Antimicrobial resistance: Journey without end

without end T HE THEME FOR THE ORIGI NAL AR TI CLES IN THIS IS SUE IS an ti mi cro bial re sis tance. Scriver et al (pages 7682) re port an in vi tro crossCanada re view of ac tiv ity of se lected an ti mi cro bi als against no so comial Gramnegative rods, par ticu larly or gan isms with in duci ble chro mo so mal betalactamase. Loo et al (pages 8387) de scribe ac tiv ity of se lected an ti mi cro bi als against sus cep ti ble and in ter me di ately penicillinresistant Strep to coc cus pneu mo niae iso lated in Que bec. Burdge et al (pages 97101), in Van cou ver, de scribe eradi ca tion of pul mo nary methicillinresistant Staphy lo coc cus au reus (MRSA) with clin da my cin and ri fampin in two cys tic fi bro sis pa tients. An ti mi cro bial re sis tance is here – a cur rent and fu ture chal lenge for Ca na dian phy si cians and their pa tients. Some com fort is found in ob serv ing that the ex tent of re sis tance seems less than those re ported from other coun tries. For in stance, as Scriver et al dem on strate, Kleb siel lia pneu mo niae plasmidmediated betalactamase re sis tance is not yet a prob lem in Can ada, and vancomycinresistant en te ro cocci are not yet es tab lished. The emer gence of MRSA (1) and penicillinresistant S pneu mo niae (see Loo et al) as im por tant clini cal prob lems has been de layed rela tive to many other coun tries. Per haps our widely scat tered popu la tion im pedes trans mis sion, or our an ti mi cro bial and in fec tion con trol prac tices are of a cali bre that lim its ac qui si tion and dis semi na tion of re sis tant or gan isms. There is no rea son for com pla cence; the only re al is tic fu ture is one of es ca lat ing an ti mi cro bial re sis tance. How should we re spond to re ports of in creas ing an ti mi cro bial re sis tance in Can ada? Gen er ally, a three fold front is sug gested (2). First, new an ti mi cro bi als that cir cum vent cur rent mecha nisms of re sis tance may be de vel oped. This, of course, is the his tory of antimi cro bial in tro duc tion and re sis tance de vel op ment of the past four dec ades. But in an ti mi cro bial de vel op ment, the dis tance be tween the an ti mi cro bial be ing sought and the pur su ing re sis tance is ever short en ing. There may re main un ex ploited op por tu ni ties for an ti mi cro bial de vel op ment, but a san guine ex pec ta tion of sci en tific prog ress may be na ive – the ex traor di nary adapt abil ity of mi cro or gan isms is cer tainly cau tion ary. The sec ond ap proach is to en sure ‘o pt imal’ use of cur rent an ti mi cro bi als. But can we agree on what is op ti mal an ti bi otic use? Is it us ing less of an an ti mi cro bial, as sug gested by the ex pe ri ence with vancomycinresistant en te ro coc cal out breaks in the United States, or is it us ing more, as in en sur ing full treat ment of tu ber cu lo sis cases or eradi ca tion of MRSA car riage? In some set tings, such as high in ten sity spe cialty care units in ter ti ary care hos pi tals (eg, burn or he ma tol ogy/on col ogy units), even op ti mal an ti mi cro bial use will be as so ci ated with emer gence of an ti mi cro bial re sis tance. In ad di tion, avail able re ports de scrib ing in ter ven tions to mod ify an ti mi cro bial use are, short of re stric tion, a saga of fail ure. Some prom is ing but pre limi nary ini tia tives, pri mar ily at the fam ily prac tice level, are ex plor ing the fa cili ta tion of im ple men ta tion of prac tice guide lines. These may pro vide some fu ture mod els of prac tice in ter ven tion ap pli ca ble to the dif fi cult prob lem of achiev ing ‘a ppr opr iate’ an ti mi cro bial use. There are, how ever, no im me di ately ap