in vivo 27: 873-876 (2013)

Methicillin-resistant Staphylococcus aureus Rate After Implementation of an Care Bundle Based on Results of Rapid Molecular Screening

PAOLA STANO, MANUELA AVOLIO, RITA DE ROSA, MARIA LUISA MODOLO and ALESSANDRO CAMPORESE

Department of Microbiology and Virology, S. Maria degli Angeli Hospital, Pordenone, Italy

Abstract. Aim: Colonization with methicillin-resistant bacteremia and endocarditis, particularly in patients admitted Staphylococcus aureus (MRSA) is a risk factor for subsequent to critical areas such as intensive care units (ICU) (1-3). Thus, invasive MRSA infection, particularly in patients admitted to MRSA-colonized patients should be closely monitored, being critical areas. We conducted a surveillance among patients at higher risk as compared with non-colonized patients (4, 5). admitted to our (ICU) to determine whether A rapid identification of MRSA nasal carriers is considered the implementation of a specific MRSA antibiotic care bundle essential to limit the spread of resistant strains and to reduce (ACB) based on rapid molecular screening for MRSA and de- MRSA infection rate and treatment costs (6-8). Recently colonization, reduced the total MRSA infection rate. Materials published articles conclude that MRSA screening should be and Methods: A total of 431 and 577 nasal swabs were considered a useful tool for predicting in advance the etiology obtained from ICU patients at admission from April 2009 of the MRSA infection and for starting a correct empirical through December 2010 (pre-ACB period) and, after the bundle anti-microbial treatment (9, 10). Moreover, several studies implementation, from January 2011 through December 2012 demonstrated that MRSA colonization results must be rapidly (post-ACB period), respectively. Nasal swabs were analyzed by delivered to critical care physicians to translate into an actual the rapid molecular test Xpert MRSA. All patients were clinical impact, thus the recent introduction of rapid followed-up during their whole ICU stay to determine whether molecular tests can improve infection control procedures by they developed MRSA infection. Results: Overall, 31 out of 431 providing results within hours rather than days (6, 7, 11). (7.1%) patients were colonized with MRSA at admission during Furthermore, the centers for disease control and prevention the pre-ACB period and 49 out of 577 (8.4%) were colonized (CDC) recommend that all healthcare organizations recognize with MRSA during the post-ACB period. The rate of MRSA previously-colonized patients, rapidly report MRSA infection in ICU significantly declined from 2% in pre-ACB to laboratory results and consider active surveillance screening 0.3% in post-ACB, with a total decrease of 100% in two of patients to detect colonization even without evidence of consecutive semesters between July 2011 and July 2012 infection, in order to prevent MRSA infection (12). (p<0.001). Conclusion: The analysis demonstrated a significant MRSA surveillance, in conjunction with an antibiotic care decline in MRSA following the introduction of active bundle (ACB) approach, has been recently proposed as a rapid molecular surveillance and the specific ACB at our ICU guide for correct treatment of patients admitted to ICUs (13). and in the risk associated with MRSA bacteremia. ACB is a group of key elements based on clinical features and laboratory results for the management of antibiotic Colonization with methicillin-resistant Staphylococcus aureus prescription (13, 14). (MRSA) is a risk factor for subsequent invasive MRSA We conducted surveillance among patients admitted to our infections, including ventilator-associated pneumonia, ICU and assessed the effects of implementation of specific MRSA ACB and prompt empirical anti-MRSA coverage, according to the ACB, on the prevalence of MRSA infection at our ICU. Correspondence to: Paola Stano, MD, Microbiology and Virology Department, S. Maria degli Angeli Hospital, Via Montereale 24 – Patients and Methods 33170, Pordenone, Italy. Tel: +39 0434398763, Fax: +39 0434399170, e-mail: [email protected] A specific ACB was implemented in the period from January 2011 through December 2012 at our ICU and used as a guide for Key Words: Rapid molecular screening, nosocomial infection, antibiotic treatment in patients suspected of being infected with infection prevention, methicillin-resistant, Staphylococcus aureus. MRSA. The bundle consisted of rapid molecular screening for

