime, cefoxitin and cephamandole. These drugs differfrom the first generation group by virtue of their stability to P-lactamases. Stability to (<-lactamases is also a feature of the thirdgeneration. Members of this group are distinguished by theiractivity against Ps aeruginosa. So far cefotaxime, cefsulodin, andlatamoxef disodium have been marketed.

Second genieration cephalosporinsCefuroxime (Zinacef) has useful activity against S aureus,

H infiluenizae, and many Gram negative bacteria, includingpenicillin resistant N gonorrhoeae. Compared with cefuroximecefoxitin (Mefoxin) has reduced activity against some Grampositive organisms but a spectrum of activity that includesanaerobes. Cephamandole (Kefadol) is not so resistant to 3-lactamase activity compared with cefuroxime and cefoxitin.Consequently, cefuroxime is the best broad spectrum drug inthis group except for infections caused by anaerobes, whencefoxitin may be preferred.

Third generation cephalosporins

Third generation cephalosporins are characterised by aspectrum of activity that includes Ps aeruginosa, long half lives,and poor penetration of the central nervous system. Cefotaxime(Claforan) has slightly lower activity against Ps aeruginosa butactivity against some anaerobes. Unlike most cephalosporinscefotaxime is metabolised in vivo, so reduced dosage is requiredonly in severe renal failure. Cefsulodin (Monaspor) is a relativelynarrow spectrum antipseudomonal drug, and this property isa potential advantage in treating infections caused by thisorganism. Latamoxef disodium (Moxalactam) has a spectrumthat includes Gram negative and anaerobic organisms. It mayhave a role in surgical prophylaxis. Many more drugs such asceftazidene and cefoperazone are presently being evaluated.The role of these newer agents has not yet been clarified.

AMINOGLYCOSIDES

Aminoglycosides exhibit impressive activity against Gramnegative organisms including Ps aeruginosa but relatively pooractivity against some Gram positive species, especially strepto-cocci. Toxicity is their main disadvantage. Nephrotoxicity maybe enhanced by the concomitant use of cephalosporins (includ-ing the newer agents) but not the penicillins. Ototoxicity maybe primarily vestibular (gentamicin, tobramycin, and netil-micin) or auditory (streptomycin, kanamycin, and amikacin).New developments have included the introduction of derivativesthat are less toxic and less prone to destruction by bacterialenzymes.Tobramycin (Nebcin) is considered to be more active against

Ps aeruginosa and less nephrotoxic than gentamicin. Amikacin(Amikin) is resistant to all but a few of the enzymes that destroyaminoglycosides and may therefore retain activity againstbacteria resistant to other agents. This property is shared withnetilmicin (Netillin), which is also less toxic. Unlike gentamicinand tobramycin, amikacin and netilmicin are not inactivatedby carbenicillin and ticarcillin in the presence of renal failure.

Although the use of aminoglycosides has decreased after theintroduction of the second and third generation cephalosporins,they remain valuable drugs and exhibit synergy with the acylu-reido penicillins. This combination is particularly useful inmanaging unknown serious infection, particularly in the immuno-suppressed patient. The increased safety of netilmicin suggeststhat this drug should replace older derivatives. Amikacin shouldbe reserved for infections known to be resistant to other amino-glycosides.

MISCELLANEOUS ANTIBIOTICS

Co-trimoxazole contains fixed combinations of sulphametho-xazole and trimethoprim that sequentially inhibit bacterialfolate metabolism and exhibit synergy in the ratio of 20:1.Whereas this ratio occurs in the blood after absorption, in theurine the ratio of the two components is 1:1. Under thesecircumstances there is no synergy, and antibacterial activity islargely due to the trimethoprim moiety. This observation hasled to two developments; firstly, the use of other sulphonamidesin combination with trimethoprim for the treatment of urinarytract infections-for instance, sulphadiazine as co-trimazineand sulphametrol as Lidaprim-and secondly, the marketingof trimethoprim alone. Trimethoprim alone is attractive becausemany bacterial pathogens are now resistant to sulphonamides,and the sulphonamide component of co-trimoxazole is respon-sible for most adverse reactions-for example, rashes and blooddyscrasias as well as drug interreactions such as those withwarfarin and sulphonylureas. Clinical trials have shown thattrimethoprim (Monotrim, Syraprim, Ipral, Trimopan) is aseffective as co-trimoxazole in treating urinary tract infectionsand some forms of respiratory infections. New derivatives of

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trimethoprim are presently being evaluated. Concern has beenexpressed that monotherapy may encourage the emergence ofbacterial resistance, but this contention is as yet unsubstantiated.Trimethoprim should be used in preference to co-trimoxazolein treating urinary tract infections in patients who are intolerantof sulphonamides as well as those receiving drugs with whichsulphonamides may interreact.

