sequential antibiotic therapy: effective cost management

Sequential antibiotictherapy: Effective cost

management andpatient care

LIONEL A MAN DELL MD FRCPC, MICHEL G BERG ERON MD ABIM FRCPC, MARIE J GRIB BLE MD ChB ABIM FRCPC,PETER J JEW ES SON PhD FCSHP, DON ALD E LOW MD FRCPC, THO MAS J MAR RIE MD FRCPC, LIND SAY E NICOLLE MD FRCPC

RE VIEW

Division of Infectious Diseases, McMaster University, Hamilton, Ontario; Department of Microbiology, Université Laval and Labratoire etservice d’infectiologie, Centre Hospitalier de l’Université Laval, Québec, Québec; University of British Columbia and Division of InfectiousDiseases, University Hospital, Vancouver, British Columbia; Faculty of Pharmaceutical Sciences, University of British Columbia andDepartment of Pharmacy, Department of Medicine, Division of Infectious Diseases, Vancouver Hospital and Health Sciences Centre,Vancouver, British Columbia; Departments of Microbiology and Medicine, University of Toronto and Department of Microbiology, Mount SinaiHospital and Princess Margaret Hospital, Toronto, Ontario; Dalhousie University and Department of Medicine, Victoria General Hospital,Halifax, Nova Scotia; Internal Medicine and Medical Microbiology, University of Manitoba and Infection Control Unit, Health Sciences Centre,Winnipeg, Manitoba

Correspondence: Dr Lionel A Mandell, Head, Division of Infectious Diseases, McMaster Medical Unit, Henderson General Hospital, 711Concession Street, Hamilton, Ontario L8V 1C3. Telephone 905-574-8520, fax 905-575-7320, e-mail [email protected]

Received for publication May 17, 1995. Accepted August 11, 1995

LA MAN DELL, MG BERG ERON, MJ GRIB BLE, et al. Se quen tial an ti bi otic ther apy: Ef fec tive cost man age ment and pa -tient care. Can J In fect Dis 1995;6(6):306- 315. The es ca lat ing costs as so ci ated with an ti mi cro bial che mo ther apyhave be come of in creas ing con cern to phy si cians, phar ma cists and pa tients alike. A number of strate gies have beende vel oped to ad dress this prob lem. This ar ti cle fo cuses spe cifi cally on se quen tial an ti bi otic ther apy (SAT), which is thestrat egy of con vert ing pa tients from in tra ve nous to oral medi ca tion re gard less of whether the same or a dif fer ent class of drug is used. Ad van tages of SAT in clude eco nomic bene fits, pa tient bene fits and bene fits to the health care pro vider. Po -ten tial dis ad van tages are cost to the con sumer and the risk of thera peu tic fail ure. A criti cal re view of the pub lished lit era -ture shows that evi dence from ran dom ized con trolled tri als sup ports the role of SAT. How ever, it is also clear that fur therstud ies are nec es sary to de ter mine the op ti mal time for in tra ve nous to oral changeo ver and to iden tify the vari ables thatmay in ter fere with the use of oral drugs. Pro ce dures nec es sary for the im ple men ta tion of a SAT pro gram in the hos pi talset ting are also dis cussed.

Key Words: Cost ef fec tive ness, In tra ve nous an ti bi otic ther apy, Oral an ti bi otic ther apy, Qual ity of life, Se quen tial an ti bi -otic ther apy

Antibiothérapie séquentielle : rentabilité et soinsRÉS UMÉ : Les coûts sans cesse crois sants as so ciés à l’an ti bio thé ra pie in quiètent de plus en plus les médecins, lesphar ma ci ens et les pa tients. Cer taines straté gies ont été mises au point pour répon dre à ce pro blème. Le pré sent ar ti cle s’at tarde plus pré cisément au traite ment anti bio tique séquen tiel, une straté gie par laquelle les pa tients pas sent de laforme in traveineuse à la forme orale d’un médica ment, qu’il s’agisse ou non de pro duits d’une même classe. Parmi lesavan tages de l’an ti bio thé ra pie séquen tielle, no tons l’as pect économique et la com modité pour le pa tient et pour le per -son nel soign ant. Les désa van tages po ten tiels sont les coûts as sumés par le con som ma teur et le risque d’é chec thé ra -peu tique. Une ana lyse cri tique de la litté ra ture pub liée révèle que les données ti rées d’es sais con trôlés ran domisésap pui ent l’an ti bio thé ra pie séquen tielle. Toute fois, il faut de toute évi dence pour suivre les études afin de dé ter mi ner lemo ment idéal du pas sage de la forme in traveineuse à la forme orale et d’iden ti fier les vari ables qui peu vent in terfé reravec l’em ploi des médica ments par voie orale. Les étapes né ces saires à l’ap pli ca tion d’un pro gramme d’an ti bio thé ra -pie séquen tielle dans le con texte hos pi tal ier sont égale ment dé crites.

306 CAN J IN FECT DIS VOL 6 NO 6 NO VEM BER/DE CEM BER 1995

O VER THE PAST TWO DEC ADES, OUR THERA PEU TIC ARMAMEN -tarium has been greatly ex panded with agents that pro -

vide ex cel lent an ti mi cro bial ac tiv ity com bined with im provedphar ma coki netic fea tures and im proved ad verse ef fect pro -files. At the same time, how ever, eco nomic con straints andhos pi tal bed clo sures have forced us to con sider ap proachesother than tra di tional in- hospital in tra ve nous an ti bi otic use.We now have a number of op tions that fa cili tate and sim plifypa tient care and re duce costs. These in clude home in tra ve -nous ther apy and oral ther apy us ing agents that do not com -pro mise thera peu tic ef fi cacy.

This pa per re views some of the eco nomic is sues as so ci -ated with an ti mi cro bial ther apy and ex am ines the treat ment of in fec tions with in tra ve nous an ti mi cro bi als and the sub se quent use of oral agents. This prac tice is re ferred to as se quen tialan ti bi otic ther apy (SAT); sim ply stated, it is the prac tice ofchang ing from in tra ve nous to oral dos age forms as early dur -ing a course of an ti bi otic treat ment of in fec tion as is clini callypos si ble.

