Ruolo dell’antimicrobial stewardshipnella prevenzione dell’infezione da

C. difficile

Angela Raffaella Losito

Istituto di Clinica delle Malattie Infettive

A total of 13,085 microorganisms were reported in 10,340 (52.7%) HAI.

The 10 most frequently isolated microorganisms were:

• E. coli (16.1%)

• S. aureus (11.6%)

• Klebsiella spp. (10.4%)

• Enterococcus spp. (9.7%)

• P. aeruginosa (8.0%)

• C. difficile (7.3%)

• Coagulase-negative staphylococci (7.1%)

• Candida spp.(5.2%)

• Enterobacter spp. (4.4%)

• Proteus spp. (3.8%).

HEALTHCARE- ASSOCIATED INFECTIONS

Euro Surveillance, 2018

Types of Heathcare Associated Infections

The most frequently reported types of HAI were:

- Respiratory tract infections (21.4% pneumonia and 4.3% other lower respiratory tract infections)- urinary tract infections (18.9%)- surgical site infections (18.4%)- bloodstream infections (10.8%) - gastro-intestinal infections (8.9%), with C. difficile infections accountingfor 44.6% of the latter.

A total of 4.5 million (95% cCI: 2.6–7.6 million) HAI were estimated to occur per year in the period 2016 to 2017 in ACH in the EU/EEA.

Euro Surveillance, 2018

• This study examined the introduction ASP in relation to HCA-CDI rates, and the effect of HCA-CDI on length of stay (LOS) and hospital costs

• HCA-CDI rates rose from 3.07 to 4.60 cases per 10,000 occupied bed-dayspre-intervention, and remained stable at 4 cases per 10,000 occupied bed-days post-inter-vention (P=0.24). Median LOS (17 vs six days;P<0.01) and hospital costs (AU$19,222 vs $7861;P<0.01) were significantly greater forHCA-CDI cases (N=91) than for matched controls (N=172).

• There was a 42% increase in hospital costs in HCA-CDI patients compared with controls, despite similar LOS in those groups. This highlighted the increased cost of caring for HCA-CDI patients additional to greater LOS.

Key steps in the pathogenesis of CDI

Antibacterial therapy

Alteration of colonic microflora

C. difficile exposure and colonisation

Release of toxins A and B

Colonic mucosal injury and inflammation

Kelly & LaMont. Annu Rev Med 1998;49:375–90.

2018: Guidance document for prevention of Clostridium difficile infection in acute healthcare settings

• The most important infective cause of HCA diarrhoeain high income countries and one of the most important HCA pathogens

• associated with high morbidity and mortality resulting in both societal and financial burden

• A significant proportion of this burden is potentially preventable by a combination of:

- targeted infection prevention

- control measures

- antimicrobial stewardship.

ANTIMICROBIAL STEWARDSHIP

Definizione: Insieme di azioni coordinate e volte a migliorare e misurare l’appropriatezza prescrittiva degli antibiotici promuovendo laselezione del regime ottimale in termini di dose, durata dellaterapia, via di somministrazione

Obiettivi:

Antimicrobial Stewardship

Goals

• Improve patient outcomes

• Optimize selection, dose and duration of Rx

• Reduce adverse drug events including secondary infection (e.g. C. difficile infection)

• Reduce morbidity and mortality

• Limit emergence of antimicrobial resistance

• Reduce length of stay

• Reduce health care expenditures

MacDougall CM and Polk RE. Clin Micro Rev 2005;18(4):638-56.Dellit TH, et. al. Clin Infect Dis. 2007;44:159-177

Active Antimicrobial Stewardship:Core Strategies

₁ Preauthorization and Prospective audit with intervention and feedback

Rates of nosocomial Clostridium difficile, expressed per 1,000 patient-days, before and after implementation of the antibiotic management program.

Carl ing P. et al, 2003. InfectControl Hosp Epidemiol

Intervention:

- Narrow-spectrum antibiotic policy pocket card text (targeted cephalosporins and amoxi/clav for reduction )

- Programme of audit and feedback of antibiotic usage (every 8–12 weeks, of individual antibiotic usage: the number of notional 7 day courses per 100 admissions per month) and CDI rates (cases per month)

CDI rates fell: incidence rate ratios of 0.35 (0.17, 0.73) (P=0.009).

