ORIGINAL ARTICLE The Risk of Development of Resistance in Individual Patients With Chronic Rhinosinusitis

Neil Bhattacharyya, MD; Lynn J. Kepnes, RNP

Objective: To determine if individual patients with of 157 days. Four hundred twenty-nine organisms were chronic rhinosinusitis (CRS) demonstrate an increasing isolated from these serial cultures, consisting of 255 gram- prevalence of over time. positive organisms, 120 gram-negative organisms, 48 an- aerobes, and 6 fungi. Pairwise analysis of sequential cul- Patients: A prospectively maintained database of mi- tures revealed no significant trend toward increasing crobiologic culture results for adult patients with CRS bacterial resistance within individual patients (P=.57, runs was sequentially analyzed, extracting patients who un- test). Similarly, no significant trend toward increasing derwent multiple serial sinus cultures over time. Anti- gram-positive or gram-negative resistance was demon- microbial resistance patterns were identified and quan- strated. There was no shift toward gram-negative organ- tified for each bacterium. Sequential culture results were isms (PϾ.15 for all). compared for individual patients to determine if increas- ing overall bacterial resistance, gram-positive resis- Conclusions: Individual patients with CRS do not nec- tance, gram-negative resistance, or a shift toward gram- essarily develop increasing levels of bacterial resistance negative organisms was manifested within individual over time. The use of culture-directed antimicrobial patients. therapy may “protect” against the development of se- quentially increasing antimicrobial resistance for pa- Results: During a 7-year period, 90 adult patients were tients with CRS. identified with 224 serial cultures (mean, 2.5 cultures per patient) obtained, with a median time between cultures Arch Otolaryngol Head Neck Surg. 2004;130:1201-1204

LTHOUGH THE CAUSE OF negative organisms and perhaps increas- chronic rhinosinusitis ing microbiologic resistance patterns to (CRS) remains controver- .6 sial, most investigators However, the time-dependent pat- agree that at least one com- tern of the development of antimicrobial ponentA of the pathogenesis of CRS is mi- resistance for individual patients with CRS crobial . Substantial informa- has not been previously studied, to our tion exists in the literature implicating knowledge. Although the overall preva- bacterial infection as one of the micro- lence of increasing antimicrobial resis- bial pathogens in CRS.1 Because of the pu- tance may be identified in populations tative role of bacterial infection in CRS, studied over the course of years, it is not most treatment guidelines recommend ex- clear as to the specific origin of increas- tended courses of antibiotics in the medi- ing antimicrobial resistance. Whether in- cal management of CRS before consider- dividual patients are experiencing increas- ation of surgical therapy.2 In addition, ing rates of antimicrobial resistance for From the Division of despite adequate surgical therapy, typi- their bacterial pathogens of CRS as se- Otolaryngology, Brigham and cally with endoscopic sinus surgery (ESS), quential are treated has not been Women’s Hospital a small but significant number of pa- determined. This study was conducted to (Dr Bhattacharyya and tients may continue to experience acute determine if, as they are treated for CRS Ms Kepnes), and the Division bacterial exacerbations of their CRS, of- exacerbations, patients individually de- of Otology and Laryngology, 3 Harvard Medical School ten requiring therapy. Investi- velop increased levels of antimicrobial re- (Dr Bhattacharyya), Boston, gators have analyzed microbiologic pat- sistance during the course of their dis- Mass. The authors have no terns of bacterial infection in CRS before ease. Phrased another way, do individual relevant financial interest in and after surgery.4,5 Results have con- patients acquire increasing rates of bacte- this article. firmed a substantial prevalence of gram- rial resistance as they are treated repeat-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 positive organisms acquiring increasing resistance over time for Table 1. List of 408 Recovered Organisms* an individual patient? (3) Are gram-negative organisms ac- quiring increasing resistance? (4) Is there a shift from gram- Count positive to gram-negative organisms within individual pa- Organism (% of Isolates) tients with CRS over time? Staphylococcus aureus 103 (25.2) First, the development of increasing microbial resistance ac- Staphylococcus, coagulase-negative 91 (22.3) cording to serial cultures for each patient was analyzed. For each Pseudomonas aeruginosa 59 (14.5) patient, a sequence of pairs of cultures was constructed accord- Propionibacterium acnes 31 (7.6) ing to sequentially advancing dates of culture. For example, Haemophilus influenzae 18 (4.4) patient A may have had cultures done on January 1, 1997, July Streptococcus pneumoniae 14 (3.4) 1, 1998, and January 1, 1999. From this sequence of serial Streptococcus viridans, ␣-hemolytic 11 (2.7) cultures, 2 pairs (1997-1998 and 1998-1999) exist for compari- Alcaligenes xylosoxidans subspecies xyloso 9 (2.2) son with each other. From each pair of cultures obtained in a se- Moraxella (Branhamella) catarrhalis 8 (2.0) rial fashion for each patient, the degree of resistance for the maxi- Streptococcus, ␤-hemolytic group A 8 (2.0) mally resistant bacterium (understanding that the culture results Corynebacterium species (diphtheroids) 8 (2.0) were commonly polymicrobial) was identified for the first cul- Streptococcus, ␤-hemolytic group B 7 (1.7) ture and then compared with the maximally resistant bacterium Enterococcus species 6 (1.5) isolated from the second culture. The degree of resistance for a Stenotrophomonas (Xanthomonas) maltophilia 6 (1.5) given bacterium was defined as the number of antibiotics with Bacillus species 3 (0.7) microbial resistance divided by the number of total tested anti- Escherichia coli 3 (0.7) biotics. Intermediate antimicrobial resistance according to the Na- Klebsiella pneumoniae subsp pneumonia 3 (0.7) tional Committee Clinical Laboratory Standards break points was Peptostreptococcus asaccharolyticus 2 (0.5) Acinetobacter lwoffi 2 (0.5) considered “resistant” for the purposes of this study. If the sec- Propionibacterium granulosum 2 (0.5) ond culture’s bacterium exhibited a more severe degree of anti- Streptococcus intermedius 2 (0.5) microbial resistance, this paired sequence of cultures was con- Prevotella (Bacteroides) melaninogenica 2 (0.5) sidered as having demonstrated increasing bacterial resistance over Peptostreptococcus micros 2 (0.5) time. If there was no increase in resistance severity for the sec- Enterobacter aerogenes 2 (0.5) ond culture’s isolated organism vs the first culture’s organism, this Enterobacter cloacae 2 (0.5) pair was considered as not exhibiting increasing bacterial resis- Serratia marcescens 2 (0.5) tance over time. Ties (ie, equivalent resistance percentages be- Fusobacterium nucleatum subspecies nucleat 2 (0.5) tween pairs) were considered as not showing increasing devel- opment of resistance. A comparison of proportions of increasing *Lists only those organisms isolated Ն2 times. bacterial resistance vs lack thereof was conducted with the runs test for randomness of a sequence with the Monte Carlo exact method with significance set at PϽ.05. edly for acute exacerbations of CRS over time? This would This pairwise comparison method was then used to de- have important repercussions for the treatment of indi- termine whether increasing sequential resistance could be dem- vidual patients if indeed serious increases in antimicro- onstrated specifically for the subset of gram-positive organ- bial resistance were demonstrated in patients during the isms and again for the subset of gram-negative organisms. Finally, this pairwise comparison method was used to deter- course of their disease. mine if a shift occurred within individual patients from gram- METHODS positive to gram-negative organisms over time. However, for the analysis of gram-negative shifts, persisting gram-negative This study was approved by the Committee on Clinical Inves- organisms on cultures after the first culture were considered tigations at Brigham and Women’s Hospital. We analyzed a pro- as demonstrating a shift toward gram-negative prevalence. spectively maintained electronic database of sinus culture re- sults for January 1997 through December 2003. This database RESULTS consists of all sinus cultures submitted from our hospital for adult patients with a diagnosis of CRS and includes date of cul- During the period under consideration, 834 positive si- ture, site of culture, isolated organism, gram stain character- nus cultures were obtained, yielding 1074 organism iso- istic, and sensitivity analysis. Sensitivity analysis is deter- lates. Among these cultures, 90 adult patients had 2 or mined and coded according to the National Committee Clinical Laboratory Standards break points for each bacterial species. more cultures drawn on different days, comprising 224 From this prospective database, patients who underwent serial cultures (mean, 2.5 cultures per patient). The me- 2 or more sinus cultures during the study period were identi- dian time between serial cultures was 157 days. Overall, fied and extracted. Demographic and microbiologic culture data 429 organisms were isolated from these serial cultures, were retrieved. Data were tabulated and exported to Microsoft consisting of 255 gram-positive organisms, 120 gram- Excel (Redmond, Wash). After preliminary demographic analy- negative organisms, and 48 anaerobes; 6 isolates were sis, the database was further restricted to cases for which mul- fungi. Table 1 lists the organisms recovered by fre- tiple positive cultures were isolated for each patient on sepa- quency. On average, gram-positive organisms demon- rate calendar days during the study period. Therefore, each strated a mean number of 1.7 antimicrobial resistances remaining case had 2 or more sinus cultures (serial culture data) per organism vs 5.0 antimicrobial resistances per organ- with an identified organism on each of the bacterial cultures, allowing comparative analysis among cultures by isolated or- ism for gram-negative organisms. ganism. Data were imported to SPSS version 10.0 (Chicago, Ill). Table 2 demonstrates results of the statistical analy- Statistical analyses were conducted to answer 4 basic ques- sis for the 4 hypotheses tested. No statistically signifi- tions: (1) Is there a trend toward increasing degree of antimi- cant increase in severity of antimicrobial resistance was crobial resistance for individual patients with CRS? (2) Are gram- demonstrated within patients as serial cultures were

