Pathogens Important to Infection Prevention and Control

Learning objectives List special pathogens of interest to IP&C, and for each, describe the impact on the IP&C programme Explain how antibiotic-resistant bacteria cause problems in healthcare Outline preventive measures for a given special pathogen December 1, 2013

Time involved 90 minutes December 1, 2013

Special pathogens Everyday problem microorganisms for infection prevention and control include: Mycobacterium tuberculosis Clostridium difficile Antibiotic resistant organisms MRSA, VRE Gram-negative multiply resistant organisms Enterobacteria (Escherichia coli, Klebsiella pneumoniae) Pseudomonas aeruginosa Acinetobacter baumanii December 1, 2013

Mycobacterium tuberculosis Mycobacterium tuberculosis causes tuberculosis (TB) TB affects 1/3 of the world’s population 9.4 million new cases in 2008 1.8 million deaths in 2008 Leading cause of death in people living with human immunodeficiency virus (HIV) December 1, 2013 Mycobacterium tuberculosis is one of the most resistant pathogens to different environmental conditions. It is resistant to desiccation and low temperatures and can survive in a dark environment for a long time. Therefore, bacilli can live in desiccated droplets and can spread by air through long distances. M.tuberculosis is very sensitive to UV radiation (sunlight) and high temperatures. It is acid fast and this characteristic is very important in rapid diagnosis of sputum smear positivity. Acid-fastness is a physical property of certain bacteria, specifically their resistance to de-colorisation by acids during staining procedures. Acid-fast bacteria are difficult to characterise using standard microbiological techniques (e.g., Gram stain - if you gram stained an acid-fast bacillus (AFB) the result would be an abnormal Gram positive organism, which would indicate further testing), though they can be stained using concentrated dyes, particularly when the staining process is combined with heat. Once stained, these organisms resist the dilute acid and/or ethanol-based de-colorisation procedures common in many staining protocols—hence the name acid-fast.

Transmission and pathogenesis of TB - 1 December 1, 2013 Spread by the airborne route when someone with active disease and positive sputum smear coughs, talks, sneezes, or spits Bigger droplets spread up to 1 m, smaller spread by air Bacteria inhaled into lungs In lung tissue and lymph nodes the bacteria grow and reproduce Can travel to any location in the body Only a small proportion of persons exposed to TB develop clinical symptoms (about 5-10%). Nevertheless, M. tuberculosis can remain in their body in a latent form and later in their life cause clinical infection. A positive sputum smear means that there is at least 1000 M. tuberculosis/ml of sputum. If the number is lower, transmission usually does not occur easily. If the M. tuberculosis is a fully sensitive strain, strict isolation measures can be stopped when the sputum smear is no longer positive. For extensively drug-resistant tuberculosis (XDRG) strains, three sputum smears should be negative before stopping strict isolation measures.

Transmission and pathogenesis of TB - 2 Latent TB – bacteria contained in the body 10% of people with latent TB will develop active disease Most commonly affected organ - Lungs Untreated, a person with active disease can infect 10 to 15 people a year December 1, 2013 After initial contact, so-called primary TB can develop; later on, if the immune system of a person with latent TB weakens, reactivation TB develops. Most frequently lungs are involved in both primary and reactivation TB, but other organs can be involved too (then called extrapulmonary TB). Latent TB Infection TB bacteria can live in the body without making the person sick. This is called latent TB infection. In most people who breathe in TB bacteria and become infected, the body is able to fight the bacteria to stop them from growing. People with latent TB infection do not feel sick and do not have any symptoms. People with latent TB infection are not infectious and cannot spread TB bacteria to others. However, if TB bacteria become active in the body and multiply, the person will go from having latent TB infection to being sick with TB disease. Active TB TB bacteria become active if the immune system can't stop them from growing. When TB bacteria are active (multiplying in the body), this is called TB disease. People with TB disease are sick. They may also be able to spread the bacteria to people they spend time with every day. Many people who have latent TB infection never develop TB disease. Some people develop TB disease soon after becoming infected (within weeks) before their immune system can fight the TB bacteria. Other people may get sick years later when their immune system becomes weak for another reason. Reactivation Reactivation TB may occur if an individual's immune system becomes weakened and is no longer able to contain the dormant bacteria. The bacteria then become active and make the person sick with TB. This is called TB disease.