Cinoxacin and rosoxacin are derivatives of malidixic acid.Cinoxacin is more active in vitro than nalidixic acid, androsoxacin has useful activity against N gonorrhoeae. Both areeffective against most urinary pathogens. Like the parent com-pound they achieve inadequate blood and tissue concentrations,and their use should be restricted to treating "lower" urinarytract infections.

Finally, tinidazole (Fasigyn) has a similar spectrum of activityto metronidazole. It may, however, be given as a single daily dose.

New applications

TREATMENT OF ESTABLISHED INFECTIONS

Legionnaire's disease has attracted much interest. Retro-spective clinical data have clearly indicated that the besttherapeutic response was obtained in patients who were treatedwith erythromycin. The need for high dosage intravenoustherapy has been emphasised. More recently, the impressivein vitro activity of rifampicin against the legionella bacillus hasbeen recognised, and now the combined use of erythromycinand rifampicin is recommended for managing legionnaire'sdisease.Another unusual respiratory pathogen is Pneumocystis carin ii,

which is found increasingly in the immunosuppressed patient.In high dosage co-trimoxazole is effective with results similarto those obtained with pentamidine.Once the role of Clostridium difficile in the development of

postantibiotic diarrhoea and pseudomembranous colitis wasrecognised oral vancomycin was found to be effective in theseconditions. Previously, vancomycin was known to be effectivebut toxic after systemic administration, which was usuallyreserved for intractable staphylococcal infections; absorptionand therefore toxicity are not associated with oral administration.Another recently recognised intestinal infection is campylo-bacter enteritis which, unlike other forms of bacterial gastro-enteritis, responds to antibiotics. Erythromycin is the drug ofchoice, but its use should be reserved for those patients withbacteraemia or severe disease. Indeed, one study has shownthat no benefit accrues from the routine administration oferythromycin in this condition.An important advance in managing various forms of endo-

genous infection, especially postoperatively, has followed therecognition of the importance of anaerobic bacteria. Metroni-dazole, previously used against protozoal infections, was foundto be effective against such pathogens, for which purpose itreplaced clindamycin. Recent reports have indicated that metro-nidazole may have a role in the treatment of Crohn's disease.

Finally, the tradition of present dose schedules has beenquestioned. The use of single large dose pulse therapy appearsto be of some value in the treatment of lower (but not upper)urinary tract infections. Whereas such use has many theoreticaladvantages-such as reducing drug costs, adverse reactions, andantibiotic resistance-selecting appropriate patients for singledose treatment remains a problem. This treatment, however,is reasonable in patients with frequency and dysuria in the ab-sence of pyrexia and loin pain; treatment failure or relapse bothindicate the need for a conventional course of antibiotics.

ANTIBIOTIC PROPHYLAXIS

Developments in the prophylactic use of antibiotics haveoccurred in three areas. Firstly, sulphonamides are no longer ofvalue for prophylaxis against meningococcal infections in close

contacts because 30", of the organisms are now resistant tosuch drugs. Instead, rifampicin may be used in divided dosesfor two days. Minocycline is an alternative choice, but it hasbeen associated with unpleasant adverse reactions. Secondly,the use of oral non-absorbed antimicrobial agents such asframycetin, colistin, and nystatin may considerably reduceendogenous infections in neutropenic patients. Similar claimshave been made for co-trimoxazole.

Nevertheless, the major developments have taken place insurgical sepsis. Administration of antibiotics immediately beforeoperation greatly reduces the incidence of surgical sepsis inpatients undergoing operations for gastric outflow obstruction,biliary tract disease, and disease of the colon and uterus. Underthese circumstances the combination of metronidazole with asecond generation cephalosporin or aminoglycoside is favoured,and the preoperative dose is followed by up to two postoperativeinjections. By contrast, it is important to provide cover againstStaph aureus and clostridia during some orthopaedic and vascularsurgery, and these patients receive treatment for up to five dayspostoperatively. Benzylpenicillin is the drug of choice for pro-phylaxis against clostridia while flucloxacillin provides coveragainst Staph aureus. Erythromycin is a suitable alternative inthose patients allergic to penicillin.The wide range of available drugs and changing patterns of

bacterial resistance have created problems of drug evaluationand prescribing. Whereas there are data on the potentialand actual clinical efficacy of many new agents, their relativemerits in different clinical circumstances have yet to be satis-factorily evaluated. Furthermore, their availability brings thehazard of inappropriate or unnecessarily expensive prescribingby clinicians, who may find difficulty in keeping abreast withcurrent developments. This problem is being met in some areasby the introduction of antibiotic policy documents that providelocally generated information and a consensus view on the useof antibiotics to achieve cost effective prescribing.