0258-851X/2013 $2.00+.40 873 in vivo 27: 873-876 (2013)

MRSA nasal carriage, contact precautions, single room or cohort period vs. only one case (0.2%) in the post-ACB period] with isolation, and nasal decolonization (mupirocin 2% ointment three a RRR of 91%. Moreover, the RRR of bacteremia infection times-a-day for five days) for patients colonized or infected with alone in the post-ACB period was 100% (p=0.02) (Table I). MRSA (15). At admission, we collected specimens from sterile sites for bacterial culture prior to antibiotic administration and took nasal swabs for rapid MRSA screening. A total of 431 and 577 nasal Discussion screening tests were obtained from April 2009 through December 2010 (pre-ACB period) and from January 2011 through December In the present study we demonstrated that implementation of 2012 (post-ACB period) from patients admitted to our ICU. In cases a specific ACB at admission significantly reduced the MRSA of positive nasal carriage and suspected bloodstream infection, first- infection prevalence at our ICU, from 20.8 per 1,000 line empirical anti-MRSA treatment with vancomycin, 15 mg/kg admissions to 3.4 per 1,000 admissions. The statistical loading dose, followed by 30 mg/kg/day continuous infusion was analysis showed a significant reduction of the risk of MRSA used. All patients were followed-up during their ICU stay to determine whether they developed clinical MRSA infection, infections among colonized patients managed following the confirmed by a positive culture from sterile sites. The use of anti- ACB protocol and in particular of the risk associated with MRSA agents was then re-evaluated day by day on the basis of MRSA bacteremia (RRR 100%, p=0.02). clinical and laboratory features, with positive cultures from sterile In a recently published study, we found a significantly site or signs of active infection supporting prolongation of empirical increased risk of MRSA infection in ICU patients with treatment (15). On the contrary, MRSA-negative clinical cultures MRSA colonization compared with patients without (15), in indicated a de-escalation strategy. line with recent reports which suggested that MRSA All nasal swabs were obtained by inserting a Copan Stuart swab (Copan Diagnostics, Corona, CA, USA) in both nostrils and infection rate is always higher for MRSA carriers and that analyzed using the molecular test Xpert MRSA (Cepheid, MRSA nasal carriage is strongly associated with Sunnyvale, CA, USA). The results of rapid nasal screening were development of nosocomial infections, particularly among displayed on the Laboratory Information System and subsequently critically ill patients (4, 16). Furthermore, MRSA infections available to ICU physicians within 2 h from specimen receipt. are associated with worse outcomes and a substantial Clinical samples from patients suspected as being infected with increase in healthcare costs compared to sensitive infections MRSA were tested by standard laboratory culture procedures. (17). To date, the benefit of earlier screening of MRSA nasal Comparisons of relative risk reduction (RRR), relative risk (RR) and the associated 95% confidence interval (CI) between the two study carriers as a strategy to reduce the MRSA infection rate is periods were performed using Fisher’s exact test. The significance debated and several recent studies have shown discordant level was set at p≤0.02. results (18-20). However, in many studies, the authors used traditional culture methods instead of polymerase-chain- Results reaction, reducing the sensitivity of the analysis, and even when they used molecular methods, identification and Overall, 31 out of 431 (7.1%) patients were colonized with decolonization of nasal carriers was not immediate after MRSA at admission during the pre-ACB period while 49 out admission, or the sample processing frequency and the of 577 (8.4%) were colonized with MRSA during the post- reporting time were not satisfactory (18, 21). ACB period. All colonized patients in the post-ACB period Chan et al. in a recently published article highlight the (49 of 577) were de-colonized at admission with mupirocin usefulness of active surveillance culture as a predictor of ointment. During the pre-ACB period 9 patients developed MRSA ventilator-associated pneumonia (9). In the same generalized MRSA infection, compared with only two cases journal, Toschlog et al. posed several interesting issues on in the post-ACB period. The total rate of MRSA infection the study by Chan and colleagues related to the low during the pre-ACB period was 2% (20.8 per 1,000 sensitivity of selective agars used as screening method (11 admissions) but reduced to 0.3% (3.4 per 1,000 admissions) patients developed MRSA ventilator-associated pneumonia in the post-ACB period, with a total decrease of 100% in two with negative screening cultures) and to what the impact on consecutive periods between July 2011 and July 2012 the screening performance would have been if a PCR method (p<0.001). The rate of MRSA infection among positive nasal had been used instead of cultures (10). carriers dropped from 30% in the pre-ACB period to 4% in In a recent randomized, multicenter trial (22), rapid the post-ACB period although the nasal MRSA colonization identification of S. aureus nasal carriers by a PCR assay, rate at admission increased respectively from 7.1% to 8.4%. followed by de-colonization reduced the risk of nosocomial The statistical analysis shows the RR and RRR after S. aureus infection by nearly 60%. In their study, in contrast interventions were 0.14 (95%CI=0.02-0.63) and 0.85 (95% with previous randomized trials, nasal carriage of S. aureus CI=0.36-0.97; p=0.002) respectively. Overall, during the two was detected rapidly by real-time PCR at the time of hospital study periods, low respiratory tract (LRTI) and bacteremia admission. On the contrary, Huskins and collegues in a infections were most frequent (78%) but significantly recent cluster-randomized trial had different results, showing declined after ACB [seven cases (1.6%) in the pre-ACB no effect on reducing the trasmission of MRSA after the