COST CON TAIN MENT IS SUESAn ti bi ot ics are among the most com monly pre scribed

drugs in Can ada. Ac cord ing to the Fifth An nual Re port of thePat ented Medi cine Prices Re view Board (1), to tal Ca na dianpat ented pre scrip tion drug reve nue was over $2 bil lion in1992. Anti- infective agents, cost ing $354 mil lion, ac countedfor the larg est number of pat ented drug prod ucts sold in Can -ada. The cost of in jecta ble an ti bi ot ics alone was $110 mil lion(2). In any Ca na dian hos pi tal, an ti bi ot ics of ten rep re sent thesin gle larg est com po nent of the hos pi tal phar macy budget,ac count ing for 20 to 40% of to tal drug costs.

In an at tempt to cope with in creas ing costs, sev eral strate -gies have been de vel oped and im ple mented and may beclas si fied as ‘ed uc ative and per sua sive’, ‘f acil it ative’ and ‘r -estri ctive’ strate gies (3). The fol low ing list in cludes most ofthese:

• pre scriber edu ca tion• for mu lary re stric tion and re served an ti mi cro bial pro -

gram• se lec tive re port ing of sus cep ti bil ity test ing• auto matic stop poli cies• thera peu tic in ter change pro grams• an ti mi cro bial or der forms• re quired con sul ta tion and phy si cian or serv ice re stric -

tion• SAT (3).It is be yond the scope of this ar ti cle to deal with all these

cost con tain ment strate gies; our pur pose is to fo cus spe cifi -cally on SAT.

SE QUEN TIAL AN TI BI OTIC THER APYSAT re fers to the prac tice of lim it ing the use of in tra ve nous

an ti bi ot ics to the early stages of in fec tion and then con vert ingto oral agents for the du ra tion of treat ment.

SAT is not as new an ap proach to cost ef fec tive an ti bi oticpre scrib ing as one might think. Stud ies pub lished in the 1970s in volv ing chil dren with os teo mye li tis and sep tic ar thri tis dem -

on strated the ef fi cacy and safety of ini tial treat ment with par -enteral an ti bi ot ics fol lowed by con ver sion to oral agents assoon as the acute signs and symp toms of in fec tion were con -trolled (4-8).

In a 1991 sur vey of an ti bi otic de ci sion mak ing at a 1000- bed ter ti ary care hos pi tal, Quin tili ani et al (9) re ported that an -ti bi otic ther apy could be ‘strea mlined’ in ap proxi mately 75% of pa tients in one of three ways: first, by chang ing from com bi na -tion ther apy to mono ther apy; sec ond, by chang ing to an otheragent with a nar rower an ti mi cro bial spec trum of ac tiv ityand/or to one with pref er able phar ma coki net ics; and third, bychang ing the route of ad mini stra tion from in tra ve nous to in tra -mus cu lar or oral.

This con cept of stream lin ing from a more com plex, of tenmore ex pen sive, regi men to a less com plex one has alsobeen re ferred to in the lit era ture as ‘ste pdown ther apy’, ‘switc -hing’ or ‘s eque ntial ther apy’. How ever, these terms have notal ways been used syn ony mously.

For ex am ple, step down ther apy and switch ing have beenused to de note not only a change from in tra ve nous to the oralform of the same drug, but also a change to a dif fer ent drugonce the con ver sion to oral ther apy has been made (10,11).Like wise, se quen tial ther apy has been used to de note achange from in tra ve nous to oral forms of the same drug or dif -fer ent drugs (12,13). Stream lin ing has also been used to de -note the change from com bi na tion ther apy to mono ther apy(14). It might, there fore, avoid con fu sion by es tab lish ing acom mon ter mi nol ogy for de scrib ing con ver sion from in tra ve -nous to oral medi ca tions. Not only would this make dis cus sion of such treat ment strate gies eas ier, it would aid in cata logu ing the medi cal lit era ture deal ing with this sub ject. We pro posethat the term ‘s equen cing’ or ‘s eque ntial an ti bi otic ther apy’ beused to de fine the strat egy of con vert ing pa tients from in tra ve -nous to oral medi ca tions, re gard less of whether the same or a dif fer ent class of drug is used.

AD VAN TAGES AND DIS AD VAN TAGES OF SATThere are sound clini cal and fi nan cial rea sons to pur sue a

thera peu tic strat egy that in cor po rates ap propri ate early con -ver sion from in tra ve nous to oral anti microbials. Some phy si -cians re main re luc tant to do this, per haps be cause of a lack of knowl edge and ap pre cia tion of the ef fi cacy and ad van tagesof such a strat egy, as well as the sense of se cu rity pro videdby the se rum and tis sue drug lev els ob tained us ing in tra ve -nous drugs. This re luc tance has, un for tu nately, fos tered theun nec es sar ily pro longed use of in tra ve nous medi ca tions inthe hos pi tal set ting for treat ment of in fec tions that could bene -fit from a short ened course of in tra ve nous treat ment fol lowedby oral ther apy.Ad van tages of SAT: Three main bene fits are as so ci ated with the use of SAT: eco nomic bene fits, pa tient bene fits and bene -fits to the health care pro vider.Eco nomic bene fits: With any drug, there are two costs tocon sider: the more ob vi ous or ap par ent cost of the agent, re -ferred to as the ac qui si tion cost, and the sec on dary costs re -lated to de liv ery or ad mini stra tion of the drug. The lat terin clude a va ri ety of fac tors, such as a phar ma cist’s prepa ra tion

CAN J IN FECT DIS VOL 6 NO 6 NO VEM BER/DE CEM BER 1995 307

Se quen tial an ti bi otic ther apy

and de liv ery time; a nurse’s ad mini stra tion time; an cil lary sup -plies, such as in tra ve nous bags and tub ing; loss due to wast -age; and the need for labo ra tory moni tor ing of drug se rumlev els, as is re quired with ami no gly cosides and van co my cin.All these fac tors con trib ute to the cost of drug ther apy andshould be con sid ered when the cost of a par ticu lar drug isevalu ated.