Clinical forms Pulmonary TB (active) Extra pulmonary TB Cough with thick cloudy, sometimes bloody sputum Tiredness Appetite loss/unexplained weight loss Night sweats Fever/chills Shortness of breath Extra pulmonary TB Signs and symptoms vary with site of infection Other common sites include central nervous system, bones, joints, and genitourinary system December 1, 2013 While active pulmonary TB is highly contagious, extra-pulmonary TB is not contagious. TB meningitis tends to be more severe than other forms of meningitis.  Although 70 - 85% of those affected will survive, up to one quarter of those may have long-term after effects.  This is mainly because it is so difficult to recognise the disease at an early stage. By the time treatment begins, there may be damage to brain tissue as well as nerves and blood vessels in the area around the brain. 

Risk Factors Weakened immune system Contact with someone with active TB Caring for active TB patients Living or working in crowded conditions with someone with active TB e.g., prisons, nursing homes, homeless shelters Poor access to healthcare Alcohol or drug abuse Travel to places where TB is endemic Being born in a country where TB is endemic Some medications for rheumatoid arthritis December 1, 2013 These risk factors are important for both primary and reactivation TB. An impaired immune system is the most important risk factor in cancer patients and HIV-positive persons. Age is also a very important risk factor: very young and very old persons have a naturally weaker immune system.

Vaccination BCG strain of Mycobacterium bovis is used as a vaccine BCG is given to infants (best soon after birth) Vaccination against TB does not protect against infection but only against severe forms of disease Meningitis Disseminated TB (miliary) December 1, 2013 The BCG strain (Bacillus Calmete-Guerin) is an attenuated strain of M. bovis that shares antigens with M.tuberculosis and is not virulent. Vaccination against TB is not universally used. In some countries it is mandatory and given to newborns, in other countries it is available, however it is not mandatory. The World Health Organization recommends BCG be given to all children born in countries highly endemic for TB because it protects against miliary TB and TB meningitis.

Diagnosis & Management Chest x-ray Sputum smear for acid fast bacilli Tuberculin skin test (TST) Can take up to 3 months for those newly exposed to develop positive test May be falsely positive because of BCG vaccination Interferon gamma release assays (IGRA) in vaccinated persons Culture (can take up to six weeks) and sensitivity test December 1, 2013 Tuberculin skin test (TST) is used when there is clinical suspicion of TB, after performing a chest X-ray and sputum smear for acid fast bacilli (if negative) to determine previous contact with TB. As tuberculin is not highly specific for TB, TST will be positive in persons who were vaccinated. An IGRA test is performed with protein antigens specific for M.tuberculosis. It has no cross reactivity with the BCG strain or most atypical mycobacteria. TST and IGRA tests cannot distinguish between active and latent TB.

Management & Treatment Management of Exposure Confirmation of positive infection Medical evaluation to determine follow up Treatment of patients Treatment for latent or active TB should follow World Health Organization recommendations Incomplete treatment can cause resistance Adherence to therapy is critical December 1, 2013 As healthcare workers are in risk of acquiring TB during their work, it is usefull to test them for TB before beginning work, and then periodically during employment in healthcare. WHO Treatment of tuberculosis: guidelines for national programmes - http://www.who.int/tb/features_archive/new_treatment_guidelines_may2010/en/index.html

IP&C Measures Engineering controls Negative pressure rooms High efficiency particulate air (HEPA) filtration system Enhanced ventilation Ultraviolet irradiation (only in empty room) Sunlight exposure Open window (last resort if no other options) December 1, 2013 Various engineering controls are available depending on the facility’s resources. Negative pressure rooms are relatively expensive to build; not all hospitals have them. They are necessary for patients with X-MDR TB, together with HEPA filters. If this is not possible, the patient is to be placed in single room with doors closed at all times. Enhanced ventilation will dilute the bacteria and decrease the chance of transmission. UV irradiation is possible only as terminal disinfection of the air, when a patient is discharged and the room is empty. Very often the only possible measures are exposure of the room to sunlight and opening windows to dilute airborne bacteria.