Active Antimicrobial Stewardship:Core Strategies

₂ Formulary restriction and preauthorization requirements for specific agents

Restriction of antibiotic agents/classes is effective in reducing CDI rates (strong recommendation both in outbreak and endemic setting - CMI 2018)

Reducing the duration of antibiotic therapy is effective in reducing CDI rates (strong recommendation both in outbreak and endemic setting - CMI 2018)

Pear SM, et al. Ann Intern Med 1994; 120:272–7.

Quale J, et al. Clin Infect Dis 1996; 23: 1020–5.

Antibiotici e rischio di C. difficile

E’ noto che l’esposizione ad antibioticoterapia quasi sempre precede l’infezione da C. difficile.

Gli antibiotici ad ampio spettro comunemente prescritti sono particolarmente implicati:

Frequentemente associati

Occasionalmente associati

Raramente associati

Clindamicina Macrolidi Metronidazolo

Fluorochinoloni β-latt/inibitore β-latt Vancomicina

Cefalosporine Carbapenemi Aminoglicosidi

TMP-SMZ Tetracicline

• Critical illness and the associated interventions have a detrimental impact on the microbiome.

• Given the potency of antimicrobials utilized to treat septic patients, the effects on the gut microbiome are often rapid and long-lasting

• The overgrowth of opportunistic pathogens is of significant concern as they can lead to infections that become increasingly difficultto treat.

• The balance between the overuse of antimicrobials and the clinical need in these situations is often difficult to delineate.

J Antimicrob Chemother 2019

Cumulative Antibiotic Exposures Over Time and the Risk of Clostridium difficile Infection (CDI)

Clin Infect Dis 2011;53:42

• Observed dose dependent increases in the risk of CDI associated with increasing cumulative dose, number of antibiotics, and days of antibiotic exposure(duration).

• Compared to patients who received only 1 antibiotic, the adjusted hazard ratios (HRs) for those who received 2, 3 or 4, or 5 or more antibiotics were 2.5, 3.3, and 9.6, respectively(overlapping).

• The receipt of fluoroquinolones was associated with an increased risk of CDI, while metronidazole was associated with reduced risk.

Supplemental AntimicrobialStewardship Strategies

• Education (should be used to complement other AS activities)• Guidelines and clinical pathways (can be an effective way to standardize prescribing

practices based on local epidemiology)• Antimicrobial cycling (available data do not support the use of antibiotic cycling as an

ASP strategy) and scheduled antimicrobial switch• Antimicrobial order forms• Combination therapy: prevention of resistance versus redundant

antimicrobial coverage (insufficient data to recommend the routine use of

combination therapy to prevent the emergence of resistance)• Streamlining or de-escalation of therapy (resulting in decreased antimicrobial

exposure and substantial cost savings)• Dose optimization (PK monitoring for aminoglycosides and vancomycin)• Conversion from parenteral to oral therapy (can decrease the length of

hospital stay and health care costs)

Antibiotic Restrictive Approaches• Although even appropriate use of antibiotics can lead to development of

CDI, it is estimated that up to 50% of antimicrobials prescribed are done so improperly

• Though cephalosporins, clindamycin and fluoroquinolones are most often associated with CDI, virtually every antibiotic utilized in clinical practice has been implicated.

• This widespread overuse and misuse of antimicrobials presents a tremendous opportunity for ASPs to optimize patient care.