Prepa ra tion and ad mini stra tion costs vary among hos pi -tals. Rush (15) re ported that the cost of prepa ra tion and ad -mini stra tion added US$7.00 to the cost of each dose ofin tra ve nous an ti bi otic. In Aus tra lia, such costs add be tweenAUS$4.55 and $10.58 to the cost of each in tra ve nous dose(16). Oth ers have re ported that, by sim ply re plac ing one in tra -ve nous an ti bi otic with an other that is given less fre quently,sub stan tial cost sav ings are re al ized, even when the ac qui si -tion cost of the re place ment drug is higher (17,18). For ex am -ple, at one Ameri can hos pi tal, the to tal daily ad mini stra tioncost of peni cil lin G 3x106 U given in tra ve nously every 4 h isUS$29.26 (17), yet the cost of ce fa zolin 1 g in tra ve nouslyevery 8 h is only US$14.60.

Gen er ally, ac qui si tion costs for the in tra ve nous form of adrug are greater than those of the oral form. Some ex am plesof these com para tive costs are given in Ta ble 1. The use oforal agents ob vi ates the need for most, if not all, an cil larycosts.

At the Van cou ver Hos pi tal and Health Sci ences Cen tre, an in tra ve nous to oral an ti bi otic con ver sion pro gram has been inplace since 1987. Chang ing from in tra ve nous to oral ther apyus ing drugs such as met roni da zole, clin da my cin, cipro floxa -cin, flu cona zole, ce fu rox ime and ce fixime has re sulted in sav -ings of at least $30,000 yearly (10,11). Hart ford Hos pi tal inCon necti cut pro jected an an nual sav ing of US$107,637 based on an an ti bi otic stream lin ing pro gram (14).

An other ma jor fi nan cial sav ing is re al ized by the ear lier dis -charge of the pa tient from the hos pi tal. This elimi nates the ex -penses as so ci ated with hous ing a pa tient in an acute care

fa cil ity solely for the pur pose of ad min is ter ing in tra ve nous an -ti bi ot ics (19).

The mag ni tude of cost sav ings that can ac crue by se -quenc ing from in tra ve nous to oral treat ment is ap par ent froma mul ti cen tre study in the United States in volv ing 766 hos pi -tal ized pa tients. Af ter suc cess ful con ver sion to oral cipro -floxa cin from a va ri ety of par enteral an ti mi cro bial agents, 418pa tients were dis charged from the hos pi tal ear lier than wouldhave oth er wise oc curred. An es ti mated to tal of 2266 hos pi taldays were saved, re sult ing in sav ings of US$793,100. Pro -jected sav ings for to tal drug plus hos pi tali za tion costs wereUS$980,246 (20).Pa tient bene fits: Al though less quan ti fi able than the moretan gi ble fi nan cial gains, patient- related bene fits are nev er the -less real and im por tant. In hos pi tal, the use of oral in stead of in tra ve nous drugs in creases pa tient com fort and mo bil ity, the lat ter be ing a par ticu larly im por tant con sid era tion in the eld -erly. By not us ing in tra ve nous lines, there is less risk of phle bi -tis and line- related in fec tions. The ear lier dis charge fromhos pi tal also de creases the risk of de vel op ment of other no -so comial in fec tions. An ear lier re turn to fam ily and, pos si bly, to work pro vides bene fits in terms of en hanced qual ity of life aswell as pos si ble eco nomic bene fits.Health care pro vider bene fits: Con sid er able time is spent by phar ma cists and nurses in pre par ing and ad min is ter ing in tra -ve nous an ti bi ot ics. Use of SAT de creases the amount of per -son nel time as so ci ated with drug de liv ery and, al though theac tual bene fits of ‘saved time’ are dif fi cult to as sess, it mayserve to free the in di vid ual for other tasks that may im provepa tient care and en hance job sat is fac tion for the health carepro vider.Dis ad van tages of SAT: There are two per ceived dis ad van -tages with SAT: eco nomic and risk of thera peu tic fail ure.Eco nomic dis ad van tages: While re ceiv ing medi ca tion in the hos pi tal, the pa tient is not re spon si ble for any of the drug- related costs. How ever, once dis charged, the con sumer mustbear the cost of ther apy. It is there fore im por tant to dis cuss thecost of ther apy with the pa tient be fore dis charge.Risk of thera peu tic fail ure: Pa tient com pli ance with treat -ment while in the hos pi tal is taken for granted. How ever, onceout side the hos pi tal this be comes much more dif fi cult to en -sure. Poor com pli ance with the planned oral treat ment regi -men could re sult in treat ment fail ure or re lapse of in fec tion.Re ad mis sion of the pa tient to the hos pi tal would quickly off setany cost sav ings re al ized by a change to oral ther apy.

An other po ten tial prob lem is that in com plete or in ade quate treat ment of in fec tion may con trib ute to the de vel op ment ofmi cro bial re sis tance, mak ing it nec es sary to use more ex pen -sive or pos si bly more toxic agents to treat in fec tion.

In a study that spe cifi cally ex am ined pa tient com pli ancewith an oral regi men, Paladino et al (21) docu mented an 81%com pli ance rate in out- patients tak ing cipro floxa cin twice daily fol low ing ini tial treat ment with in tra ve nous an ti bi ot ics in hos pi -tal. Thera peu tic out comes in this group were ex cel lent de -spite com pli ance rates of less than 100%. Com pli ance rateswere also ex am ined by Cra mer et al (22), who showed re sults iden ti cal to those de scribed by Paladino et al for twice- daily

TA BLE 1Ac qui si tion cost of one dose of com monly pre scribed an -ti bi ot ics*

Drug Dose (route) Ac qui si tion cost ($)Ampicil lin 1-2 g (IV) 0.70-1.40Amox icil lin 500 mg (PO) 0.08Ce fu rox ime 750 mg-1.5 g (IV) 6.93- 12.29Ce fu rox ime axetil 500 mg (PO) 2.60Cipro floxa cin 400 mg (IV)

250-750 mg (PO)33.00

2.22-4.73Clin da my cin 600 mg (IV)

300- 450 mg (PO)12.86

1.58-2.38Met roni da zole 500 mg (IV)

500 mg (PO)1.490.04

Tri methoprim-sul famethoxa zole

160 mg/800 mg (IV)160 mg/800 mg (PO)

3.200.04

*Prices sup plied by pur chas ing de part ment, Hender son Gen eral Di vi sion,Ham il ton Civic Hos pi tals, Ham il ton, On tario, De cem ber 1993. IV In tra ve nous;PO Oral

MAN DELL et al


dos ing, while slightly higher com pli ance rates were seenwhen medi ca tion was given once daily (87%). When dos agefre quency was in creased to four times a day, com pli ancerates dropped dra mati cally, ie, from 87% to 39%.