Patient with active TB isolated in negative pressure room Negative presssure room December 1, 2013 HEPA filter Air flow It is important that staff always wear masks when entering this room even though the air flow is directed to a filter unit. Patient with active TB isolated in negative pressure room

IP&C Measures - 1 Administrative Controls Identify patients with signs and symptoms of TB Additional precautions for patients suspected to have active TB Prompt treatment Vaccination of healthcare personnel Respiratory etiquette December 1, 2013 Identification of patients with active TB is not often easy to do. We have to educate patients to perform respiratory etiquette: every patient who coughs or sneezes should wear mask when coming to the doctor. It is very practical to have a box of surgical masks together with a poster about the use of these masks in a waiting room for emergency admissions, or in a waiting room of a doctor’s office. Additional precautions to prevent spread are placement in an isolation room and use of personal protective equipment. It is not necessary for the patient to have marked crockery (special dishes or silverware), and no special precautions are needed for bed linen, books, or other personal items.

IP&C Measures - 2 Personal Protective Equipment* N-95 fit tested masks for healthcare workers If not available, then surgical masks Surgical masks for patients leaving their rooms December 1, 2013 * Typically used for pulmonary TB if the patient is expectorating or has an open lesion N-95 fit tested masks- A mask or respirator that blocks out 95 percent of airborne particles larger than 0.3 microns. FFP3 masks could also be used. These medical masks are a type of disposable respirator that may be used in a medical setting. They function by filtering out particulates in the air before they reach the respiratory system. Both the USA’s Food and Drug Administration and the National Institute for Occupational Safety and Health approve the use of N95 respirator masks to protect against tuberculosis transmission.

Conclusion Despite the high global impact of TB, it is treatable and preventable Occupation exposures remain a significant risk for healthcare workers IP&C measures are needed to decrease exposures to patients and healthcare workers December 1, 2013 One could also say that despite known measures of prevention and treatment, TB is still a large global problem. The main reasons might be an unavailabilty of health care and antituberculous drugs in many areas of the world, low compliance to treatment that is protracted and consists of multiple drug regimens (3 or 4 drugs for 6 to 24 months), and unavailability of negative pressure isolation rooms.

Clostridium difficile: Background There is a global increase in Clostridium difficile infections (CDI) and outbreaks over the past 10 years; however the illness is not a problem in all countries CDI primarily occurs in those patients exposed to antibiotics in healthcare facilities December 1, 2013 Clostridium difficile was first recognized as a cause of antibiotic-associated colitis (pseudomembranous colitis) and antibiotic-associated diarrhoea in hospitalised patients receiving clindamycin and other antibiotics. Nowadays it is well known that chemotherapeutic drugs can also cause CDI. In addition, CDI can develop in outpatients not receiving any drugs. CDI is now more common than MRSA infections in some countries. The clinical forms range from uncomplicated self-limiting diarrhoea to pseudomembranous colitis, ileus or toxic megacolon and death. CDI is often a recurrent disease. C. difficile is more common is some countries than in others.

Pathology - 1 A Gram-positive spore forming anaerobic bacillus Widely distributed in the environment In its vegetative state Produces toxins Can be killed by antibiotics Spore form Dormant No toxin production Resistant to antibiotics and disinfectants Can persist for months in the environment December 1, 2013 C. difficile is a fastidious anaerobic microorganism that cannot easily survive in the human gut as long as normal flora is preserved. If normal flora is destroyed by antibiotics (especially antibiotics that are active against Gram-negative anaerobic flora), C. difficile has the space and the food for unhampered growth. If the strain produces toxins, disease can develop. Antibiotics that kill C. difficile are vancomycin and metronidazole

Pathology - 2 Produces 2 toxins Toxin A and Toxin B Bind to intestinal epithelial cells causing inflammation and diarrhea Toxins are cytotoxic and enteropathic Alteration of the gut flora by antibiotics an important risk factor (decrease of normal gut flora) December 1, 2013 Toxin B is necessary for disease development. This is important for diagnostic methods that have to identify existence of toxin B. The two major toxins, A and B, have been studied intensively since their initial recognition as major C. difficile virulence factors. In addition to their contribution to disease, A and B are the primary markers for diagnosis of C. difficile disease and are detected in the stools of patients by antibody-based and cytoxicity assays. Most pathogenic strains of C. difficile produce both toxin A and B. Strains that are A-B+ are fully pathogenic and capable of producing the full spectrum of disease.