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 drawn. In fact, a general trend toward decreasing anti- microbial resistance was noted overall, with many pa- Table 2. Results of Statistical Analysis for Culture Trends tients showing reversion to lesser degrees of antimicro- bial resistance over time. Similarly, no significant increase No. of No. of P in antimicrobial resistance was demonstrated for sub- Tested Variable Sequences Runs Value groups of gram-negative organisms or gram-positive or- Increasing resistance within individual 134 63 .57 ganisms. Again, a trend toward decreasing antimicro- patients cultured serially Increasing gram-positive resistance 95 37 .75 bial resistance was noted over time. Finally, no statistically Increasing gram-negative resistance 40 17 .17 significant shift toward increasing prevalence of gram- Shift to gram-negative organisms 134 47 .89 negative organisms was identified on an individual pa- tient basis. CRS, especially in the preoperative state. Typically, au- COMMENT thors recommend 4 to 6 weeks of broad-spectrum anti- microbials in the initial medical management of CRS.2 During the past decade, substantial interest and con- However, there are no specific randomized trials for ex- cern have surfaced regarding the increasing prevalence tended-course antimicrobial therapy in CRS, and, to date, of antimicrobial resistance in medicine, prompting high no specific antibiotic carries a Food and Drug Adminis- levels of attention even at the governmental level.7 Sev- tration–approved indication for the treatment of CRS (as eral medical societies and federal agencies have cau- opposed to approval for the treatment of acute bacterial tioned the health care industry and the public, and they rhinosinusitis). have called for more judicious, evidence-based prescrib- The problem of recurrent acute bacterial exacerba- ing rules for antibiotic treatment in an effort to stem what tions of CRS, especially after ESS, has drawn some sig- is believed to be a potential serious problem in the treat- nificant attention in the literature. We have previously ment of common infectious diseases. Many otolaryngo- demonstrated a somewhat concerning prevalence of gram- logic conditions arise from or are in part due to chronic negative organisms in patients experiencing recurrent infections, and one of the most common of these enti- acute exacerbations of CRS after ESS.3 Other investiga- ties is CRS. Therefore, the problem of antimicrobial re- tors have shown similar prevalences of gram-negative or- sistance has a significant bearing on our specialty. ganisms and some trends toward increasing antimicro- Several potentially disturbing trends have emerged bial resistance in patients after ESS.4 In the postoperative in the bacteriology and infectious epidemiology of CRS. setting, oral antibiotics are sometimes recommended, Recently, several authors have identified increasing preva- whereas topical antibiotics, some delivered by novel meth- lence for gram-negative organisms in CRS in native and ods, have also demonstrated efficacy.11 The use of anti- surgically treated cases.3,4,6,8 In a study of patients tran- biotics for the treatment of postoperative acute exacer- sitioning from acute to chronic rhinosinusitis, Brook et bations of CRS seems warranted given that recent data al9 demonstrated a microbiologic transition from com- have shown that these infections occurring after sur- mon offenders such as Staphylococcus pneumoniae for acute gery are due to growth of noncolonizing bacteria.12 rhinosinusitis to more refractory bacteria such as Staphy- The use of culture-directed therapy has been pro- lococcus aureus. Increases in ␤-lactamase activity were also posed as one conceivable method for reducing the preva- demonstrated. In addition, patients experiencing acute lence of antimicrobial resistance in patients with CRS. exacerbations of CRS after ESS have been demonstrated Advocates of culture-directed therapy suggest that, by to have a significant prevalence of gram-negative organ- obtaining cultures at the time of an acute exacerbation of isms, often with elevated levels of antimicrobial resis- CRS, likely organisms may be identified and targeted an- tance.3 tibiotic therapy instituted, avoiding the need for empiric Recently, the Sinus and Allergy Health Partner- therapy with overly potent broad-spectrum antibiotics.13 ship10 put forth recommendations for the