par ent short term so lu tions. The third sug gested ap proach for man ag ing antimi cro bial re sis tance is through strength en ing in fec tion con trol prac tices. This ap proach would be tar geted to in sti tu tional set tings, where the goal is to pre vent the in ter pa tient trans mis sion of or gan isms among pa tients, which is fa cili tated in the in sti tu tional set ting. Re ports of con trol of no so comial out breaks of mul ti ply re sis tant tu ber cu lo sis and vancomycinresistant en terococci are con vinc ing evi dence that ap pro pri ate, in ten sive, in fec tion con trol prac tices are ef fec tive in pre vent ing trans mis sion of re sis tant or gan isms. These suc cess sto ries, how ever, emerge from cri sis situa tions. The dual chal lenges of re source limi ta tion and of man ag ing hu man be hav iour are sub stan tial im pedi ments, in the non cri sis situa tion, to the ef fec tive ness of in fec tion con trol meas ures in man ag ing en demic an ti mi cro bial re sis tance. This is not, how ever, a time for pes si mism. We must get past number count ing and hand wring ing to ac tion and com mit ment. It is time for a dis pas sion ate, re al is tic ap praisal of the prob lem, and ac know ledge ment that we are em bark ing on hos tili ties that will shadow the re main der of our pro fes sional ca reers. The meas ure ment of the im pact of re sis tance, in par ticu lar, is criti cal to the de vel op ment of strate gies for man age ment of an ti mi cro bial re sis tance. How much is it an in vi tro phenome non? What are the clini cal mor bid ity, mor tal ity and cost to our so ci ety of an ti mi cro bial re sis tance? This in for ma tion is es sen tial to al low us to pri ori tize com pet ing is sues, to meas ure the im pact of in ter ven tions, and to un der stand the tradeoffs in clini cal man age ment and pro fes sional in de pend ence nec es sary in man ag ing this prob lem of an ti mi cro bial re sis tance. Our im me di ate and long term goal is to main tain the EDI TO RIAL

T HE THEME FOR THE ORIGI NAL AR TI CLES IN THIS IS SUE IS an timi cro bial re sis tance. Scriver et al (pages 76-82) re port an in vi tro cross-Canada re view of ac tiv ity of se lected an ti micro bi als against no so comial Gram-negative rods, par ticu larly or gan isms with in duci ble chro mo so mal beta-lactamase. Loo et al (pages 83-87) de scribe ac tiv ity of se lected an ti mi cro bi als against sus cep ti ble and in ter me di ately penicillin-resistant Strep to coc cus pneu mo niae iso lated in Que bec. Burdge et al (pages 97-101), in Van cou ver, de scribe eradi ca tion of pul monary methicillin-resistant Staphy lo coc cus au reus (MRSA) with clin da my cin and ri fampin in two cys tic fi bro sis pa tients.
An ti mi cro bial re sis tance is here -a cur rent and fu ture challenge for Ca na dian phy si cians and their pa tients. Some comfort is found in ob serv ing that the ex tent of re sis tance seems less than those re ported from other coun tries. For in stance, as Scriver et al dem on strate, Kleb siel lia pneu mo niae plasmid-mediated beta-lactamase re sis tance is not yet a prob lem in Can ada, and vancomycin-resistant en te ro cocci are not yet es tab lished. The emer gence of MRSA (1) and penicillin-resistant S pneu mo niae (see Loo et al) as im por tant clini cal prob lems has been de layed rela tive to many other coun tries. Per haps our widely scat tered popu la tion im pedes trans mis sion, or our an ti mi cro bial and in fec tion con trol practices are of a cali bre that lim its ac qui si tion and dis semi na tion of re sis tant or gan isms. There is no rea son for com pla cence; the only re al is tic fu ture is one of es ca lat ing an ti mi cro bial re sistance.