Clinical Significance Mild disease Non-bloody diarrhoea, often mucoid and foul smelling, cramping, nausea, dehydration, low grade fever, leukocytosis Severe disease Colitis, watery diarrhoea, abdominal pain, fever, nausea, abdominal distension, pseudomembranes in the gut, toxic mega colon, death December 1, 2013 Severe disease is important for transmission of C. difficile. In severe disease, the patient is often incontinent and bacteria are dispersed widely to the patient’s environment.

New Strain Increased incidence of B1/NAP1/027 strain Causes severe disease More resistant to standard therapy More likely to relapse Associated with higher mortality 16x more toxin A; 23x more toxin B Related to excessive use of certain drugs/antibiotics December 1, 2013 B1/NAP1/027 is called a hypervirulent strain as the toxin production is greatly enhanced due to a gene mutation. Besides hypervirulence, this strain also has enhanced epidemiological potential. This strain causes more severe disease and increased mortality. The epidemic strain produces a third toxin, binary toxin; its role in human disease is not yet defined, but it is suggested that it may contribute to the pathogenesis of CDI. This strain has increased antimicrobial resistance, notably to clindamycin and fluoroquinolones [gatifloxin and moxifloxacin]. Research shows that the epidemic strain produces toxins A and B and common antigen (glutamate dehydrogenase) and reacts in commercial C. difficile tests specific for the toxins or for antigen.

Colonisation Approximately 3-5% of healthy adults and 20 to 40% of hospitalised patients may be colonised Colonised patients generally are not symptomatic May be a potential reservoir for transmission Evidence suggest spores on the skin of asymptomatic patients can contaminate the hands of the healthcare worker No recommendations to treat carriers nor to perform admission screening December 1, 2013 Patients can be infected not only by the hands of staff but also by their own hands, if they are mobile, and touch different areas in the room that may be contaminated. This is important to keep in mind as this is the reason why there is a high percentage of colonised patients in hospitals. Therefore it is important to teach patients about hand hygiene. C. difficile is transmitted from person to person by the faecal-oral route.

Transmission and Control Measures Patients at Risk Previous antibiotic use Severe underlying illness Prolonged hospital stay Advanced age Gastrointestinal surgery/manipulation History of irritable bowel disease Patients on proton pump inhibitors Admission Screening No Route of Transmission Contact Isolation Precautions Yes Accommodation Single room preferred Separate toileting facilities Documentation (flagging of patients) May be of benefit to implement a system to designate patients known to be colonised or infected for early notification on readmission Environmental Cleaning Routine cleaning with attention to high touch surfaces and use of a sporicidal agent Consider double-cleaning for outbreak situations Discontinuation of Precautions No diarrhoea for at least 48 hours Follow-up of Contacts Point Prevalence Additional Outbreak Measures Strict cleaning of multi-use equipment between patients Dedicated patient equipment to positive cases Education of staff, patients and visitors Auditing of outbreak unit/area including hand hygiene, isolation practices and environmental cleaning December 1, 2013 The most important measure to decrease transmission of C. difficile is hand hygiene as hands of staff and of patients are the most important means of transmission. Alcohol hand rub will kill vegetative forms, however it will not kill spores. Therefore hands should be washed with soap and water before and after every contact with a patient and/or the patient’s environment. Non-sterile (clean) gloves should be used for patient care. After removing gloves, hand washing with soap and water should be performed.

