For

Rational

D rug

DECEMB ER 6, 1993

Selection

a n dU s e VOLUME 2, NO. 11 ISSN 1172-0360

Penicillins - StillUseful After AllThese Years

CONTENTS New Drugs and Therapeutics

The mo. t important considerations when prescribing penicillins are the likely . usceptibilitj of the pathogen and the ri k of serious hypersensitivity reaction . Benzylpenicillin (penicillin 0) and phenoxymethylpenicillin (penicillin V) retain activit) against streptococci. and represent effective therapies with low acquisition co . ts. Similarly. benzylpenicillin remain the preferred empirical therapy for adult bacterial meningitis and is generally uitablc for pneumococcal infec tions. Amoxicillin is recommended for the prophylaxis of po topcrative streptococcal cndocarditi '. In other indication. . for example empirical therapy of re. piratory tract infections. newer agents such as rnacrolides. fluoroquinolones and/or cephalo. porin are now preferred.

• Penicillins - Still Useful After All These Years

1

• Tiapride May Benefit Some Agitated Elderly Patients

4

• Hirudin Shows Potential Advantages Over Heparin

6

• Impro ving PCP Treatment in HIV-Infe cted Patients

7

• Management of , Renovascular Hypertension

9

Penicillin t prescribing guidelines must be frequently revi sited to keep abreast of local change s in bacterial epidemiology. Penicillins are still widely prescribed, I despite increa sing bacterial resistance.2.3 Indeed, more phenoxymethylpenicillin (penicillin V) was prescribed in Sweden in 1991 than any other orally administered antibacterial.! Since the discovery of penicillin in 1929, the range of available penicillins has expanded such that the class provides effective therapy for a wide range of Gram-positive and Gram-negative bacterial infections (see Differential Features table).2 However, bacteria have also progressed during this time . Pneumococci, gonococci and streptococci have become resistant to benzylpenicillin (penicillin G) in many parts of the world , and other antibacterials are now preferred in these area s.2.3

13

Clinical Use

Drug Reactions and Interactions • ECG May Give Early Warning of Drug Toxicity

The Differential Features table shows the penicillins recommended for use in selected indications.

Drug Economics and Quality of Life • Adjuvant Therapies in Women with Early Breast Cancer

Jais INTERNATIONAL

Staphylococci 14

Over 80% of Staphylococcus aureus strains produce ~-lactamase and so are resistant to benzylpenicillin and phenoxymethylpenicillin.P Therefore, a ~-lactamase-stable penicillin is generally required when staphylococcal infections are suspected. Cloxacillin , dicloxacillin, flucloxacillin, oxacillin, methicillin, ampicillinlsulbactam, amoxicillinlclavulanic acid , ticarcill in/clavulanic acid and piperacillin/tazobactam all have suitable antibacterial activity.f Methicillin may cause interstitial nephritis, and so other agents are preferred.I Of the other ~-lactamase-stable penicillins, the choice will be determined by local availability, route of administration and acqui sition costs, since all are similarly effective.I The penicillin/S-lactamase inhibitor combinations may be preferred as empirical therap y since they have activity again st Gram-negative and anaerobic organisms.> However, once infection with penicillin-sensiti ve S. aureus infection has been confirmed, penicillin monotherapy should be instituted. t The re is wide variation in the availability of penicillin s aro und the world. Opti ons discussed in this article are intend ed as a guide only.

-

2

Drugs & Therapy Perspecti ves Ed itor : Janel Kenyon Ass ocia te Ed it or: Mark Ca ldwe ll Group Ed itor ia l Di r ector: Ren nie C. Heel International Ed itor ia l Development Manager : Trevor M. Speight Editors. Cl inica l Pharmacology a nd Therapeutics: Paul Chrisp (Sen io r Editor ) Lee B. Barradell : Alan S, Beedl e: Step hen G. Co leman : Martin G, Harri s: Heathe r D. Langtry: Richard J. Milne: Katharine J. Palmer Editors. Drug Eva luati ons : Eugene M. Sorkin (Senio r Editor) Ju lia A. Balfour: Pau l Benfield: Rex I . Broudcn: Harriet M, Bryson; Rick Davis : Dian a Faulds: Andrew"Fillon: James E. Frampton: Jane C. Gillis : Karcn L. Goa: Malini Haria: Stephen M. Ho lliday: C. Rhoda Lee: Donna McTav ish: Anthon y Markham : David H. Peters: Grcg L. Plosker: Carolinc M . Spe ncer: Antona Wagstaff; Ruth Whittingtou: Michelle I. Wilde : Lynda R. Wiseman R 'se a rc h Ed ito rs :