874 Stano et al: Effect of Rapid MRSA Screening

Table I. Methicillin-resistant Staphylococcus aureus (MRSA) infection rate and associated risks.

Pre-intervention Post-intervention Relative risk Relative risk p-Value period (n=431) period (n=577) reduction (95% CI) (95% CI)

Variable n (%)

MRSA-positive nasal screen 31 (7.1) 49 (8.4) MRSA infections 9 (2) 2 (0.3) 0.85 (0.36-0.97) 0.14 (0.02-0.63) (0.002)

MRSA infection site Low respiratory tract infection and bacteremia 7 (1.6) 1 (0.2) 0.91 (0.32-0.99) 0.09 (0.004-0.67) (0.005) Bacteremia 4 (0.9) – 1 (0.075-1.000) 0 (0.000-0.92) (0.02) CVC-related infection 1 (0.2) – Ascitic fluid 1 (0.2) 1 (0.2)

CI: Confidence interval; CVC: central venous ; n: number of patients.

intervention (20). In their study, several factors may have to improve cost-effectiveness. However, other investigators influenced the effects of the intervention, but the average believe that restricting molecular screening for MRSA to time from when a surveillance culture was obtained until the high-risk patients, such as those admitted to ICU, could be a reporting time to clinicians of five days, surely limited the cost-effective strategy to reduce infection rates and efficacy of surveillance (23). transmission of MRSA (25, 26). In conclusion, although more In a recently point–counterpoint article, Peterson reports randomized controlled trials are needed to determine the a summary of published studies that show how the level of potential impact of our approach on patient outcomes, our test sensitivity and reporting time of results modify the results underscore the importance of using active surveillance reduction of MRSA infection. For each of these studies for improving management and outcome of ICU patients. Peterson calculated the percentage of captured potential However, we believe that the impact is strictly dependent on MRSA isolation days based on level of test sensitivity, the sensitivity of the test used, initiation of MRSA nasal reporting time and length of hospital stay. Interestingly, in screening, de-colonization immediately after admission, and those reports, a reduction of MRSA transmission or infection rapid reporting. during the intervention periods was achieved only when the estimated captured MRSA isolation days exceeded 80%, References which implies that the assay sensitivity and a rapid reporting time are critical to the outcome. On the contrary, in the same 1 Davis KA, Stewart JJ, Crouch HK, Florez CE and Hospenthal article Diekema highlighted that in some studies other DR: Methicillin-resistant Staphylococcus aureus (MRSA) nares infection control strategies, such as hand hygiene or colonization at hospital admission and its effect on subsequent clorhexidine body washes for all ICU patients, may be more MRSA infection. Clin Infect Dis 39: 776-782, 2004. effective in reducing the incidence of MRSA, rather than 2 Patel M, Weinheimer JD, Waites KB and Baddley JW: Active rapid screening tests (18). surveillance to determine the impact of methicillin-resistant Staphylococcus aureus colonization on patients in intensive care In our study, we detected MRSA carriage immediately units of a Veterans Affairs Medical Center. Infect Control Hosp after admission, by a rapid PCR method, with results being Epidemiol 29: 503-509, 2008. reported within two hours, factors that certainly improved the 3 Lawrence KR, Golik MV and Davidson L: The role of primary efficacy of our intervention. Although the cost associated with care prescribers in the diagnosis and management of community- the PCR-based assay is substantially more expensive, this associated methicillin-resistant Staphylococcus aureus skin and screening method is sensitive and capable of providing results soft tissue infections. Am J Ther 16: 333-338, 2009. within 2-3 h, significantly shorter than cultures. It allows 4 Safdar N and Bradley EA: The risk of infection after nasal MRSA-positive ICU patients who will more likely develop colonization with Staphylococcus aureus. Am J Med 121: 310- 315, 2008. MRSA infections to be rapidly detected and managed 5 Viale P, Gesu G, Privitera G, Allaria B, Petrosillo N, Zamparini appropriately, not only by guiding empirical therapy decisions E and Scudeller L: Multicenter, prospective surveillance study but also by implementing meaningful measures to limit the of Staphylococcus aureus nasal colonization in 28 Italian person-to-person transmission (24). Some believe it is intensive care units: The ISABEL Study. Infect Control preferable to use active surveillance cultures instead of PCR HospEpidemiol 32: 193-197, 2011.

875 in vivo 27: 873-876 (2013)

