WMW. 7/8/2003 163

From the Division of Infectious Diseases, Department of Internal Medicine I, University of Vienna

Determination of the Frequency of Inadequate Antibiotic Therapy Using Calculation of Indication Failure (IF), Cumulative Indication Failure (CIF), and Balanced Indication Failure (BIF) H e i n z B u r g m a n n

K e y w o r d s : I n a d e q u a t e a n t i b i o t i c t h e r a p y - I C U - G r a m -

n e g a t i v e b a c t e r i a - n o s o c o m i a l p n e u m o n i a - c a l c u l a t i o n s .

S c h l i i s s e l w 6 r t e r : I n a d d q u a t e a n t i m i k r o b i e U e T h e r a p i e - I C U

- G r a m - n e g a t i v e B a k t e r i e n - n o s o k o m i a l e P n e u m o n i e -

B e r e c h n u n g e n .

Summary: Because results of pathogen identification are often lacking when antibiotic therapy is initiated, treat- men t mus t frequently be inst i tuted on an empirical basis. The type of empirical therapy will depend on the anti- cipated pathogen spectrum and natural ly also on the prevailing resistance patterns. Inadequate antibiotic therapy may not only be associated with increased overall t reatment costs, bu t will also have adverse effects on mortality. The clinician is frequently faced with an over- a b u n d a n t variety of microbiological data and may fail to interpret them correctly. Therefore, the present s tudy has attempted to "translate" the available microbiological resistance data, frequently presented in the form of per- centage rates, into concrete patient number s and thus illustrate the frequency of inadequate antibiotic therapy. For this purpose, "Indication Failure" (IF), "Cumulative Indication Failure" (CIF) and "Balanced Indication Fail- ure" (BIF) have been calculated based on available micro- biological data. For the indication "nosocomial pneumonia", calculations of the BIF show that only one out of 67 or one out of 63 pat ients is inadequately treated with a therapy with cefe- pime or imipenem, while one out of 25 pat ients is inad- equately treated when using ceftazidime. However, it mus t be pointed out that these calculations only represent an interpretation of microbiological data and the success of antibiotic therapy will ultimately also depend on parameters such as the pharmacodynamic properties of an antibiotic or on the immunocompetence of the pat ient treated. (Wien. Med. Wschr. 2003; 153; 163-165)

B e s t i m m u n g der inadi iquaten ant imikro- b ie l l en Therapie m i t t e l s B e r e c h n u n g des , Indicat ion Failure' (IF), des ,Cumulat ive Indicat ion Failure' (CIF) und des ,Balanced Indicat ion Failure' (BIF) zusammenfassung: Aufgrund des oft zu Therapiebeginn fehlenden Keimnachweises erfolgt die Antibiotikatherapie htiufig empirisch. Sie richtet sich dabei nach dem zu erwar- tenden Keimspektrum und natfirlich auch der Resistenz- lage. Inadtiquate Antibiotikatherapie hat neben erh6hten Gesamttherapiekosten auch Auswirkungen auf die Mortali- ttit. Der klinisch ttitige Arzt ist oft mit den vorliegenden mi-

Corresponding address: Heinz Burgmann, M. D., Division of Infectious Diseases, Department of Internal Medicine I, W&hringer Gtirtel 18-20, A-1090 Vienna. Fax: ++43 / 1 / 4 04 00-44 18 E-mail. Heinz. Burgmann@akh-wien. ac. at

krobiologischen Daten tiberfordert bzw. k a n n sie nicht rich- tig deuten. In der vorliegenden Arbeit soil n u n versucht werden, die mikrobiologisch ermittelten Resistenzdaten, die htiufig als Prozentzahlen vorliegen, auf Pat ientenzahlen um- zurechnen, und somit die Htiufigkeit inadtiquater Antibioti- katherapie zu verdeutlichen. Dazu werden auf der Grundla- ge von mikrobiologischen Daten der ,Indication Failure', der ,Cumulative Indication Failure' (CIF) und der ,Balanced Indi- cation Failure' berechnet. Ftir die Indikation ,nosokomiale Pneumonie ' konnte mittels des BIF berechnet werden, daJ3 bei Verwendung von Cefepim und Imipenem n u r j e d e m 67. bzw. 63. Patient inad&quat, bei Ceftazidim hingegen bereits jeder 25. Patient inadtiquat be- handel t wird. Einschrt inkend mu~ allerdings erwtihnt werden, da,6 es sich bei diesen Berechnungen nu r u m die Interpretat ion mikro- biologischer Daten handel t - ob die antibiotische Therapie erfolgreich ist, htingt nicht zuletzt von Parametern wie der Pharmakodynamik eines Antibiotikums oder aber auch von der Immunkompetenz des Patienten ab.