Scott Mcwi lliams (Senior Editor; Claire Bcrkahn: hirlcv Co leman : Tracey E;.rI: Mar tin Gallagher: Ian Hutc hi~son : Stephanie lrvine: Pauline

McW illiams : Helen Me llsop: Robyn Millar: Toni Milne: Ca therine Rees: Nicola Ryan : Trac ey Taylor: Kelley Watson : Angela Woods

Publisher: Graeme S. Avery International Editorial Board D.J{.Aberneth y, Providence, NI. USA: C. D. Ha) 'IiO', London, Canada : E..I. Begg, Christchurch. Nt'II ' Zealand; T. Bergan. Oslo. NUI1\'al'; G. Bianchi Porro. Milan, ltalv: C. Bruter; Indianapolis, IN. USA: A.M. Bre ckcn r idge, Liverpoo]. UK: W.W. Busse. Madison, WI. USA: S.G . c«rr uth ers, Hulifax. Canada: G. Ca rstens , Hanover; Gl'I"IIUlIl\': .I.A..I.H. C r itc hlev, Hong Kong: R.O. Day. Sydl/e.': NSW A" :I'//'(//io: c. Dureau • . Paris. FI'lIIH'c: M. N.G. Dukes, Sorborg, DCI/II/ark; A. Ehihara, Tochigi-ken, Japan; L. E res hefsky, SanAntonio, TX. USA: S. Er ill, Barcelona, Spain ; S. E r us h, Phi/adelphia, H\. USA: P. Fallet, Paris. Fran ce ; .I. Feelv, DIIIJ/ill . lreland: R.G. Finc h. Nottingham. UK: S F rias . Madl:id. Spain : \ .H. Frishman. Bronx, NY, USA: S.T. Ga r ne r. Nottingluun, UK; 0 ..1. Greenblatt. BO.l'IoIl. MA . USA: R. G ug ler, Karlsruhe, Germanv: F,D. Hart. 1.0/1(/011, UK: D.A. Hen rv, Newcastle. NSlY. A/;slmlia: I. Hindmarch , Godulming, UK: T. Ish iza k i. Tokyo, Japan: R. .lnnknegt, Sittard. Netherlands ; G.L. Kearns, Lil/It, Nock. AN, USA: S.K. Lam, 1I 0II g KOlI g; P.P. Lam". Baltimore, MD. U A: M . Lev v, } el'll,\£III'III. Israel: W..I. Lou'is. Heidelberg. lIie. Australia: H'.1. Maibach, Sail Francisco. CA. USA; G . Mancla, MOI/ :a. ltalv; A. l\Ic Lelln . Melb ourne. Vic. Australia: A. Melander; Mal; ,;ij, Sweden: G.I<: Miselli, Neggio Ell/ilia, Italy ; P.A Mitcnko, Nanaitno, Canada: H:I: Mourldsen, Cop enhagen. Denmark; D. Nas h. Philadelphia. m. USA: i\l.O. Nielsen. /1/11'111'. Denmark: P.L. Nielsen, Frederikshavn, Denmark: H.C. eu, Nell' York. NY, USA; K. O·Malley. Dublin. Ireland: L.P. Opie, Cupt'

South Africa; M. Pucker, Nev: YtJrk. NY. USA; R. Pauwels. Ghent, Helgium: P. Persson. Stockholtn. Sweden: M.M. Reldcnberg, Ncll' Yurk, NY. USA: .I. Schentug, Bllflit/o, NY, USA: D-R . Suh n, Chilljll , Korea: Dc K. Sommers, Pretoria, South Africa; .A Terrugno, Buenos Aires. Argentina: i\l. Thomas, vcllorre. lndia: .I-I'. T illement, Cretcil, F/'(/II£.'e: G. Tognoni. Milan, ltuly: .I.H. Toogood. London. Canada ; C. Tugwell. Lon don, UK; T. ematsu, H OlI/ll l/I(J/ S Ii . Japan: c..I. van Boxtcl, Amsterdam. Neth erlands; R. E. Vesta l. Boise, ID. USA: H.B. Wong, Singapon: 7(111'1/.