Even if the pa tient is com pli ant, thera peu tic fail ures maystill oc cur be cause of drug in ter ac tions that de crease thebioa vail abil ity of oral an ti bi ot ics. It is im por tant that all pre -scrip tion medi ca tions be re viewed with the pa tient at the timeof dis charge from hos pi tal to en sure that no un to ward drug in -ter ac tions oc cur while the an ti bi ot ics are be ing taken at home. It is also im por tant to re view the use of any non pre scrip tionagents. For ex am ple, ant ac ids have been shown to re ducethe ab sorp tion of oral qui nolones, tet ra cy cline, met roni da zoleand cefpo dox ime proxetil; thus, pa tients should be ad vised tosepa rate ant acid use from in ges tion of these an ti bi ot ics by atleast 2 h (23). The use of oral iron prepa ra tions should also be avoided in pa tients be ing treated with qui nolones and tet ra cy -clines be cause iron de creases the ab sorp tion of these drugs(24). In ges tion of milk and other dairy prod ucts can also in ter -fere with the ab sorp tion of oral tet ra cy cline and, to a lesser ex -tent, of qui nolones (25).

CRI TE RIA FOR SE LEC TION OF PA TIENTS ANDDRUGS FOR SAT

Phy si cians have al ways been more com fort able us ing par -enteral rather than oral drugs when treat ing se ri ous in fec tion,ow ing to con cerns about drug ab sorp tion, bioa vail abil ity, andse rum and tis sue lev els when oral agents are used. In the se -lec tion of pa tients for con ver sion to oral ther apy, sev eral cri te -ria should be ful filled: the pa tient should be he mo dy nami callysta ble, able to in gest and swal low oral drugs and should havea function ing gas tro in tes ti nal tract. Yet, al though oral anti -microbial ac tiv ity can of ten be con sid ered as early as threedays af ter ini tia tion of in tra ve nous ther apy in sta ble pa tients,some in di vidu als are not given oral ther apy un til they are dis -charged, ie, usu ally af ter at least seven days of in tra ve noustreat ment.

There are nu mer ous re ports in the lit era ture of the suc -cess ful use of in tra ve nous fol lowed by oral an ti bi ot ics fortreat ment of se ri ous in fec tions. Many in volve in tra ve nous tooral se quenc ing within the same class of drugs, while somein volve a change in drug class. Among the con di tions treatedwith SAT are pneu mo nia (both com mu nity and hos pi tal ac -quired), pye lonephri tis, sep tic ar thri tis, os teo mye li tis, and skin and skin struc ture in fec tions.

If the above cri te ria are ful filled, the next step is to se lectthe an ti mi cro bial that is most ap pro pri ate. The main thera peu -tic ob jec tive in chang ing from in tra ve nous to oral ther apy is toob tain se rum and tis sue an ti mi cro bial ac tiv ity that is com pa ra -ble with that ob tained with the in tra ve nous for mu la tion(26,27). Many oral agents have bioa vail abili ties that are simi -lar to those of their par enteral forms. These in clude suchdrugs as met roni da zole, clin da my cin, chlo ram phenicol, flu -cona zole and cipro floxa cin (10,28-32). Sev eral of these drugs have vir tu ally equiva lent bioa vail abil ity whether given in tra ve -nously or orally.

Use of these drugs as part of a se quen tial ther apy regi men



can help to al le vi ate the phy si ci an’s con cerns about subop ti -mal drug con cen tra tions when the switch to oral ther apy ismade, be cause it is gen er ally ac cepted that these oral agentspro vide ade quate thera peu tic ef fi cacy (10,11,27). Some an ti -bi ot ics with oral bioa vail abili ties lower than those of their in tra -ve nous for mu la tions have nev er the less been use ful inse quen tial ther apy. Such is the case for trimethoprim- sulfa -methoxazole, ampicil lin and ce fu rox ime axetil (9,10, 33).

Much has been writ ten about the phar ma coki net ics of in -tra ve nous and oral cipro floxa cin sup port ing the use of the oral form in in tra ve nous to oral se quenc ing (30,31,34,35). For ex -am ple, with an av er age un im peded bioa vail abil ity of 75% (inthe ab sence of sub stances that in ter fere with ab sorp tion), anoral dose of 500 mg cipro floxa cin pro vides an amount of drugequiva lent (ie, sta tis ti cally simi lar to the area un der the curve)to that ob tained with a 400 mg in tra ve nous dose (36).

Other qui nolones, such as ofloxa cin (not avail able par -enter ally in Can ada), also have nearly iden ti cal phar ma coki -netic char ac ter is tics when given in tra ve nously and orally, and all qui nolones ap pear to have high vol umes of dis tri bu tion and rela tively low pro tein bind ing (31). Most qui nolones at tain tis -sue con cen tra tions that ex ceed the mini mal in hibi tory con -cen tra tion val ues of the com mon aero bic patho gens (37).

When se lect ing an oral agent, the phy si cian should takeinto ac count a number of fac tors in clud ing bio a vail abil ity, clini -cal ef fi cacy, tol er abil ity and cost.