Bibliography

Anders BJ, Lauer BA, Paisley JW, Reller LB. Double blind placebo con-trolled trial of erythromycin for treatment of campylobacter enteritis.Lancet 1982;i: 131-2.The routine use of erythromycin was evaluated in unselected patients

with campylobacter gastroenteritis.Anderson JD, Adams MA, Barrington JC. Comparison of the epidemiology

of bacterial resistance to mecillinam and ampicillin. Antirnicrob AgentsChemiother 1976;10:872-7.

Reviews patterns of drug resistance in coliforms causing urinary tractinfection with particular reference to the use of ampicillin and mecil-linam.

Baily RR. The aminoglycosides. Drugs 1981 ;22:321-7.Antimicrobial activity, toxicity, and clinical use of established and

new aminoglycoside derivatives are discussed.Brogden RN, Carrmine A, Heel RC, Morley PA, Speight TM, Avery GS.

Amoxycillin-clavulanic acid: a review of its antibacterial activity,pharmacokinetics, and therapeutic use. Drugs 1981 ;22:337-62.A review of current experience.

Coppens L, Klastersky J. Comparative study of anti-pseudomonas activityof cyclocillin, mezlocillin and ticarcillin. Antlimicrob Agents Chemnother1979;15 :396-9.Compares the antipseudomonal activity of some new penicillin

derivatives.Cuhna BA, Ristuccia AM. Third generation cephalosporins. Med Clin

North An 1982;66:283-91.The antimicrobial spectrum and potential role of forthcoming third

generation ceplialosporins are reviewed.Feathers RS, Lewis AA, Sager GR, Amirak ID, Noone P. Prophylactic

systemic antibiotics in colorectal surgery. Lancet 1977;ii:4-8.The value of perioperative antibiotics in reducing postoperative

sepsis was studied in patients undergoing colonic surgery.Fu KP, Ness HC. Azlocillin and mezlocillin: new ureido penicillins. Anti-

microb Agents Chemother 1978 ;13:930-8.The antibacterial spectrum and clinical applications of new ureido

penicillins are described.Hughes WT. Treatment of pneumocystis carinii pneumonitis. N Engl J Med

1976;295 :726-7.Reviews Pneumnocystis carinii infection and treatment in the immuno-

suppressed patient.Jackson D, Phillips I. From penicillin to piperacillin.J Anitiinicrob Che?nother

1982;9, suppl B.

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A historical review of the development of penicillins with particularreference to the antimicrobial spectrum and clinical evaluation ofpiperacillin.

Keighley MRB, Burdon DW, Arabi Y, et al. Randomised controlled trialof vancomycin for pseudomembranous colitis and postoperative diar-rhoea. Br MedJ3 1978;ii:1667-9.

This study showed that vancomycin was an effective and safe treat-ment for pseudomembranous colitis.

Ness HC. Current practices in antimicrobial dosing. Rev Infect Dis 1981;3:12-8.Reviews current practice relating to dosage and duration of antibiotic

treatment.Selwyn S. Mechanisms and range of activity of penicillin and cephalosporins.

In: The 3-lactam antibiotics: penicillins and cephalosporins in perspective.London: Hodder and Stoughton, 1980;1-55.

The antibacterial spectrum and mode of action of penicillins andcephalosporins are discussed.

Shaw EJ, Datta N, Jones G, Marr FM, Froud WJB. Effect of stay in hospitaland oral chemotherapy on the antibiotic sensitivity of bowel coliforms.J Hygiene 1973;71 :529-34.

Reviews the emergence of resistance in bowel coliforms during anti-biotic treatment.

Swartz MN. Clinical aspects of legionnaires disease. Ann Intern Med 1979;90:492-5.

Clinical features of legionnaires disease and its management arediscussed.

Wise R, Reaves DS. Advances in therapy with antibacterial folate inhibitors.7 Antimicrob Chemother 1979;5, suppl B.