Vol 2, No. 11; December 6, 1993

For staphylococcal meningitis, ~-lactamase-stable penicillins are needed . Combinations with ~-lactamase inhibitors are not useful , since the inhibitors do not penetrate the blood-brain

barrier-' The management of infections caused by methicillin-resistant S. au reus has been discussed previously ('Control of MRSA require s a range of measures' Drugs & Therapy Perspectives 2: 7- 10, 2 Aug 1993). Penicillins have no place in the control of such infections.l

Streptococci Benzylpenicillin remains the preferred drug for most streptococcal infections, although its usefulness in Streptococcus pneumoniae infections is diminishing. Strains of S. pneumoniae resistant to benzylpenicillin have been recorded in Europe, North America, Africa and Asia. 2•3 Antibacterials from other drug classes must be prescribed for patients with penicillin-resistant S. pneumoniae infection s, Vancomycin is the most active drug for use in this indication, although cefotaxime and ceftriaxone may be suitable alternatives.' For other streptococcal infections, benzylpenicillin remains very useful. 2 Intravenous dosages of 18 to 35 g/day t are needed for severe infections such as pneumonia, meningitis and endocarditis.? For less severe streptococcal infections, such as erysipelas, cellulitis and scarlet fever, lower dosages (8 to 20 g/day) may be administered intravenously or intrarnuscularly.I For the mildest infections, such as pharyngitis, orally administered phenoxymethylpenicillin may be used instead of parenteral benzylpenicillin.I S. viridans and S. faecalis are common causes of bacterial endocarditis. In patients susceptible to this infection (e.g. patients with congenital heart disease or heart valves affected by rheumatic fever) prophylaxis with amoxicillin is recommended as follows for adults in the UK. t • 3g orally I hour before dental extraction, scaling or periodontal surgery perfo rmed with no anaesthetic or under local anaesthesia. • For dental/periodontal procedures performed under general anaesthesia, choose between : Ig in 2.5ml of lidocaine (lignocaine) I% intramuscularly ju st before induction and 0.5g orally 6 hours later; 3g orally 4 hours before induction and 3g orally as soon as possible after surgery; or 3g plus probenecid Ig orally 4 hours before operation.P Children aged <5 years should receive 25% of the adult dose and children aged 5 to 10 years should receive 50% of the adult dose .? Clindamycin is recommended as endocarditis prophylaxis in penicillin-allergic patients," and aminogl ycosides are recommended in patients who have received amoxicillin more than once in the previous month .?

Neisseriaceae Penicillin resistance has become wide spread among strains of N. gonorrhoeae, and in many areas a third-generation cephalosporin or quinolone is preferred as initial therapy of uncomplicated gonorrhoea.I However, where susceptibility remains, benzylpenicillinor long-actingbenzylpenicillinsalts may be used-' Intravenous benzylpenicillin 10 to 15 g/day for 5 days is recommended as initial therapy of meningococcal meningitis in adults . Resistant N. meningitidis strain s do occur, but clinical failures are reported extremely rarely.i t In Germ any. the maximum dosage o f benzylpenicillin is 18 g/day (30 million IV) ; recommendations for endocarditis prophylaxis may vary between countri es: for example, in Germ any a regimen of phenox ymeth ylpenicillin O,6g I hour before and 6 hours after dental procedures may be used ,

ISSN JI72-0360/93//206-002/$/ ,OO
3

~

,7

I

Differential Features Comparison of the features of representatives of different classes of penicillins2,A Characteristic / featur e

Amp

Amox/c1av

Benzyl

Clox

Phen

Pip

Tem

Tic

Penicillin groupO

4

4

1

3

2

5

6

5

Oral bioavailability (%)

30-55

60 b

NPO

37-90

60-7 3

NPO

NPO

NPO

Reduce dosage in renal impairment? Mild Moderate Severe

./

./ ./

./C

./ ./

./ ./

./ ./

Recommended indicotionsd Gram-positive infections Staphylococcus aureus Coagulase-negative staphylococci Group A, B, C, and G streptococci Strep. pneumoniae Grom-neqotive infections BacteroIdes spp.h Citrobacter spp.. Escherichia coli

Klebsiella pneumoniae Proteus m/rabi!is P. vulgaris Neisseria gonorrhoeae N. meninr;fitidis Haemop.hllus influenzae Moroxella (Bronhamella) catarrhalis Treponema pallidum