• One successful approach for has been the restriction of the availability and/or the prescribing of antibiotics known to pose a high risk of subsequent CDI acquisition

implementation of ASPs had a protective benefit

with a risk reduction in the rate of CDAD of 52%

• A restrictive antibiotic policy banning routine use of ceftriaxone and ciprofloxacin wasimplemented in a 450-bed district general hospital following an educational campaign

• Between the first and final 6 months of the study, average monthly consumption of ceftriaxone reduced by 95% and that for ciprofloxacin by 72.5%. Over the same periods, hospital-acquisition rates for C.difficile reduced by 77% (2.398 to 0.549 cases/1000 pt-bds)

• An audit performed 3 years after the policy showed sustained reduction in C.difficile rates(0.259 cases/1000 pt-bds)

Int Journal of Antimicrobial Agents 41 (2013) 137– 142

Significant decrease in mortality following introduction of the guidelines (OR 0.49, P=0.004)

Interventions:

-GL avoiding high risk antibiotics(removed from ward stocks)-Antibiotic management team (ward rounds 5/7)-Education: teaching session, pocket size GL cards, GL app

An evaluation of the impact of antibiotic stewardship on reducing the use of high-risk antibiotics and its effect on the incidence ofClostridium difficile infection in hospital settings

Conclusions: The restriction of the high-risk antibiotics contributed to both a reduction in their use and a reduction in the incidence of CDI in the study site hospital.

Aldeyab MA. J Antimicrob Chemother2012

(a) high-risk antibiotic group

(b) medium-risk antibiotic group

(c) low-risk antibiotic group

What Measures Best Reflect the Impact of Interventions to ImproveAntibiotic Use and Clinical Outcomes in Patients With Specific

Infectious Diseases Syndromes?

Background: epidemic C .difficile ribotypescharacterised by multidrug resistance might depend on antibiotic selection pressures arising from population use of specific drugs.

mixed persuasive and restrictive AS intervention

Limiting use of 4C antibiotics (ciprofloxacin/fluoroquinolones, clindamycin, co-amoxiclav, and cephalosporins) reduced selective pressures favouring multidrug-resistant epidemic ribotypes and was associated with substantial declines in total CDI.

Non-Restrictive Approaches

• Non-restrictive approaches to reducing CDI incidence in the healthcare setting have primarily centered around prospective audit and feedback.

• Other methods have been evaluated with varying success including education, hospital guidelines and policy change

• ASPs are intimately involved in educating physicians and other colleagues within the healthcare system and implementing and updating institution wide antimicrobial use guidelines.

Persuasive interventions, primarily the prospective audit and feedback method, were associated with a 51% reduction in CDAD rates

A striking consequence of local guidelines implementation was a durable decrease in the overall consumption of antibiotics. During the period of surveillance, total antibiotic and targeted antibiotic consumption, respectively, decreased by 23% and 54%, and n-CDAD incidence decreased by 60%.

INTERVENTIONS:-staff education-Infection Control: strict isolationuntil discharge, dedicatedequipment-environmentalcleaning-Local guidelines (pocket-size antibiotic guide on empirical treatment of common infections) -No formal restriction (pharmacist phone call)

Long-term effects of an antimicrobial stewardship programme at a tertiary-care teaching hospital

The result of these interventions as a whole was a 42.6% reduction in hospital-acquired CDI and total antimicrobial use decreased by 62.8% (P < 0.0001) between 2003 and 2010.

P.P. Cook, M. Gooch / International Journal of Antimicrobial Agents 45 (2015) 262–267

AS implementation was associated with significant reductions in the incidence of MDR GN bacteriaand C difficile infections (32%; 0·68, 0·53–0·88; p=0·0029) in hospital inpatients.

ASPs implemented with infection control measures had a greater effect on reduction of antibiotic resistance (31% IR 0·69, 0·54–0·88; p=0·0030), especially with hand-hygiene interventions (66% 0·34, 0·21–0·54; p<0·0001), than did implementation of ASPs alone (19%; 0·81, 0·67–0·97; p=0·0210 )

EXAMPLES OFIMPLEMENTATION STRATEGIES

I. Engage: multidisciplinary team

II. Educate: personnel; patients and their families

about CDI

III. Execute: Initiate a CDI prevention program; Pilot-test in one patient care location; replicate program in other patient care areas

IV. Evaluate: Performance monitoring; Feedback to staff

Dubberke ER, 2014, Infect Control and Hosp Epidemiol

Education• Educate healthcare workers on prevention of CDI to enhance their knowledge

and skills on prevention strategies

• Implement intensified teaching in conjunction with other intervention measures to reduce CDI rates