How should we re spond to re ports of in creas ing an ti mi crobial re sis tance in Can ada? Gen er ally, a three fold front is suggested (2). First, new an ti mi cro bi als that cir cum vent cur rent mecha nisms of re sis tance may be de vel oped. This, of course, is the his tory of anti-mi cro bial in tro duc tion and re sistance de vel op ment of the past four dec ades. But in an ti mi crobial de vel op ment, the dis tance be tween the an ti mi cro bial be ing sought and the pur su ing re sis tance is ever short en ing. There may re main un ex ploited op por tu ni ties for an ti mi cro bial de vel op ment, but a san guine ex pec ta tion of sci en tific progress may be na ive -the ex traor di nary adapt abil ity of mi cro organ isms is cer tainly cau tion ary.
The sec ond ap proach is to en sure 'o pt imal' use of cur rent an ti mi cro bi als. But can we agree on what is op ti mal an ti bi otic use? Is it us ing less of an an ti mi cro bial, as sug gested by the ex pe ri ence with vancomycin-resistant en te ro coc cal outbreaks in the United States, or is it us ing more, as in en sur ing full treat ment of tu ber cu lo sis cases or eradi ca tion of MRSA carriage? In some set tings, such as high in ten sity spe cialty care units in ter ti ary care hos pi tals (eg, burn or he ma tol ogy/on cology units), even op ti mal an ti mi cro bial use will be as so ci ated with emer gence of an ti mi cro bial re sis tance. In ad di tion, available re ports de scrib ing in ter ven tions to mod ify an ti mi cro bial use are, short of re stric tion, a saga of fail ure. Some prom is ing but pre limi nary ini tia tives, pri mar ily at the fam ily prac tice level, are ex plor ing the fa cili ta tion of im ple men ta tion of prac tice guide lines. These may pro vide some fu ture mod els of practice in ter ven tion ap pli ca ble to the dif fi cult prob lem of achieving 'a ppr opr iate' an ti mi cro bial use. There are, how ever, no im me di ately ap par ent short term so lu tions.
The third sug gested ap proach for man ag ing antimi crobial re sis tance is through strength en ing in fec tion con trol practices. This ap proach would be tar geted to in sti tu tional set tings, where the goal is to pre vent the in ter pa tient transmis sion of or gan isms among pa tients, which is fa cili tated in the in sti tu tional set ting. Re ports of con trol of no so comial outbreaks of mul ti ply re sis tant tu ber cu lo sis and vancomycinresistant en terococci are con vinc ing evi dence that ap pro priate, in ten sive, in fec tion con trol prac tices are ef fec tive in prevent ing trans mis sion of re sis tant or gan isms. These suc cess sto ries, how ever, emerge from cri sis situa tions. The dual chal lenges of re source limi ta tion and of man ag ing hu man behav iour are sub stan tial im pedi ments, in the non cri sis situation, to the ef fec tive ness of in fec tion con trol meas ures in man ag ing en demic an ti mi cro bial re sis tance. This is not, how ever, a time for pes si mism. We must get past number count ing and hand wring ing to ac tion and commit ment. It is time for a dis pas sion ate, re al is tic ap praisal of the prob lem, and ac know ledge ment that we are em bark ing on hos tili ties that will shadow the re main der of our pro fessional ca reers. The meas ure ment of the im pact of re sis tance, in par ticu lar, is criti cal to the de vel op ment of strate gies for man age ment of an ti mi cro bial re sis tance. How much is it an in vitro phenome non? What are the clini cal mor bid ity, mor tal ity and cost to our so ci ety of an ti mi cro bial re sis tance? This in forma tion is es sen tial to al low us to pri ori tize com pet ing is sues, to meas ure the im pact of in ter ven tions, and to un der stand the trade-offs in clini cal man age ment and pro fes sional in de pendence nec es sary in man ag ing this prob lem of an ti mi cro bial resis tance. Our im me di ate and long term goal is to main tain the sub stan tial bene fits that ef fec tive an ti mi cro bial ther apy has pro vided to our popu la tion over the past four dec ades. In fec tions caused by Can dida spe cies have emerged as a promi nent en tity in the lat ter part of the 20th cen tury. This trend is ex em pli fied by can dide mia, which was con sid ered to be rare 40 years ago, but to day as sumes a sig nifi cant role as a no so comial in fec tion. The in creas ing role of both su per ficial and sys temic can dida in fec tions is di rectly re lated to the mush room ing popu la tion of im mu no com pro mised pa tients with can cer, or gan trans plan ta tion, AIDS and on long term immu no sup pres sive agents.