EVI DENCE SUP PORT ING SATRules of sci en tific evi dence that can be used to as sess

pub lished data have been de vel oped and pub lished as part of a se ries of clini cal epi de mi ol ogy rounds (38). Six cri te ria areused to as sess ar ti cles and to de ter mine the va lid ity and ap -pli ca bil ity of the re sults. These are:

1. Was the assignment of patients to treatment trulyrandomized?

2. Were all clinically relevant outcomes reported?

3. Were the study patients recognizably similar to yourown?

4. Were both statistical and clinical significanceconsidered?

5. Is the therapeutic manoeuvre feasible in yourpractice?

6. Were all patients who entered the study accounted forat its conclusion?

A lit era ture search re vealed 32 pub lished stud ies of in fec -tions treated us ing SAT. Of these, 13 were ran dom ized con -trolled tri als and 19 were non ran dom ized. These stud ies aresum ma rized in Ta bles 2 and 3, re spec tively.

The rules of evi dence “con sti tute ap plied com mon senseand are de signed to maxi mize the ef fi ciency as well as the ac -cu racy” of one’s jour nal read ing (38). With this in mind, the ar -ti cles were first strati fied into those that would be sub jected tothe rules of evi dence and those that would not. Since the criti -cal is sue is whether SAT would per form as well as stan dardther apy, the stan dard, or con trol arm of a com para tive study,

ide ally should con sist of in tra ve nous ther apy. If both the ex -peri men tal and con trol arms use SAT, the is sue is con founded. Also, since the ran dom as sign ment of pa tients mini mizesmuch of the bias as so ci ated with non ran dom ized clini cal tri -als, use of a ran dom ized con trol de sign is es sen tial. Of the 32pa pers, only six meet these cri te ria (Ta ble 4). The rest are ei -ther ran dom ized con trolled tri als, but with in ap pro pri ate con -trol arms, or are non ran dom ized tri als.

For the pur poses of this pa per, clini cally rele vant out -comes were suc cess ver sus fail ure of clini cal re sponse. Suc -cess in cluded both cure and im prove ment. Bac te rio logi calre sponse per se was not con sid ered as im por tant and wasviewed as a sur ro gate marker. Sta tis ti cal sig nifi cance has nobear ing on whether the re sult is im por tant, but sim ply re fers to the like li hood that a par ticu lar re sult was ob tained by chance.Con sid era tion of sta tis ti cal is sues took into ac count whethersta tis ti cal tests were done and, if so, whether a dif fer ence was found that was as so ci ated with P<0.05 or, if not sta tis ti callysig nifi cant, whether the sam ple size was large enough to ruleout a type II er ror.

Clini cal sig nifi cance, on the other hand, does re late to theim por tance of a par ticu lar find ing. A dif fer ence in out comesbe tween treated and con trol pa tients “be comes clini cally sig -nifi cant when it leads to changes in clini cal be hav ior” (38). Inthe case of SAT ver sus con ven tional ther apy, ei ther a dif fer -ence in fa vour of SAT or no dif fer ence be tween them is rele -vant since, in the lat ter in stance, the im pli ca tion is that byus ing in tra ve nous to oral switchover money is saved, there isim prove ment in the qual ity of life for the pa tient, or both.

Among these six pa pers, the main flaws are in the sta tis ti -cal con sid era tions. From the point of view of ex peri men tal de -sign, the best study was that of Kalager et al (39). The con trolarm con sisted of two drugs – both ef fec tive against mostaero bic Gram- negative ba cil lary patho gens. The sam ple sizewas the larg est, and the sta tis ti cal analy sis was the most rig -or ous. Only three of the six stud ies (40- 42) ex am ined pa tients with only one type of in fec tion, while the other three(39,42,43) stud ied pa tients with a va ri ety of in fec tions, eg,lower res pi r a tory tract, uri nary tract, and skin and soft tis suein fec tions.

In one trial (not in cluded in any of the ta bles) both com -para tive and non com para tive study arms were used (45). The com para tive arm ran dom ized pa tients to ei ther ofloxa cin or athird- generation cepha lo sporin (cef tazidime or cef tri ax one)for treat ment of pneu mo nia, uri nary tract in fec tion, or skin and soft tis sue in fec tion. How ever, of the 22 pa tients ran dom izedto re ceive ofloxa cin, only eight were given se quen tial in tra ve -nous to oral treat ment. It is not clear from the pa per whether adi rect com pari son was made be tween this small group ofeight pa tients and those re ceiv ing in tra ve nous ther apy alonewith a third- generation cepha lo sporin. The authors do, how -ever, state that “none of the eight sub jects who were ran dom -ized to ofloxa cin and who re ceived ini tial par enteral ther apyde te rio rated when switched to oral ofloxa cin ther apy.” In thenon com para tive study arm, pa tients were treated with oralofloxa cin only.

MAN DELL et al


IM PLE MEN TA TION OF SATIn hos pi tals where SAT pro grams are par ticu larly suc cess -

ful, they are usu ally de vel oped jointly by the in fec tious dis -ease and phar macy de part ments work ing in con junc tion withthe Phar macy and Thera peu tics Com mit tee. To fa cili tate thein tro duc tion of SAT into a par ticu lar hos pi tal, the ap pro pri atein fra struc ture must first be cre ated. To do this, the col labo ra -tive ef forts of mem bers of the phar macy, mi cro bi ol ogy, in fec -tious dis ease, nurs ing and ad mini stra tion de part ments arere quired. The mul ti dis ci plin ary per spec tive pro vided by thesegroups al lows the suc cess ful im ple men ta tion of rec om men -da tions made by the Phar macy and Thera peu tics Com mit tee.

In te gral to this pro gram is the use of ‘s eque ntial ther apy re -mind ers’. These edu ca tional tools, de vel oped at the Van cou -ver Hos pi tal and Health Sci ences Cen tre, are highly visi bleprinted forms with the nec es sary in for ma tion on them (46). Atthe Hender son Gen eral Di vi sion of the Ham il ton Civic Hos pi -tals, for ex am ple, when a pa tient is started on a drug in tra ve -nously for which an oral prepa ra tion is also avail able, thephar ma cist sends the se quen tial ther apy re minder, printed on bright yel low pa per, to the ward to gether with the in tra ve nousdrug. The ward nurse then at taches this yel low sheet to thefront of the pa ti ent’s chart, where it re mains un til the in tra ve -nous drug is ei ther dis con tin ued or changed to an oral form.An ex am ple of such a form is pro vided in Fig ure 1. In for ma tion rele vant to SAT is printed on the form, thereby pro vid ing anedu ca tional serv ice as well as a re minder to the phy si cian that oral ther apy should be con sid ered.