./ ./ ./

./ ./ ./ ./

./9

./9

./ ./ ./

./ ./

./

./

./

a Group 1 = benzr~enicillin and its long-acting parenteral formulations; 2 = orally' absorbed penicllins similar to benzylpenicillin; 3 = staphylococca - Iactamase-resistant penicillins; 4 = extended spectrum penicillins; 5 = penicillins active ag a inst Pseudomonos aeruf}inosa; 6 = ~- actamase-resistant penicillins. b Wide individual variation. c Maximum 6 g/day. d Agents likely to be suitable for use as monotherapy in infections caused by sensitive strains of the pathogens shown. Local bacterial susceptibility must be considered. e Strains that do not produce ~- Iacta mase f Il-Lactamase-producins strains. 9 Phenoxymethyipenicillin should not be used to treat serious infections. It is mainly used for mild streptococcal pharyngitis or skin Infections and mild pneumococcal infections. h Except B. [ragilis. i Reserve for cepha losporin-resistant infections . Abbreviations and symbol: Amp = ampicillin; Amox/dav = amoxicillin/c1avulanic acid; Benzyl = benzylpenicllin [penicillin GIl' Clox = cloxacillin; phen = phenoxymethylpenicillin (penicillin V); Pip = piperacillin; Tem = temocillin; Tic = ticarcillin; NPO = not ora Iy administered; ./ = dosage reduction required!recommended Indication.

Enterobacteriaceae Enterobacteriaceae are generally resistant to penicillins in groups 1-4 (see Differential Features table for classification). Moreover, there is increasing resistance to group 4 penicillins among previously susceptibleEnterobacteriaceae such as Escherichia coli, Salmonella spp. and Shigella sfP . Fluoroquinolones may now be preferred in such infections. Groups 5 and 6 retain some activity against the Enterobacteriaceae, and activity may be conferred by combination with ~-lactamase inhibitors. 2,8 Nonetheless, bacterial resistance is of concern. Notably, piperacillin/tazobactam does not provide sufficient cover against Enterobacter cloacae.' For resistant Enterobacter species, thirdor fourth-generation cephalosporins or aminoglycosides should be used.2 Temocillin may be a suitable alternative for infections caused by cephalosporin-resistant Enterobacteriaceae. This drug may also be an alternative to imipenern/cilastatin in infections caused by multiresistant Gram-negative aerobes.?

Haemophilus influenzae and Pseudomonas aeruginosa H. influenzae is becoming increasingly resistant to the group 4 penicillins, and ampicillin is no longer suitable as

ISSN 1/72 -0360/93//206-003/$/.00 if)'Adis International Ltd

empirical therapy for upper and lower respiratory tract infections .? Amoxicillin/clavulanic acid, cephalosporins and macrolides are now recommended.2,10 However, ampicillin remains suitable for susceptible infections.? Ticarcillin , carbenicillin, azlocillin, mezlocillin and piperacillin all have useful antipseudomonal activity.I However, bacterial resistance can occur, and strains that are resistant to a group 4 penicillin are likely to be resistant to that penicillin in combination with a ~-lactamase inhibitor.f Ticarcillin and carbenicillin formulations have a high sodium content and the other agents are preferred.I Antipseudomonal penicillins should be combined with aminoglycosides for empirical therapy in neutropenic patients.I

Tolerability Penicillins are generally well tolerated. I I The most common adverse reaction is skin rash, which occurs most frequently with ampicillin. I I Ampicillin-induced rash appears different to the classical hypersensitivity reaction seen with other penicillins (see below), and does not seem to predispose patients to hypersensitivity reactions to other agents. I I

Vol. 2, No. 1/; December 6, 1993

-

4

I.

Adis Evaluation

8

Key po ints in the overall evaluation of penicilli ns CLINICAL BENEFITS _ • • • • • • • • • • • •

•

Chemica l modificationsand combination with p-Ia cta ma se inhibitors make different penicillins suitable for a wide range of indications

•

Generally well toleroted

POTENTIAL LIMITATIONS • • • • • • • • •_

•

Hypersensitivity reactions occur in up to 10% of patients treated, and there is cross-sensitivity between penicillins a nd some cephalospa rins

•

Bacterial resistance to penicillins is increasing

Penicillins may cause diarrhoea, particularly orally administered drugs that are not well absorbed (e.g. ampicillinj .l Hepatic disorders have been reported with isoxazolyl penicillins (e.g. flucloxacillin) and amoxicillin/clavu lanic acid, but not with amoxicillin alone. 12- 14 Interstitial nephritis is a significant drawback of methicillin therapy, and other agents are preferred.I Sod ium loads may be significa nt (>5 mmoUg for carbenicillin and ticarcillin, 1.85 to 2.17 mmol/g for azlocillin, mezlocillin and piperacillin j.f Drugs with lower sodium loads are preferred, particularly in patients with renal failure. Penicillins may cause encephalopathy, and should not be administered intrathecally,"

when making formulary and prescribing decisions. The temptation to prescribe broad spectrum antibacterials must be resisted. Always substitute specific therapy for broad spectrum empirical therapy once bacterial susceptibilities are known. Other factors include the route of administration required, the acquisition costs of the drug, and the availability of alternative agents with similar antibacterial activity. When prescribing for individual patients, penicillin hypersensitivity should be considered. In susceptible infections, ampicillin is preferred in pregnant women. This drug readily achieves therapeutic concentrations in maternal and fetal tissues, and is well tolerated by both mother and fetus.l ''