6 Olchanski N, Mathews C, Fusfeld L and Jarvis W: Assessment 17 Shorr AF, Micek ST and Kollef MH: Inappropriate therapy for of the influence of test characteristics on the clinical and cost methicillin-resistant Staphylococcus aureus: Resource utilization impacts of methicillin-resistant Staphylococcus aureus screening and cost implications. Crit Care Med 36(8): 2335-2340, 2008. programs in US hospitals. Infect Control Hosp Epidemiol 32(3): 18 Peterson LR and Diekema DJ: To screen or not to screen for 250-257, 2011. methicillin-resistant Staphylococcus aureus. J Clin Microbiol 7 Robotham JV, Graves N, Cookson BD, Barnett AG, Wilson JA, 48(3): 683-689, 2010. Edgeworth JD, Batra R, Cuthbertson BH and Cooper BS: 19 Jain R, Kralovic SM, Evans ME, Ambrose M, Simbartl LA, Screening, isolation, and decolonisation strategies in the control Obrosky DS, Render ML, Freyberg RW, Jernigan JA, Muder RR, of methicillin-resistant Staphylococcus aureus in intensive care Miller LJ and Roselle GA: Veterans Affairs initiative to prevent units: Cost effectiveness evaluation. BMJ 343: d5694, 2011. methicillin-resistant Staphylococcus aureus infections. N Engl J 8 Humphreys H: Can we do better in controlling and preventing Med 364(15): 1419-30, 2011. methicillin-resistant Staphylococcus aureus (MRSA) in the 20 Huskins WC, Huckabee CM, O’Grady NP, Murray P, Kopetskie intensive care unit (ICU)? Eur J Clin Microbiol Infect Dis 27: H, Zimmer L, Walker ME, Sinkowitz-Cochran RL, Jernigan JA, 409-413, 2008. Samore M,Wallace D and Goldmann DA: Intervention to reduce 9 Chan JD, Dellit TH, Choudhuri JA, McNamara E, Melius EJ, transmission of resistant bacteria in intensive care. N Engl J Med Evans HL, Cuschieri J, Arbabi S and Lynch JB: Active surveillance 364(15): 1407-1418, 2011. cultures of methicillin-resistant Staphylococcus aureus as a tool to 21 Marlowe EM and BankowskiMJ: Conventional and molecular predict methicillin-resistant S. aureus ventilator-associated methods for the detection of methicillin-resistant Staphylococcus pneumonia. Crit Care Med 40(5): 1437-1442, 2012. aureus. J Clin Microbiol 49(9) Suppl: 53-56, 2011. 10 Toschlog EA and Ramsey KM: Active surveillance cultures to 22 Bode LG, Kluytmans JA,Wertheim HF, Bogaers D, predict ventilator-associated pneumonia resulting from methicillin- Vandenbroucke-Grauls CM, Roosendaal R, Troelstra A, Box AT, resistant Staphylococcus aureus: Is there a role beyond search and Voss A, van der Tweel I, van Belkum A, Verbrugh HA and Vos destroy? Crit Care Med 40(5): 1651-1652, 2012. MC: Preventing