Additional Control Measures Discontinuation of all antibiotics in a symptomatic patient (except for CDI) Facility-wide antibiotic control policies Early notification of patients with diarrhoea to the IC team Not recommended Routine identification of carriers Repeat testing post treatment for clearance December 1, 2013 The hypervirulent strain is resistant to fluoroquinolones; in an outbreak situation, fluoroquiolones should not be widely used. If possible, patients with healthcare-associated diarrhoea should be immediately placed in single room. There is a CDI prevention bundle*: Antibiotic prescribing (stop antibiotic or go to a narrow spectrum) Early diagnosis Prompt isolation Implementation of infection prevention & control precautions Clean and disinfect environment Decontaminate/sterilise patient care items/equipment *Clostridium difficile infection: How to deal with the problem, Health Protection Agency, Department of Health, 2008 - http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1232006607827 and High Impact Intervention Care bundle to reduce the risk from Clostridium difficile - http://webarchive.nationalarchives.gov.uk/20120118164404/hcai.dh.gov.uk/files/2011/03/Document_Clostridium_difficile_Infection_High_Impact_Intervention_FINAL_101210.pdf

Antibiotic Resistant Microorganisms December 1, 2013 The second part of the presentation deals with antibiotic resistant microorganisms. Some of these organisms are already well known and widespread, while others are newly developed and often first a local problem, which then becomes widespread. These are: methicillin-resistant Staphylococus aureus (MRSA) vancomycin-resistant Enterococci (VRE) extended spectrum beta lactamase producing Enterobacteriacae (ESBL) carbapenamase producing Klebsiella ( a carbapenem resistant Enterobacteriacae or CRE) multidrug resistant Pseudomonas aeruginosa (MDR PA) and multidrug resistant Acinetobacter baumannii (MDR AB).

Methicillin Resistant Staphylococcus aureus (MRSA) December 1, 2013 Methicillin Resistant Staphylococcus aureus (MRSA)

Background Staphylococcus aureus is a Gram-positive bacteria 30% of people are permanently colonised Nose Pharynx Perineum Transient colonisation occurs, mainly on hands Colonisation although harmless, increases the risk of infection and transmission December 1, 2013 S. aureus is the most frequent bacterial pathogen of humans (along with Escherichia coli). S.aureus causes an array of infections – from self-limited skin infections to severe sepsis, pneumonia and osteomyelitis.

Clinical Significance of MRSA First a problem in 1960s Globally has reached epidemic proportions Both community associated (CA) and healthcare associated (HA) strains of MRSA Rates vary by Country Region Individual healthcare facility December 1, 2013 MRSA strains are resistant not only to all beta lactam antibiotics (although nowadays we have a new antistaphylococcal cefalosporins) but very often to most antistaphylococcal antibiotcs except glycopeptodes (vancomycin, teicoplanin) and linezolid. CA MRSA are very important problem in the USA; it is not so pronounced in other parts of the world.

MRSA Transmission and Control Measures Patients at Risk Previous antibiotic use Severe underlying illness Prolonged hospital stay Previous contact with medical facility Use of invasive procedures Close proximity to a patient colonised or infected with MRSA Admission Screening Sites Yes, based on patient risk factors Nares, rectal, wounds, exit sites Route of Transmission Contact (plus droplet for symptomatic patients with pneumonia) Isolation Precautions Yes Accommodation Single room preferred Documentation (flagging of patients) May be of benefit to implement a system to designate patients known to be colonised or infected for early notification on readmission Environmental Cleaning Routine cleaning with attention to high touch surfaces Discontinuation of Precautions Unresolved issue: Some institutions use the following criteria: Negative results from all colonised/infected body sites- 3 consecutive cultures taken at least one week apart in the absence of antibiotic therapy Note: Re-colonisation is known to occur so on-going monitoring is recommended Consider maintaining isolation precautions in an outbreak setting Follow-up of Contacts Two sets of specimens taken on different days with one taken a minimum of 7 days after the last exposure, especially in an outbreak setting Point Prevalence In an outbreak setting: Conduct serial (e.g., weekly) unit specific point prevalence cultures to determine if transmission has decreased or ceased Consider discharge and/transfer screening of patients until transmission has decreased or ceased Additional Outbreak Measures Strict cleaning of multi-use equipment between patients Dedicated patient equipment to positive cases Education of staff, patients and visitors Auditing of outbreak unit/area including hand hygiene, isolation practices and environmental cleaning December 1, 2013

VISA and VRSA Vancomycin is drug of choice for treating MRSA infections Staphylococcus aureus with decreased (intermediate) susceptibility to vancomycin = VISA Staphylococcus aureus with resistance genes Van A or Van B = VRSA So far only few isolates in different parts of the world December 1, 2013 VISA strains first appeared in Japan in 1996, now they have been found in different parts of the world (United Kingdom, Asia, Brazil, United States, France, Croatia. True VRSA with the enterococcal Van A or Van B genes is so far very rare and mostly sporadic cases are reported from different parts of the world.