Introduction Antibiotic t reatment is frequently inst i tuted on an empirical basis, because results of pathogen ident i fca t ion often are not available when therapy is initiated (1, 2, 5). Naturally, coverage of the anticipated pathogen spectrum and resist- ance pat terns mus t be considered when selecting an appro- priate empirical therapy. Inadequate antibiotic therapy does not only increase overall t reatment costs bu t will also affect mortality (5). Thus, studies of nosocomial pneumonia have shown that initial therapy mus t make sure to cover the com- plete spectrum of potential causative pathogens because later modifications (after results of a BAL are available) will dramatically worsen the pat ient 's prognosis (5). Evidently, local resistance pat terns will also be an important consider- ation in selecting an appropriate therapy. Thus, the results of studies conducted in the United States cannot be directly related to the resistance s i tuat ion in Europe, or more specifi- cally in Austria, because, for example, we are not faced with such a high n u m b e r of MRSA and penici l l in-resistant pneu- mococci. The practicing clinician is frequently confronted with an overwhelming variety of microbiological data or may fail to interpret such data correctly. Hence, the present s tudy has attempted to t ranslate microbiological resistance data, frequently provided as abstract percentage rates, into con- crete patient number s and thus illustrate the frequency of inadequate antibiotic therapy.

Methods The calculations have been based on the report of K r a u s e

et al. (3) evaluating the resistance data for Enterobactericeae and non-fermenters collected by 9 laboratories throughout Austria. The s tudy includes specimens provided by ICUs and compared carbapenems, fourth-generation cepha- losporins, ceftazidime, and piperacil l in/ tazobactam. An additional quinolone (ciprofloxacin) was included as compa- rative substance. The pertaining microbiological data were

U.S. Copyright Clearance Center Code Statement: 0043-5341 /2003 /5307-0163 $15 .00 /0

164 W M W - 7 / 8 / 2 0 0 3

Tab. 1. Percentage distribution o f the most frequent reported pathogens encountered in nosocomial pneumonia (Lode et al., see reference 4).

obtained from a recent s tudy of W~st et al. (7). Relevant resis tance data for S. aureus and S. pneumoniae used for the determinat ion of balanced indication failure (BIF) in nosocomial pneumonia were taken from the textbook of U. Theuretzbacher (6) and include pathogens isolated from ICU specimens in Germany.

To translate the ra ther abstract percentage rates into conspicuous "patient data", the following calculat ions were performed:

Indication Failure (IF) The number of resis tant strains per antibiotic has been ex- pressed as frequency of inadequately treated pat ients when using a given antibiotic (100 divided by the percentage of resis tant strains}.

Cumulative Indication Failure (CIF) The IFs of the most frequently encountered pathogens in a given indication have been added up, divided by the number of different pathogens and expressed as frequency of inad- equately treated patients. If no res is tance was found, one out of 100 patients was assumed as having been inad-

equately treated, which corresponds to an antibiotic effi- ciency of 99 %.

For the present study, the CIFs for the Enterobacter iaceae and non-fermenters included in the study of Krause et al. were calculated.

Balanced Indication Failure (BIF) The IFs for the most common pathogens in each indication were multiplied with the respective, empirically determined percentage rates of the occurrence of the pathogen in the specific indication and divided by the cumulat ive percentage rate of the pathogens used. For nosocomial pneumonia , the pathogen distribution of Lode etal . was used (4} (Tab. 1).

R e s u l t s a n d D i s c u s s i o n

Table 2 lists both the IFs for the antibiotics used in relation to Enterobacter iaceae or non-fermenters and the cumulat ive CIFs calculated for all pathogens used.