CMI 2018Dubberke ER. Infect Control and Hosp Epidemiol 2014

• Educate CDI patients and visitors on prevention measures for CDI

• Educate patient and their families about CDI (may help to alleviate patient and family fears regarding being placed in isolation)

ADDITIONAL and FUTURE DIRECTIONS

• Prescriber Restriction

• Rapid Diagnostics

• Treatment Paradigm

• Infection Control

• Public Awareness

• Outpatient ASPs

Prescriber restriction-

- Strategies to encourage routine review: antibiotic time-outs, stop orders (Prescriber-Led Review)

- Addition prospective audit and feedback to prescribers

- Restricting the prescribers: restrict the ability to prescribe antibiotics to those who are uniquely qualified to understand both the individual risks and collateral damage associated with prescribing antimicrobials

Lancet Infect Dis. 2014

Respondents from Italy and Spain were more accepting of antibiotic prescribing being limited to specifically trained professionals, than were those from Germany, the UK, Sweden, and France. This may be because of an increased awareness of the need to limit antibiotic prescribing in Italy and Spain following the recent ECDC report, which showed that Italy and Spain had the highest antimicrobial use of the countries observed.

Rapid Diagnostics

• we have moved from CD toxin detection by enzyme immunoassay and glutamate dehydrogenase antigen detection to molecular biology studies (with increased sensitivity and specificity)

• The advancement in rapid diagnostic technologies has proven to be a powerful tool in the hands of ASPs.

• These molecular methods have also afforded the ability to perform both rRNA gene complex identification and ribotyping for infection control and diagnostic purposes

• benefit of rapid detection of CD via molecular methods also allows ASPs to recommend more rapid patient isolation and prevention of further patient-to-patient transmission of CD.

M.J.T. Crobach et al. / Clinical Microbiology and Infection 22 (2016) S63eS81

Recommended algorithms for CDI testing.

Treatment Paradigm

• increased perturbation of the normal microbiome by metronidazole compared to oral vancomycin and fidaxomicin

• fidaxomicin has proven to be useful in the real-world setting, as salvage therapy for patients with multiple recurrences , and in high-risk patient population including those with hematologic malignancies and inflammatory bowel disease.

• ASPs will need to consider the economic impact of increased utilization of fidaxomicin as its cost effectiveness in both initial treatment and recurrences compared to other treatment

• human gut microbiota plays an important role in human health, and the modulation of the gut microbiota has currently used in this field (FMT, prebiotics, probiotics.. )

• ASPs will need to continually monitor the ever-changing treatment landscape for CD and evaluate individual prevention and treatment strategies according to the needs of their institutions

CMI 2018

Targeted infection preventionand control measures

• SurveillancePerform surveillance of CDI in combination with timely feedback of infection rates (strong recommendation both in outbreak and endemic setting - CMI 2018)

• ScreeningNot recommended: screening for C. difficile to identify colonised/carrier patients as a way of altering the risk of developing CDI; HCW screening for C. difficile gut colonization as a routine control measure for CDI

• Hand hygieneSwitch from alcohol-based hand rub (AHR) to hand washing due to the lack of in vitro activity of AHR against spores in outbreak and endemic setting (CMI 2018)

• Barrier precautionsUse PPE (gloves and gowns/disposable aprons) to decrease transmission of C. difficile or incidence of CDI (strong recommendation for outbreak setting, conditional for endemic)

• Patient isolation and cohortingSingle room preferred to reduce patient-to-patient spread of the organism/Cohorting is acceptable when single rooms are not availableUse contact precautions to decrease the transmission of C. diff and reduce the incidence of CDI

• Use of disposable medical devices• Environmental disinfectionIntroduce daily environmental sporicidal disinfection and terminal disinfection of rooms of patients with CDI to decrease the transmission of CDI (strong recommendation for outbreak setting, conditional for endemic)

Implement a laboratory-based alert system to provide immediate notification to IPC and clinical personnel about newly diagnosed CDI patients

Infection Control

• Currently, CDC and the SHEA/IDSA Compendium of Strategies to Prevent Clostridium difficile in Acute-Care Hospitals recommend the discontinuation of contact precautions 48 hours after the resolution of diarrhea among patients diagnosed with C. difficile colitis

• Environmental contamination rates of CD have been reported as high as 58%

• Preventing the horizontal transmission of CD represents a major challenge for healthcare institutions primarily due to the ability of CD to survive in its vegetative state as a spore and resist typical hospital cleaning methods, including alcohol based hand sanitizers

• At this time, insufficient evidence exists to make a formal recommendation as to whether patients with CDI should be placed on CP if they are readmitted to the hospital.