Reviews the role and development of folate inhibitors.

Clinical curio: perforating eye injury from an unusualcause

Two young men in two months presented to the eye casualty depart-ment of the Leicester Royal Infirmary with perforating eye injuriesfrom the same unusual cause. Both had been struck in the eye by alarge fencing staple while they were pulling down nylon netting stapledto wooden posts. Both still have normal visual acuity.

Case 1-A 16 year old boy presented with a fencing staple 2 cmslong transfixing his left lower eyelid (fig la). X ray appearances (figslb, lc) and clinical examination showed that the globe was perforatedby one arm of the staple, the tip of which could be seen with a fundu-scope in the vitreous compartment. He had little discomfort and thevisual acuity in the affected eye was 6/36. The staple was removed

..~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~....

Clinical and x ray appearances of staple injury to the left eye (cast 1).

under general anaesthesia, requiring quite forceful traction to extract it.The perforation lay 6 mm posterior to the limbus. The scleral defectwas sutured with 5/0 Dacron, and cryotherapy was applied around thewound and behind it. He was given intensive prophylactic local andsystemic antibiotics. Seven days later he had regained left visual acuityof 6/9 unaided. Fifteen months later the vision was 6/5, the eye was notinflamed, and the retina was flat.

Case 2-A 21 year old man presented with a painful right eye afterbeing struck by a fencing staple. Examination showed a full thicknesspuncture wound of the periphery of the right cornea, which wasapparently self sealing; the anterior chamber was present but reduced.The iris was adherent to the back of the wound, though there was noprolapse of iris tissue through the wound. The lens was undamaged,and the visual acuity was 6/18 in the affected eye. He was treatedconservatively with topical and systemic antibiotics. The cornealwound healed well, and the anterior chamber reformed to normaldepth. A small scar remains with iris anterior synaechias. Fourteenmonths later the visual acuity had returned to 6/5.No similar cases have been reported. Smith' and Blake2 described

ocular injuries in agricultural workers, in whom perforating injuriesby tools or metal are rare. Johnston3 reported a wider range of per-forating injuries, but did not give all the causes, although, again,injuries with metal are rare in agricultural workers but prevalent inindustrial workers. It is clear, especially in case 1, that the staple waspropelled with considerable force into the eye. The elastic nature ofnylon netting presumably produced a catapult effect when the staplecame free. Perforating puncture wounds of the eye, even whenapparently severe, are compatible with the retention of good visionif promptly and appropriately treated. Perforating injuries wherevegetable matter may contaminate the wound are vulnerable to infec-tion, a devastating complication. Both these patients were treatedvigorously with antibiotics prophylactically, and neither developedinfection. Both were fortunate in the outcome of their injuries fromthis previously unrecognised hazard.

I should like to thank Miss D Callaghan for the photographic help,Mrs J Wood for her secretarial help, and Mr D B Goulstine and MrD J Austin for permission to report these cases.-A B BECKINGSALE,ophthalmologist, Leicester.

Smith FPE. Eye injuries in agriculture. Tranis Ophthahnol Soc UK 1950;60:252-7.

Blake J. Eye injuries in agriculture. J Irish Med Assoc 1971;64:420-3.Johnston S. Perforating eye injuries: a five year survey. Tranis Ophthalmiol SocUK 1971-;19:895-921.

I find that circumcision of adults done under local anaesthesia using abasal ring block of xylocaine without adrenalin is satisfactory, exceptfor some brief discomfort when cutting through the frenulum withscissors. Stitching this area causes few complaints. Can this discomfort beexplained on anatomical and physiological grounds and can it be remedied?

The distribution of sensory nerve fibres from the dorsal netve of thepenis is particularly profuse not only to the glans penis but also to theskin of the frenulum. Indeed, this region is characterised by thepresence within the papillae of the skin of specialised encapsulatedsensory nerve terminals. The most likely explanation for the dis-comfort on cutting the frenulum relates to this rich innervation andsuggests that the dorsal nerves of the penis are only partially blocked atthe time of surgery. An indication of the efficiency of the block can beachieved by testing sensation over the surface of the glans. It seemsunlikely that other nerves supplying the penis that lie deep to the siteof injection could be responsible for pei sistent sensation of thefrenulum. These autonomic cavernous nerves supply the vasculatureof erectile tissue and are not considered to carry afferent nerves fromthe skin of the penis.-JOHN GOSLING, professor of anatomy, Man-chester.

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