The resul ts for Pseudomonas aeruginosa show that in the best case one out of 25 patients, and in the worst case one out of 7 patients is inadequately treated. Together with the fact that infections with Pseudomonas aeruginosa are mostly seen in patients with severe underlying diseases, this ex- plains the high lethality rate reported for such infections. En- terobacter, another problem organism, is somewhat better covered when selecting the appropriate antibiotic therapy. Thus, only one out of 50 pat ients is inadequately treated when using imipenem and cefepime, while this number de- creases to 6.6 when using ceftazidime, and even to 5.5 with the use of piperaci l l in/ tazobactam. For E. coli, no resistan- ces are seen for most subs tances with the exception of piper- ac i l l in / tazobactam and ceftazidime (with both agents one out of 33 pat ients is inadequately treated}. Similarly, Klebe- sieUa spp. can be adequately treated (almost no resistance) with all antibiotics studied with the exception of pipera- c i l l in / tazobactam (one out of 25 pat ients inadequately trea- ted).

Stenotrophomonas maltophilia is considered a problem pathogen, because it is frequently shown to be resis tant to most antibiotics. This fact could also be confirmed in the present study. In the best case scenario (ceftazidime), only one out of 4 pat ients was inadequately treated.

The number 100 was used in the absence of res is tant pathogens, this reflects the ideal case of adequate t rea tment (corresponding to a 99 % efficiency: one out of 100 patients

Tab. 2. Indication Failure (IF)for Enterobacteriaceae und non-fermenters: Microbiological data have been derived from the stu- dy of Krause et al (3) and for +ciprofloxacin from Wrist et al. (7) (It has to be noted that no exact comparison of ciprofloxacin with the other antibiotics tested in the study of Krause et al was possible because of other resistance pattern of the mentioned bacte- ria in both studies).

* means no resistance - means no data available

W M W �9 7 / 8 / 2 0 0 3 165

Tab. 3. Balanced Indication Failure (BIF) for the indication 'nosocomial pneumonia'.

Fig. 1. BIF for nosocomial pneumonia.

in i n a d e q u a t e l y t r ea ted) . In t h e p r e s e n t s t u d y of E n t e r o b a c - t e r i a c e a e a n d n o n - f e r m e n t e r s , i m i p e n e m a n d ce fep ime c o m e c lo se s t to t h i s idea l s i t u a t i o n - w i t h t h e s e s u b s t a n c e s o n e o u t of 6 0 p a t i e n t s a n d 1 o u t of 62 p a t i e n t s , respec t ive ly , is i n a d e q u a t e l y t r ea t ed . Cef t az id ime r a n g e s in t h e lower t h i r d of t h e sca le , a n d t h e f r e q u e n t l y u s e d p i p e r a c i l l i n / t a z o b a c - t a m d o e s n o t exceed t h e b o t t o m qua r t e r .

Fo r t h e i n d i c a t i o n " n o s o c o m i a l p n e u m o n i a " , t h e BIF s h o w s t h a t t h e r a n k i n g of a n t i b i o t i c s is h a r d l y c h a n g e d (Tab. 3 a n d Fig. 1). E v e n c o n s i d e r i n g t h e m o s t f r e q u e n t G r a m - p o s i t i v e o r g a n i s m s , ce fep ime a n d i m i p e n e m a re in t he top p o s i t i o n s for t h i s c o m p a r i s o n w i t h one o u t 67 or one o u t 63 p a t i e n t s , respec t ive ly , b e i n g i n a d e q u a t e l y t r e a t e d (Tab. 3). B e c a u s e G r a m - p o s i t i v e o r g a n i s m s h a v e b e e n i n c l u d e d , p ipe rac i l l i n h a s g a i n e d s o m e g r o u n d , t h o u g h only in c o m p a r i s o n to cef- t a z i d i m e a n d c iprof loxac in , b o t h s u b s t a n c e s k n o w n for t h e i r p o o r ac t iv i ty a g a i n s t G r a m - p o s i t i v e o r g a n i s m s .

However, i t m u s t b e n o t e d t h a t t h e s e c a l c u l a t i o n s a r e b a s e d p u r e l y o n mic rob io log ica l da t a . W h e t h e r a p a t i e n t is a d e q u a t e l y t r e a t e d will to a la rge e x t e n t a l so d e p e n d o n t h e p h a r m a c o d y n a m i c s of t h e a n t i b i o t i c u s e d (i. e. w h e t h e r effec- t ive a n t i b i o t i c c o n c e n t r a t i o n s a re a c t u a l l y a c h i e v e d a t t h e s i t e of infect ion) a n d o n t h e s u p p o r t i v e t r e a t m e n t u s e d . In add i t i on , u n d e r l y i n g d i s e a s e a n d a n t i b i o t i c p r e - t r e a t m e n t will h a v e a s i gn i f i c an t i m p a c t o n m o r t a l i t y in p a t i e n t s w i t h n o s o c o m i a l p n e u m o n i a .