Persistence of skin contamination and environmental shedding of C. difficile during and after treatment of infection.

Potential for transmission of spores by patients awaiting laboratory testing to confirm suspected Clostridium difficile infection.

Banach DB, 2018. Infect Control Hosp Epidemiol.Donskey CJ, 2015. Infect Dis Clin North Am

Sethi AK, 2010. Infect Control Hosp Epidemiol .

These results provide support for the recommendation that contact precautions be continued until hospital discharge if rates of CDI remain high despite implementation of standard infection-control measures.

Evaluation of hospital room assignment and acquisition of Clostridium difficile Infection

The CDI status of a prior room occupant in this study was a statistically significant risk factorfor acquisition of CDI in the medical ICU, independent of such known CDI risk factors asgreater age, greater severity of illness, and proton pump inhibitor and antibiotic use.

Infect Control Hosp Epidemiol. 2011

Impact of an intervention to control Clostridium difficileinfection on hospital- and community-onset disease; an

interrupted time series analysis

• Before intervention, considerable efforts to improve infection control practice were already ongoing and this is the likely explanation for the downward trend in CDI cases before the intervention.

• there was a significant increase in the rate of reduction after the intervention from 3% to 8% per month (0.92, 95% CI 0.86–0.99, p = 0.03).

• The initiative resulted in a reduced level of cephalosporin and quinolone use (22.0% and 38.7%, respectively, both p <0.001) and changes in the trends of antibiotic use

Price J et al. Clin Microbiol Infect 2010

Public Awareness

• Knowledge amongst the general public is crucial to combating difficult to treat and rapidly spreading infectious disease pathogens, especially those that cause a tremendous amount of morbidity such as CD.

• The ultimate goal of any ASP should be to make everyone a better steward; this includes patients, their families, and the general public.

Outpatient ASP

• The majority of prescriptions for antimicrobials are writtenfor patients in the outpatient setting where overuse andmisuse are common

• many of the previous interventions, including prescriberfeedback/communication and diagnostic testing, areeffective in reducing antimicrobial overuse and improvingprescribing in the non-acute care setting [Drekonja DM, et al.2015. Infect Control Hosp Epidemiol]

• ASPs must begin to expand their services within thehealthcare system in order to reach patients outside theacute care setting in order to combat non-nosocomiallyacquired CDI

Predicting the risk of Clostridium difficile infection following an outpatient visit: development and external validation of a pragmatic, prognostic risk score

J. L. Kuntz, et al. Clin Microbiol Infect2015;21:256–262

Outpatient Healthcare Settings and Transmission ofClostridium difficile

Patients diagnosed with CDI as an inpatient who have follow up visits in the clinic afterwards have been shown to contaminate the outpatient environment with CD spores

2013

Decreased mobility, fecal incontinence, and treatment with non-CDI antibiotics were associated with positive cultures,whereas vancomycin taper therapy was protective.

outpatient clinics could be an important source for acquisition of community-associated CDI

In conclusion:

• The use of ASPs with regards to CDI must not be static but must be a dynamic process that is constantly be reassessed

• Establish potential future directions for ASPs in the fight against CDI that may be added to the tactics that have already documented success

• Improved diagnostic methods and a robust antibiotic stewardship program, in addition to infection control policies and practices, environmental cleaning, improving hand hygiene practices, hospital design, and better identification of asymptomatic carriers should all result in better control of CDI

• A focus on transitions of care is also vitally important as previous stay in a healthcare setting has been shown to be an independent predictor of identifying CDI in the outpatient setting

angelaraffaella.losito@policlinicogemelli.it