Vancomycin Resistant Enterococcus (VRE) December 1, 2013 Vancomycin Resistant Enterococcus (VRE)

Background Enterococci are normal gut bacteria May also be present in the oropharynx, vagina, or on skin Causes serious bacterial infections Wound infections Urinary tract infections Endocarditis Sepsis Often resistant to ampicillin (the drug of choice); infections then treated with glycopeptides December 1, 2013 The most serious infections caused by VRE are endocarditis and sepsis in immunocompromised hosts. These infections are always treated with combination therapy using ampicillin or vancomycin plus gentamicin.

VRE Epidemiology VRE is enterococcus that is resistant to the glycopeptide vancomycin First isolated in the 1980’s Spread globally causing asymptomatic colonization, infections, and outbreaks The prevalence of VRE varies worldwide December 1, 2013 The prevalence of VRE is highest in the USA, especially in intensive care units. It is identified much less in Europe and other parts of the world.

Clinical Significance Clinically relevant strains carry Van A or Van B resistance genes Limited antibiotics to treat VRE infections Transfer of resistance genes to other microorganisms such as MRSA is a great concern December 1, 2013 People with colonised VRE (bacteria are present, but have no symptoms of an infection)  do not need treatment. Most VRE infections can be treated with antibiotics other than vancomycin. Laboratory testing of the VRE can determine which antibiotics will work. For people who get VRE infections in their bladder and have urinary catheters, removal of the catheter when it is no longer needed can also help get rid of the infection.

VRE Transmission and Control Measures Patients at Risk Previous antibiotic use Severe underlying illness Prolonged hospital stay Previous contact with medical facility Use of invasive procedures Close proximity to a patient colonised or infected with VRE Admission Screening Sites Yes, based on patient risk factors. Rectum Route of Transmission Contact Isolation Precautions Yes Accommodation Single room preferred Separate toileting facilities Documentation (flagging of patients) May be of benefit to implement a system to designate patients known to be colonised or infected for early notification on readmission Environmental Cleaning Routine cleaning with attention to high touch surfaces Consider double cleaning in outbreak situations Discontinuation of Precautions Unresolved issue: Some institutions use the following criteria: Negative results from all colonised /infected body sites- 3 consecutive cultures taken at least one week apart in the absence of antibiotic therapy Note: Re-colonization is known to occur so on-going monitoring is recommended. Consider maintaining isolation precautions in an outbreak setting Follow-up of Contacts Two sets of specimens taken on different days with one taken a minimum of 7 days after the last exposure, especially in an outbreak setting Point Prevalence In an outbreak setting: Conduct serial (e.g., weekly) unit specific point prevalence cultures to determine if transmission has decreased or ceased Consider discharge and/transfer screening of patients until transmission has decreased or ceased Additional Outbreak Measures Strict cleaning of multi-use equipment between patients Dedicated patient equipment to positive cases Education of staff, patients and visitors Auditing of outbreak unit/area including hand hygiene, isolation practices and environmental cleaning December 1, 2013 Admission screening is is not usefull in low prevalence areas.

Multi-Drug Resistant Gram- Negative Microorganisms (MDRGN) December 1, 2013 Multi-Drug Resistant Gram- Negative Microorganisms (MDRGN)

MDRGN - 1 The “Enterobacteriaceae” family of bacteria are a normal part of the gastrointestinal flora The most frequent isolates are: Escherichia coli Klebsiella pneumoniae Serratia marcescens Enterobacter species December 1, 2013 While E.coli is most often susceptible to various antibiotics, and only occasionally (less than 5% of strains) is multidrug resistant, K.pneumoniae, Serratia marcescens and Enterobacter spp are very often highly resistant to antibiotics. In general, E.coli is the most frequent cause of infections in outpatients and inpatients; K.pneumoniae, Serratia spp and Enterobacter spp cause mostly infections of inpatients.