References I. Norrby SR. Pharma coliconomics 2: 238-244, 1992 2. Nathwani D, Wood MJ. Drugs 45: 866-894, 1993 3. Caputo GM , et al. Arch Intern Med 153: 1301-1 31 0, 1993 4. British National Formu lary 25:207-214,1993 5. Turnridge J. GraysonML. Drugs 45: 353-366. 1993 6. Simmons NA. etal. Lan cet 335: 88-89, 1990 7. Simmons NA, etal. Lancet 339: 1292-1 293. 1992 8. AcarJF. etal. J Antimicrob Chemother 31(Suppl. A) : 23-28. 1993 9. Livermore DM. J Antimicrob Chemo ther 31(Suppl. A): 9-21, 1993 10. Anon. Pharmaceutical Business News : 16-17. 26 Jul 1993 11. BrumfittW, Hamilton-Miller l MT. In Speight TM (Ed.) Avery's Drug Treatment 3rd edn, pp 1207-1235. Adis Press, Auckland, 1987 12. WongTS, ct al. Med J Au st 154: 698-70 I, 1991 13. Fairley CK, et al. Lanc et 339: 679, 1992 14. D'Arcy PE /IlI Pharm J 7: 140,1993 15. Lin RY. Arch Intern Med 152: 930-937, 1992 16. SognDO, et al. Arc h Intern Med 152: 1025-1032, 1992 17. Martin lA , ct al. Clin lnfect Dis 14: 592-593, 1992 18. NauH, Mirkin BL. In Speight TM (Ed.) Avery's DrugTreatment 3rd edn. pp 79-1 17, Adis Press,Auckland, 1987

Hypersensitivity Hypersensitivity reactions to penicillins have been estimated to affect up to 10% of treated patients. Estimates for anaphylaxis and fatal anaphylaxis indicate rates of 5 : 10000 and ~2 : 100000 patients treated, respectively.15 Patients with a positive history of penicillin allergy should undergo skin testing if penicillin therapy is indicated. Patients with a positive skin test reaction and a positive history should either undergo penicillin desensitisation or receive an alternative antibacterial. 15 Patients with a positive history but a negative skin test reaction appear to have an overall reaction rate similar to that in the general population, and penicillin administration may be appropriate.15 Clinicians must weigh the benefits of penicillin therapy against the relatively low risk of serious adverse effects in these patients. 15 Moreover, physicians should be aware that there is a 4-fold increase in risk of hypersensitivity reactions to first- and secondgeneration cephalosporins in patients with a history of penicillin allergy. The risk of hypersensitivity reactions in such patients appears to be much lower with third-generation cephalosporins.15 Controversy remains over which reagents to use when performing skin tests for penicillin allergy.15,16 Patients may be allergic to some penicillin groups but tolerant of others, so a comprehensive battery of skin test reagents may be required.17

Prescribing and Formulary Considerations As with all antibacterial drugs, penicillins must only be prescribed for infections known or suspected to be caused by sensitive bacteria. Thus, local bacterial epidemiology must be considered in conjunction with the broad outlines given above

Vol 2, No. JJ; December 6,1993

Tiapride May Benefit Some Agitated Elderly Patients Tiapride is worthy of consideration in elderly patient' with agitated behaviour, It appears to be at least as effective as other drugs used in thi: condition. including typical anti psychotics and bcnzodiazepincs. However. there is limited evidence for the efficacy of any drug in this indication. Thus. it is important to identify any underlying disorder for which a more defi nitive treatment is available. If there is no treatable underlying disorder, tolerability considerations direct the symptomatic control of agitat ion. Tiapride has tolerability advantages compared with benzodiazepines andotheruniipsychotics. andso may bepreferred over thcsc options. Agitation has been defined as inappropriate verbal, vocal or motor activity that is not considered to result directly from confusion or the needs of the patient. I Agitated behaviour includes cursing, pacing, hitting, inappropriate dressing and undressing, repetitive actions and questioning, and restlessness.' The behaviour of an agitated patient may be classified as aggressive, verbally agitated or as non-aggressive physical activity.I

/SSN 1/ 72-0360/93// 206 -004/$/ .00 0 Adis In ternational lid