antimicrobial As it is believed that overuse of broad-spectrum antibiot- treatment of acute bacterial rhinosinusitis. Because of the ics may be a key step in the promotion of bacterial resis- increasing prevalence of ␤-lactamase–producing strains tance, culture-directed therapy has been adopted by many of bacteria, recommendations have now shifted to more investigators.11 Unfortunately, culture-directed therapy re- potent ␤-lactam–stable antibiotics with broader spectra quires significant cooperation on the part of the patient of antibacterial action. These recommendations, when em- and is more expensive because of the costs of a physi- pirically followed for patients with CRS rather than acute cian’s visit and laboratory culture compared with empiric bacterial rhinosinusitis, could lead to the formation of antibiotic therapy. Although may be less refractory antimicrobial resistance. Unfortunately, little expensive in the short term, resulting antimicrobial resis- attention has been paid to antimicrobial treatment guide- tance may have more serious implications in the long term lines for CRS. Two separate areas of debate exist. First, for these patients. what is the appropriate-spectrum antibiotic for the ini- We advocate culture-directed therapy for all pa- tial treatment of CRS, and what is the appropriate treat- tients after ESS and for patients not operated on after the ment duration with antibiotic regimens before consid- failure of first-line . To some degree, we eration of ESS? The second area of debate surrounds the believe that the demonstrated lack of increase in antimi- treatment of acute exacerbations of CRS before or after crobial resistance in the present patient population may ESS. Little scientific data exist concerning the appropri- be accounted for by our reliance on culture-directed ate use of antimicrobials in the medical management of therapy. In addition, in our clinical practice, a strong ef-

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 fort is made to avoid broad-spectrum antimicrobials when 2. Benninger MS, Anon J, Mabry RL. The medical management of rhinosinusitis. possible; this avoidance may have helped prevent a shift Otolaryngol Head Neck Surg. 1997;117(pt 2):S41-S49. 3. Bhattacharyya N, Kepnes LJ. The microbiology of recurrent rhinosinusitis after toward gram-negative organisms on serial culture for in- endoscopic sinus surgery. Arch Otolaryngol Head Neck Surg. 1999;125:1117- dividual patients. 1120. In conclusion, the present study demonstrates that, 4. Nadel DM, Lanza DC, Kennedy DW. Endoscopically guided cultures in chronic in patients undergoing serial culture and treatment for sinusitis. Am J Rhinol. 1998;12:233-241. 5. Chan J, Hadley J. The microbiology of chronic rhinosinusitis: results of a com- acute exacerbations of CRS, the risk of developing anti- munity surveillance study. Ear Nose Throat J. 2001;80:143-145. microbial resistance over time remains small. Indi- 6. Hsu J, Lanza DC, Kennedy DW. Antimicrobial resistance in bacterial chronic si- vidual patients with CRS are not more likely to develop nusitis. Am J Rhinol. 1998;12:243-248. antimicrobial resistance as recurring infections are treated. 7. Interagency Task Force on Antimicrobial Resistance of the Centers for Disease Therefore, patients should not necessarily be more con- Control and Prevention. Second annual progress report: implementation of a pub- lic health action plan to combat antimicrobial resistance, I: domestic issues. Avail- cerned about their individual potential development of able at: http://www.cdc.gov/drugresistance/actionplan/index.htm. Accessed May antimicrobial resistance when culture-directed therapy 1, 2004. is used. 8. Ramadan HH. What is the bacteriology of chronic sinusitis in adults? AmJOto- laryngol. 1995;16:303-306. 9. Brook I, Yocum P, Frazier EH. Bacteriology and ␤-lactamase activity in acute and Submitted for publication May 4, 2004; accepted June 16, chronic maxillary sinusitis. Arch Otolaryngol Head Neck Surg. 1996;122:418- 2004. 423. Correspondence: Neil Bhattacharyya, MD, Division of 10. Anon JB, Jacobs MR, Poole MD, et al; Sinus and Allergy Health Partnership. An- Otolaryngology, Brigham and Women’s Hospital, 333 Long- timicrobial treatment guidelines for acute bacterial rhinosinusitis [published cor- rection appears in Otolaryngol Head Neck Surg. 2004;130:794-796]. Otolaryn- wood Ave, Boston, MA 02115 ([email protected]). gol Head Neck Surg. 2004;130(suppl):1-45. 11. Vaughan WC, Carvalho G. Use of nebulized antibiotics for acute infections in chronic REFERENCES sinusitis. Otolaryngol Head Neck Surg. 2002;127:558-568. 12. Bhattacharyya N, Gopal HV, Lee KH. Bacterial infection after endoscopic sinus surgery: a controlled prospective study. Laryngoscope. 2004;114:765-767. 1. Bhattacharyya N. The role of infection in chronic rhinosinusitis. Curr Allergy Asthma 13. Gold SM, Tami TA. Role of middle meatus aspiration culture in the diagnosis of Rep. 2002;2:500-506. chronic sinusitis. Laryngoscope. 1997;107(pt 1):1586-1589.

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