Mechanisms of Resistance Escherichia coli and Klebsiella pneumoniae can have extended spectrum beta-lactamase (ESBL) enzymes that cause resistance to beta-lactam antibiotics including: Penicillins Cephalosporins Cephamycins Monobactams December 1, 2013 ESBL production is coded by genes on plasmids, so this gene spreads very easily among different Gram-negative bacteria. On the same plasmid there are genes that confer resistance to many other antibiotics, including aminoglycosides and fluoroquinolones. Therefore, ESBL strains are often susceptible to only carbapenems.

Epidemiology of ESBL strains There are various types of ESBLs including TEM SHV CTX-M ESBLs were first detected in Europe in 1980s Surveillance data from several surveillance systems indicate high rates of ESBLs in many parts of the world including USA, Canada, Europe, China, India and Latin America December 1, 2013 ESBL - Extended-spectrum beta-lactamases – enzymes produced by some bacteria. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam. TEM-1 is the most commonly encountered beta-lactamase in Gram-negative bacteria. Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1. SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most commonly found in K. pneumoniae and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species. CTX-M enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. The most comprehensive surveillance systems are SENTRY and SMART surveillance systems that are industry sponsored systems for surveillance of resistance among Gram-negative bacteria. SENTRY - http://www.jmilabs.com/surveillance/ SMART - http://www.globalsmartsite.com/login.aspx?ReturnUrl=%2fdefault.aspx

Epidemiology of CRE Carbapenem antibiotics are the treatment of choice for serious infections due to ESBL-producing bacteria Carbapenem Resistant Enterobacteriaceae (CRE) has also been reported Carbapenemases of importance include KPC, VIM, OXA and NDM-1 CREs have been reported in many areas of the world and have also been associated with outbreaks December 1, 2013 Carbapenem resistant Enterobacteriaceae are relatively new strains of E.coli and K.pneumoniae that are spreading very successfully throughout the world. The origin of some of them appears to be Asia; tourists bring it to Europe and the USA. However, some of these resistance mechanisms originated in developed countries as well. Carbapenemases are a diverse group of β-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems. The VIM family, was reported from Italy in 1999 and now includes 10 members, which have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. The OXA group of β-lactamases occur mainly in Acinetobacter species and are divided into two clusters. OXA carbapenemases hydrolyse carbapenems very slowly in vitro, and the high MICs seen for some Acinetobacter hosts (>64 mg/L) may reflect secondary mechanisms. A few class A enzymes, most noted the plasmid-mediated KPC enzymes, are effective carbapenemases as well. NDM-1 (New Delhi metallo-β-lactamase) - Originally described from New Delhi in 2009, this gene is now widespread in Escherichia coli and Klebsiella pneumoniae from India and Pakistan. K. pneumoniae carbapenemase (KPC) is particularly important in Greece, the USA and Israel. A CRE prevention toolkit is at http://www.cdc.gov/hai/organisms/cre/cre-toolkit/index.html WHO information at http://www.who.int/bulletin/volumes/89/5/11-088435/en/ and http://www.who.int/csr/resources/publications/drugresist/en/infection_control.pdf Case study at http://www.who.int/gpsc/5may/share/Case_Study_Hospital-Pablo-Tobon-Uribe_Medellin/en/

MDRGN - 2 The following bacteria are present in aquatic environments Acinetobacter baumannii Pseudomonas aeruginosa Opportunistic pathogens in humans A major cause of healthcare-associated infections Septicemia Ventilator-associated pneumonia Urinary tract infections December 1, 2013 Pseudomonas aeruginosa is a major causative agent of ventilator-associated pneumonia in Iintensive care unit patients. It also causes severe sepsis and skin/soft tissue infections in immunocompromised patients, as welll as urinary tract infections in urologic patients. P. aeruginosa is very sensitive to drying; it lives in every humid part of the facility. It can also colonise the mouth, gut and other areas of patients. Acinetobacter baumannii can also be found in aquatic environments; however it often colonises the skin of humans. A. baumannii is very resistant to desiccation and can survive very long in dust. Infections are usually not so severe as infections caused by P. aeruginosa, but can be severe in immunocompromised patients.