Neve r the l e s s , i t h a s b e e n a t t e m p t e d to r e p r e s e n t t h e fre- q u e n t l y h igh ly " theore t i ca l " p e r c e n t a g e r a t e s u s e d in v a r i o u s p u b l i c a t i o n s in t h e fo rm of m o r e c o n s p i c u o u s "prac t ica l" da t a . U s i n g t h e IF ca l cu l a t i on , t h e s e p e r c e n t a g e r a t e s h a v e b e e n t r a n s l a t e d in to n u m b e r s i n d i c a t i n g a f t e r h o w m a n y pa - t i e n t t r e a t m e n t s a s t h e r a p y fa i lu re c a n b e expec ted .

T h e s e f g u r e s a re to a s s i s t t h e t r e a t i n g p h y s i c i a n in se lec t - ing a n a p p r o p r i a t e emp i r i ca l a n t i b i o t i c t h e r a p y . As a l r e a d y m e n t i o n e d above , t r e a t m e n t of n o s o c o m i a l p n e u m o n i a m u s t a l r e a d y b e i n i t i a t e d w i t h a s effect ive a t h e r a p y a s poss ib le . U s i n g t h e BIF, t h e i n d i v i d u a l a n t i b i o t i c s m a y b e c o m p a r e d for t h e d i f fe ren t i n d i c a t i o n s ( p n e u m o n i a , s eps i s , pe r i ton i t i s , etc.}, a n d a f t e r a p p r o p r i a t e c o n s i d e r a t i o n of al l c i r c u m s t a n - ces. t h e an t ib io t i c s h o w n to b e m o s t effect ive for t h i s i nd i ca - t ion c a n b e se lec ted . It m u s t once a g a i n b e n o t e d t h a t for se- l ec t ing t h e m o s t effective a n t i b i o t i c t h e r a p y , t h e p h y s i c i a n m u s t keep i n f o r m e d o n t h e r e s i s t a n c e p a t t e r n s p r e v a i l i n g in t h e r e s p e c t i v e hosp i t a l . T h e IFs p r o v i d e d in t h i s r e p o r t r ep re - s e n t a n A u s t r i a - w i d e s u m m a r y a n d m a y s h o w s o m e d iver - g e n c e s for a spec i f ic hosp i t a l , t h o u g h t h e s t u d y c lear ly re- f lects a n A u s t r i a - w i d e t r e n d .

R e f e r e n c e s (1) Alvarez-Lerma F, and the ICU-acquired Pneumonia Study Group: Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. Intensive Care Med 1996,22:387- 394. (2) Girou E, Stephan F, Novara A, Safa M, Fagon JY: Risk factors and out- come of nosocomial infections: Results of a matched case-control study of ICU patients. Am J Respir Crit Care Med 1998; 157:1151 - 1158. (3) Krause R, Mittermayer H, Feierl G, AUerberger F, Wendelin I, Hirschl A, Reisinger EC: In vitro activity of newer broad spectrum beta-lactam antibiotics against Enterobacteriaceae and non-fermenters: A report from Austrian Intensive Care units. Wien Klin Wochenschr 1999;111:549- 554. (4) Lode HM, Schaberg T, Raffenberg M, Mauch H: Nosocomial pneumo- nia in the critical care unit. Critical Care Clinics 1998; 14:119-133. (5) Luna CM, Vujacich P, Niederman MS, Vay C. Gherardi C, Matera J. Jolly EC: Impact of BAL data on the therapy and outcome of ventilator-as- sociated pneumonia. Chest 1997; 111:676-685. (6) Theuretzbacher U, Seewald M: Mikrobiologie im klinischen Alltag. Stuttgart, Verlag Kohlhammer, 1999, p 461. {7) Wrist J. Fret R: Multicenter study of the in vitro activity of cefepime in comparison with five other broad-spectrum antibiotics against clinical isolates of Gram-positive and Gram-negative bacteria from hospitalized patients in Switzerland. Clinical Microbiology and Infection 1999;5:262- 269.