Some of the chal lenges in the im ple men ta tion of SAT arere sis tance to change on the part of medi cal col leagues; a per -ceived in crease in work load by those in volved in man ag ingthe SAT pro gram; and phy si cian re luc tance be cause of medi -cal and/or le gal con cerns. Ex pe ri ence with SAT pro gramshas shown that they are, in fact, rela tively easy to im ple -ment and are read ily ac cepted by phy si cians and otherhealth care per son nel pro vided that the ap pro pri ate leg -work is done and the nec es sary in fra struc ture is first cre -ated. To help im plement SAT, it is im pera tive that col leaguesbe edu cated con cern ing an ti mi cro bial costs, sup port of chiefsof serv ices as well as col leagues be en listed, and con tinu oussur veil lance and feed back to col leagues re gard ing the suc -cess of the pro gram be as sured.

CON CLU SIONSSince the 1970s, medi cal lit era ture has docu mented the

clini cal ef fi cacy of con vert ing pa tients from in tra ve nous an ti bi -otic ther apy to oral an ti bi otic ther apy as early as three days af -ter ini tia tion of in tra ve nous ther apy in sta ble pa tients. Yet,such pa tients tra di tion ally have not been given oral ther apyun til hos pi tal dis charge, ie, usu ally af ter at least seven days of in tra ve nous treat ment. The use of drugs that have vir tu allyequiva lent bioa vail abil ity in in tra ve nous and oral forms, suchas met roni da zole, clin da my cin, flu cona zole and cipro floxa cin, can help al le vi ate phy si cian con cerns about subop ti mal drugcon cen tra tions when con vert ing to oral ther apy, and can per -haps in crease the ac cep tance of SAT. A criti cal re view of themedi cal lit era ture sup ports the role of SAT. What is also clear,how ever, is that fur ther stud ies are nec es sary to de ter minethe ideal time for in tra ve nous to oral con ver sion and fac torsthat may limit or im pede the use of oral ther apy.

We con clude that SAT is not only an im por tant tool for re al -iz ing sub stan tial cost sav ings in the treat ment of pa tients withse ri ous in fec tions, but can greatly add to pa tient com fort and

TA BLE 4Clini cal tri als com ply ing with rules of sci en tific evi dence

Author (ref er ence)Ran dom ized

con trolled trialStudy pa tients simi lar

to your ownCon sid era tion of is sues Ma noeu vre fea si ble

in your prac ticeAll pa tients

ac counted forSta tis ti cal Clini calKalager et al (37) Yes Yes Yes Yes Yes YesDom inguez et al (38) Yes Yes No Yes Yes YesGaut et al (41) Yes Yes No Yes Yes YesFass et al (42) Yes Yes No Yes Yes YesCox (39) Yes Yes No Yes Yes YesGangji et al (40) Yes Yes No Yes Yes Yes

Fig ure 1) An ex am ple of se quen tial ther apy re mind ers (ref er ence 46)



pro duc tiv ity. Hos pi tals must play a pro ac tive edu ca tional rolein im ple ment ing SAT pro grams if this im por tant thera peu ticstrat egy is to be come the fu ture stan dard of care.

AC KNOW LEDGE MENTS: Prepa ra tion of this pa per was sup portedby Bayer Inc Health care Di vi sion.

REF ER ENCES1. Patented Medicine Prices Review Board, Canada. Fifth Annual Report, for

the year ended December 31, 1992. Ottawa: Ministry of Supply andServices Canada, 1993:16-8.

2. IMS Data: Drugstore and Hospital Purchases. Plymouth Meeting: IMSAmerica, 1992.

3. Health Services Directorate, Health Services and Promotion Branch; andBureau of Communicable Disease Epidemiology, Health ProtectionBranch, Health and Welfare Canada. Guidelines for antimicrobialutilization in health care facilities. Can J Infect Dis 1990;1:64-70.

4. Feigin RD, Pickering LK, Anderson D, Keeney RE, Shackleford PG.Clindamycin treatment of osteomyelitis and septic arthritis in children.Pediatrics 1975;55:213-23.

5. Walker SH. Staphylococcal osteomyelitis in children. Success withcephalordine-cephalexin therapy. Clin Pediatr 1973;12:98-100.

6. Tetzlaff TR, McCracken GH, Nelson JD. Oral antibiotic therapy forskeletal infections of children. II. Therapy of osteomyelitis andsuppurative arthritis. J Pediatr 1978;92:485-90.

7. Bryson YJ, Connor JD, LeClerc M, Giammona ST. High-dose dicloxacillintreatment of acute staphylococcal osteomyelitis in children. J Pediatr1979;94:673-5.

8. Prober CG, Yeager AS. Use of the serum bactericidal titer to assess theadequacy of oral antibiotic therapy in the treatment of acutehematogenous osteomyelitis. J Pediatr 1979;95:131-5.

9. Quintiliani R, Nightingale CH, Crowe HM, Cooper BW, Bartlett RC,Gousse G. Strategic antibiotic decision-making at the formulary level. Rev Infect Dis 1991;13(Suppl 9):S770-S777.

10. Frighetto L, Nickoloff D, Martinusen SM, Mamdani FS, Jewesson PJ.Intravenous-to-oral stepdown program: four years of experience in a large teaching hospital. Ann Pharmacother 1992;26:1447-51.

11. Jewesson P. Cost-effectiveness and value of an IV switch.PharmacoEconomics 1994;5(Suppl 2):20-6.

12. Daly JS, Worthington MG, Razvi SA, Robillard R. Brief report: intravenousand sequential intravenous and oral ciprofloxacin in the treatment ofsevere infections. Am J Med 1989;87(Suppl 5A): 232S-4S.