surgical-site infections in nasal carriers of 11 Creamer E, Dolan A, Sherlock O, Thomas T, Walsh J, Moore J, Staphylococcus aureus. N Engl J Med 362(1): 9-17, 2010. Smyth E, O'Neill E, Shore A, Sullivan D, Rossney AS, Cunney 23 Platt R: Time for a culture change? N Engl J Med 364(15): R, Coleman D and Humphreys H: The effect of rapid screening 1464-1465, 2011. for methicillin-resistant Staphylococcus aureus (MRSA) on the 24 Stano P and Camporese A: Polymerase chain reaction-based rapid identification and earlier isolation of MRSA-positive patients. screening method is the real tool to prevent methicillin-resistant Infect Control Hosp Epidemiol 31: 374-381, 2010. Staphylococcus aureus infections in the intensive care unit. Crit 12 Siegel JD, Rhinehart E, Jackson M, Chiarello L and the Care Med 40(11): 3113-3114; author reply 3114-3115, 2012. Healthcare Infection Control Practices Advisory Committee. 5 25 Harbarth S, Fankhauser C, Schrenzel J, Christenson J, Gervaz P, December 2009, accession date. Management of multidrug- Bandiera-Clerc C, Renzi G, Vernaz N, Sax H and Pittet D: resistant organisms in healthcare settings. Centers for Disease Universal screening for methicillin-resistant Staphylococcus Control and Prevention, Atlanta, GA. http://www.cdc. aureus at hospital admission and nosocomial infection in gov/ncidod/dhqp/pdf/ar/mdroGuideline2006.pdf. surgical patients. JAMA 299(10): 1149-57, 2008. 13 Cooke FJ and Holmes AH: The missing care bundle: Antibiotic 26 Jeyaratnam D, Whitty CJ, Phillips K, Liu D, Orezzi C, Ajoku U prescribing in hospitals. Int J Antimicrob Agents 30: 25-29, 2007. and French GL: Impact of rapid screening tests on acquisition 14 Toth NR, Chambers RM and Davis SL: Implementation of a care of methicillin-resistant Staphylococcus aureus: Cluster bundle for antimicrobial stewardship. Am J Health Syst Pharm randomised crossover trial. BMJ 336(7650): 927-930, 2008. 67: 746-749, 2010. 15 Stano P, Avolio M, De Rosa R, Modolo ML, Basso SMM, Lumachi F and Camporese A: An antibiotic care bundle approach based on results of rapid molecular screening for nasal carriage of methicillin-resistant Staphylococcus aureus in the intensive care unit. In Vivo 26(3): 469-472, 2012. 16 Honda H, Krauss MJ, Coopersmith CM, Kollef MH, Richmond AM, Fraser VJ and Warren DK: Staphylococcus aureus nasal colonization and subsequent infection in intensive care unit Received August 29, 2013 patients: Does methicillin resistance matter? Infect Control Hosp Revised October 22, 2013 Epidemiol 31: 584-591, 2010. Accepted October 23, 2013

876