All-inclusive text on candidiasis
Writ ing a text book on the patho gene sis, di ag no sis and treat ment of can didia sis is a daunt ing task. In his sec ond edi tion on this sub ject, Dr Ger ald Bodey has as sem bled an ar ray of promi nent ex perts in their re spec tive fields. The com pi la tion of their work is a book that is gen er ally well written and full of per ti nent in for ma tion about can didia sis. The edi tor has di vided the book into sec tions on the mi cro bi ol ogy of Can dida spe cies, patho logi cal cor re la tions, epi de mi ol ogy of can didia sis, labo ra tory di ag no sis, ra dio logi cal fea tures, clini cal mani fes ta tions of can dida syn dromes and, fi nally, thera peu tic op tions. There are sec tions of the text, how ever, that are poorly or gan ized and that pres ent data su per fi cially.
Wor thy of praise are the chap ters Bi ol ogy and Patho genic ity, Patho gene sis, Epi de mi ol ogy, Labo ra tory Di ag no sis, Oral Can didia sis, Geni tal Can didia sis, Neo na tal Can didiasis, He ma toge nous and Or gan Can didia sis, Can dida Ophthal mi tis and Cen tral Nerv ous Sys tem In fec tion, and An ti fun gal Agents that sum ma rize the state of the art of these sub jects. The in clu sion of data on can dida hy per sensi tiv ity syn drome ex em pli fies the all-inclusive na ture of this book.
How ever, the chap ters de scrib ing patho logi cal cor re lations and ani mal mod els are su per fi cial and lack the in sight one would ex pect in this type of book. The pres en ta tion of the ra dio logi cal fea tures of can dida in fec tions is poorly organ ized. It is for mu lated along a ra dio graphic or gan sys tem ap proach rather than ac cord ing to clini cal syn dromes. The lat eral ap proach may have proven more use ful to cli ni cians. The authors failed to de tail the ad van tages of one ra diographic pro ce dure com pared with an other in the di ag no sis of can didia sis. The use of sen si tiv ity and speci fic ity measures would have been bene fi cial for the reader in de cid ing which in ves ti ga tive pro ce dure is war ranted. The authors' report on cu ta ne ous can didia sis is also su per fi cial. Par ticularly de fi cient is the treat ment of cu ta ne ous can didia sis, al though this topic is cov ered in more de tail in a later chap ter on an ti fun gal agents. In ad di tion, the chap ter on uri nary candidia sis should have been ex panded to in clude the cur rent thought on can diduria in in ten sive care unit pa tients and the pre dis po si tion of these pa tients to sys temic can didia sis. Some thoughts on colo ni za tion with Can dida spe cies in the in ten sive care unit set ting and the con comi tant ef fect of this colo ni za tion on mor tal ity would have been wel come. The inclu sion of pro phy lac tic an ti fun gal tri als cur rently un der way to pre vent can dida colo ni za tion in this clini cal set ting would have been pru dent. Fi nally, on more than two oc ca sions, the con tent of one chap ter over lapped with that of an other.
De spite its flaws, the sec ond edi tion of Can didia sis: Patho gene sis, Di ag no sis and Treat ment of fers a com prehen sive look at this emerg ing sub ject. It is a worth while ad dition to one's li brary and serves as a jump ing off point for the cli ni cian de sir ing to probe fur ther into the ever ex pand ing field of clini cal my col ogy.

Cole man Rot stein MD Hender son Gen eral Hos pi tal -McMas ter Medi cal Unit
Ham il ton, On tario