13. Nelson JD, Bucholz RW, Kusmiesz H, Shelton S. Benefits and risks ofsequential parenteral-oral cephalosporin therapy for suppurative boneand joint infections. J Pediatr Orthop 1982;2:255-62.

14. Briceland LL, Nightingale CH, Quintiliani R, Cooper BW, Smith KS.Antibiotic streamlining from combination therapy to monotherapy utilizingan interdisciplinary approach. Arch Intern Med 1988;148:2019-22.

15. Rush DR. Antimicrobial formulary management: meeting the challenge inthe community hospital. Pharmacotherapy 1991;11(1 pt 2):19S-26S.

16. Plumridge RJ. Cost comparison of intravenous antibiotic administration.Med J Aust 1990;153:516-8.

17. Quintiliani R, Cooper BW, Briceland LL, Nightingale CH. Economic impactof streamlining antibiotic administration. Am J Med 1987;82(Suppl4A):391-4.

18. Wright DB. Antimicrobial formulary management: a case study in ateaching hospital. Pharmacotherapy 1991;11(1 pt 2):27S-31S.

19. Chrysanthopoulos CJ, Skoutelis AT, Bassaris HP. Shortened hospital stay with sequential intravenous oral ciprofloxacin. Drugs 1993;45(Suppl3):464.

20. Grasela TH Jr, Paladino JA, Schentag JJ, et al. Clinical and economicimpact of oral ciprofloxacin as follow-up to parenteral antibiotics. DICP.Ann Pharmacother 1991;25:857-62.

21. Paladino JA, Sperry HE, Backes JM, et al. Clinical and economicevaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics. Am J Med 1991;91:462-70.

22. Cramer JA, Mattson RH, Prevey ML, Scheyer RD, Ouellette VL. Howoften is medication taken as prescribed? A novel assessment technique.JAMA 1985;261:3273-7.

23. Antibiotic drug interactions. Drug Interact Updates 1993;13:199-284.24. Intravenous ciprofloxacin. Med Lett Drugs Ther 1991;33:75-6.25. Nelson JD. A critical review of the role of oral antibiotics in the

management of hematogenous osteomyelitis. Curr Clin Top Infect Dis1983;4:64-74.

26. McCracken GH Jr. New era for orally administered antibiotics: use ofsequential parenteral-oral antibiotic therapy for serious infectiousdiseases of infants and children. Pediatr Infect Dis J 1987;6:951-3.

27. Earl P, Sisson PR, Ingham HR. Twelve-hourly dosage schedule for oraland intravenous metronidazole. J Antimicrob Chemother 1989;23:619-21.

28. Yogev R, Kolling WM, Williams T. Pharmacokinetic comparison ofintravenous and oral chloramphenicol in patients with Haemophilusinfluenzae meningitis. Pediatrics 1981;67:656-60.

29. Grant SM, Clissold SP. Fluconazole. A review of its pharmacodynamicand pharmacokinetic properties, and therapeutic potential in superficialand systemic mycoses. Drugs 1990;39:877-916.

30. Nightingale CH. Pharmacokinetic considerations in quinolone therapy.Pharmacotherapy 1993;13:34S-8S.

31. Hoffken G, Lode H, Prinzing C, Borner K, Koeppe P. Pharmacokinetics ofciprofloxacin after oral and parenteral administration. Antimicrob AgentsChemother 1985;27:375-9.

32. Monk JP, Campoli-Richards DM. Ofloxacin: a review of its antibacterialactivity, pharmacokinetic properties and therapeutic use. Drugs1987;33:346-91.

33. McCracken GH Jr. Comparative evaluation of the aminopenicillins for oraluse. Pediatr Infect Dis 1983;2:317-20.

34. Bergan T, Thorsteinsson SB, Solberg R, et al. Pharmacokinetics ofciprofloxacin: intravenous and increasing oral doses. Am J Med1987;82(Suppl 4A):97-102.

35. Wise R, Griggs D, Andrews JM. Pharmacokinetics of the quinolones involunteers: a proposed dosing schedule. Rev Infect Dis 1988;10(Suppl1):S83-S89.

36. Cipro Product Monograph. Etobicoke: Bayer Inc, 1994.37. Gentry LO. Prescribing considerations in fluoroquinolone therapy.

Pharmacotherapy 1993;13(2 pt 2):39S-44S.38. Department of Clinical Epidemiology and Biostatistics, McMaster

University Health Sciences Centre. How to read clinical journals: V: Todistinguish useful from useless or even harmful therapy. Can Med AssocJ 1981;124:1156-62.

39. Kalager T, Andersen BM, Bergan T, et al. Ciprofloxacin versus atobramycin/cefuroxime combination in the treatment of serious systemicinfections: a prospective, randomized and controlled study of efficacy and safety. Scand J Infect Dis 1992;24:637-46.

40. Dominguez J, Palma F, Vega ME, et al. Brief report: prospective,controlled, randomized non-blind comparison of intravenous/oralciprofloxacin with intravenous ceftazidime in the treatment of skin orsoft-tissue infections. Am J Med 1989;87(Suppl 5A): 136S-7S.

41. Cox CE. Brief report: sequential intravenous and oral ciprofloxacin versusintravenous ceftazidime in the treatment of complicated urinary tractinfections. Am J Med 1989;87(Suppl 5A):157S-9S.

42. Gangji D, Jacobs F, de Jonckheer J, et al. Brief report: randomized studyof intravenous versus sequential intravenous/oral regimen of ciprofloxacin in the treatment of Gram-negative septicemia. Am J Med 1989;87(Suppl5A):206S-8S.

43. Gaut PL, Carron WC, Ching WTW, Meyer RD. Intravenous/oralciprofloxacin therapy versus intravenous ceftazidime therapy for selectedbacterial infections. Am J Med 1989;87(Suppl 5A): 169S-75S.

44. Fass RJ, Plouffe JF, Russell JA. Intravenous/oral ciprofloxacin versusceftazidime in the treatment of serious infections. Am J Med1989;87(Suppl 5A):164S-8S.

45. Nicolle LE, Guay D, Degelau J, et al. Efficacy of ofloxacin for the treatment of penumonia, skin and skin structure infection, and urinary tract infectionin an elderly population. Infect Dis Clin Pract 1993;2:414-22.

46. Bunz DM, Frighetto L, Gupta S, Jewesson PJ. Simple ways to promotecost containment. DICP. Ann Pharmacother 1990;24:546.

47. Hirata-Dulas CAI, Stein DJ, Guay DRP, Gruninger RP, Peterson PK. Arandomized study of ciprofloxacin versus ceftriaxone in the treatment ofnursing home-acquired lower respiratory tract infections. J Am GeriatrSoc 1991;39:979-85.

48. Khan FA, Basir R. Sequential intravenous-oral administration ofciprofloxacin vs ceftazidime in serious bacterial respiratory tractinfections. Chest 1989;96:528-37.

49. Menon L, Ernst JA, Sy ER, Flores D, Pacia A, Lorian V. Brief report:sequential intravenous/oral ciprofloxacin compared with intravenousceftazidime in the treatment of serious lower respiratory tract infections.Am J Med 1989;87(Suppl 5A): 119S-20S.

50. Peacock JE, Pegram PS, Weber SF, Leone PA. Prospective, randomizedcomparison of sequential intravenous followed by oral ciprofloxacin withintravenous ceftazidime in the treatment of serious infections. Am J Med1989;87(Suppl 5A):185S-90S.

51. Feist H. Sequential therapy with I.V. and oral ofloxacin in lower respiratory tract infections: A comparative study. Infection 1991;19(Suppl 7):380-3.



52. Khajotia R, Drlicek M, Vetter N. A comparative study of ofloxacin andamoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections. J Antimicrob Chemother 1990;26(Suppl D):83-91.

53. Johnson JR, Lyons MF, Pearce W, et al. Therapy for women hospitalizedwith acute pyelonephritis: A randomized trial of ampicillin versustrimethoprim- sulfamethoxazole for 14 days. J Infect Dis1991;163:325-30.

54. Chrysanthopoulos CJ, Starakis JC, Skoutelis AT, Bassaris HP. Briefreport: sequential intravenous/oral therapy with ciprofloxacin in severeinfection. Am J Med 1989;87(Suppl 5A): 225S-7S.

55. Bouza E, Diaz-Lopez MD, Bernaldo de Quiros JCL, Rodriguez-CreixemsM. Ciprofloxacin in patients with bacteremic infections. Am J Med1989;87(Suppl 5A):228S-37S.

56. Chayakul P, Krisanapan S, Kalnauwakul S. Sequential intravenous/oralciprofloxacin in the treatment of severe multiresistant Gram-negativeinfections. J Med Assoc Thai 1993;76:35-40.

57. Dworkin RJ, Sande MA, Lee BL, Chambers HF. Treatment of right-sidedStaphylococcus aureus endocarditis in intravenous drug users withciprofloxacin and rifampicin. Lancet 1989;ii:1071-3.

58. Neu HC, Davidson S, Briones F. Intravenous/oral ciprofloxacin therapy ofinfections caused by multiresistant bacteria. Am J Med 1989;87(Suppl5A):209S-12S.

59. Scully BE, Neu HC. Treatment of serious infections with intravenousciprofloxacin. Am J Med 1987;82(Suppl 4A):369-75.

60. Giamarellou H, Galanakis N. Use of intravenous ciprofloxacin indifficult-to-treat infections. Am J Med 1987;82(Suppl 4A):346-51.

61. Gentry LO, Rodriguez-Gomez G, Kohler RB, Khan FA, Rytel MW.Parenteral followed by oral floxacin for nosocomial penumonia and

community-acquired pneumonia requiring hospitalization. Am Rev RespirDis 1992;145:31-5.

62. Auten GM, Preheim LC, Sookpranee M, Bittner MJ, Sookpranee T,Vibhagool A. High-pressure liquid chromatography and microbiologicalassay of serum ofloxacin levels in adults receiving intravenous and oraltherapy for skin infections. Antimicrob Agents Chemother1991;35:2558-61.

63. Soper DE, Brockwell NJ, Dalton HP. Microbial etiology of urbanemergency department acute salpingitis: treatment with ofloxacin. Am JObstet Gynecol 1992;167:653-60.

64. Heppt W, Lutz H. Clinical experiences with ofloxacin sequential therapy inchronic ear infections. Eur Arch Otorhinolaryngol 1993;250:S19-S21.

65. Lentino JR, Augustinsky JB, Weber TM, Pachucki CT. Therapy of seriousskin and soft tissue infections with ofloxacin administered by intravenousand oral route. Chemotherapy 1991;37:70-6.

66. Gelfand MS, Simmons BP, Craft RB, Grogan J, Amarshi N. A sequential study of intravenous and oral fleroxacin in the treatment ofcomplicated urinary tract infection. Am J Med 1993;94(Suppl3A):126S-30S.

67. Aronoff SC, Scoles PV, Makley JT, Jacobs MR, Blumer JL, Kalamchi A.Efficacy and safety of sequential treatment with parenteralsulbactam/ampicillin and oral sultamicillin for skeletal infections inchildren. Rev Infect Dis 1986;8(Suppl 5):S639-43.

68. Schaad UB, Pfenninger J, Wedgewood-Krucko J. Sequentialintravenous-oral amoxycillin/clavulanate (Augmentin) therapy inpaediatric hospital practice. J Antimicrob Chemother 1987;19:385-91.

69. Buchi W, Casey PA. Experience with parenteral and sequentialparenteral-oral amoxicillin/clavulanate (Augmentin) in hospitalizedpatients. Infection 1988;16:306-12.

MAN DELL et al


Submit your manuscripts athttp://www.hindawi.com

Stem CellsInternational

Hindawi Publishing Corporationhttp://www.hindawi.com Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation http://www.hindawi.com Volume 2014

Immunology ResearchHindawi Publishing Corporationhttp://www.hindawi.com Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinson’s Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttp://www.hindawi.com

sequential antibiotic therapy: effective cost management

Documents