MDR P. aeruginosa and MDR A. baumannii These microorganisms have intrinsically lower susceptibility to antibiotics Acquiring additional resistance genes (ESBL genes, other genes for resistance to beta lactam antibiotics, resistance genes for aminoglycosides and fluoroquinolones) very often means that they are susceptible only to carbapenems or colistin or resistant to all antibiotics (panresistant) December 1, 2013

Clinical Significance MDRGN (including ESBLs, CREs, MDR PA and MDR AB) pose a significant treatment challenge including Increased length of stay Increased mortality Increased cost Contributes to the global crisis of antimicrobial resistance Control requires an aggressive world-wide strategy December 1, 2013

MDRGN Transmission and Control Measures Patients at Risk Previous antibiotic use Severe underlying illness Prolonged hospital stay Previous contact with medical facility Contact with a facility with known outbreaks with MDRGN organisms Admission Screening Sites Yes, based on local epidemiology and patient risk factors. Rectum Route of Transmission Contact (plus droplet for symptomatic patients with pneumonia) Isolation Precautions Yes Accommodation Single room preferred Documentation (flagging of patients) May be of benefit to implement a system to designate patients known to be colonised or infected for early notification on readmission Environmental Cleaning Routine cleaning with attention to high touch surfaces Discontinuation of Precautions Unresolved issue: Some institutions use the following criteria: Negative results from all colonised /infected body sites- 3 consecutive cultures taken at least one week apart in the absence of antibiotic therapy Note: Re-colonisation is known to occur so on-going monitoring is recommended Consider maintaining isolation precautions in an outbreak setting Follow-up of Contacts Based on local epidemiology and patient risk factors Point Prevalence In an outbreak setting: Conduct serial (e.g., weekly) unit specific point prevalence cultures to determine if transmission has decreased or ceased Consider discharge and/transfer screening of patients until transmission has decreased or ceased Additional Outbreak Measures Strict cleaning of multi-use equipment between patients Dedicated patient equipment to positive cases Education of staff, patients and visitors Auditing of outbreak unit/area including hand hygiene, isolation practices and environmental cleaning December 1, 2013

Management of Pathogens in Low Resource Countries December 1, 2013 IP&C measures vary based on institutional setting and available resources Hand hygiene should be a routine part of patient care in all settings Additional precautions may be considered depending on the pathogen, the institutional setting and outbreak circumstances Hand hygiene is absolutely crucial in prevention of transmission of antibiotic resistant pathogens. The appropriate use of antibiotics is also of utmost importance. So it is very important to combine hand hygiene, isolation precautions, and antimicrobial stewardship in the control of multidrug resistant pathogens.

Conclusion Antimicrobial resistance is a world-wide public health problem Solutions require a multi-faceted approach Improving behaviours is essential Global awareness and surveillance is required Implementation of appropriate IP&C practices and antimicrobial stewardship processes may be beneficial December 1, 2013

Key Points Tuberculosis and multi-drug resistant bacteria are important infection prevention and control issues Many have developed resistance to antimicrobials making them less effective Control measures vary by organism, setting and resources December 1, 2013

Further reading Apisarnthanarak A, Fraser VJ. Feasibility and efficacy of infection control interventions to reduce the number of nosocomial infections and drug resistant microorganisms in developing countries: what else do we need? CID 2009;48:22-24 EARS-Net. http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/Pages/index.aspx WHO 2010. Global tuberculosis control http://www.who.int/mediacentre/factsheets/fs104/en/index.html Special pathogens, in Damani N. Manual of infection prevention and control, 3rd ed. Oxford University Press, Oxford, 2012:183-249. December 1, 2013

Quiz When a patient with active tuberculosis has to leave the isolation room for tests, s/he has to wear a N95 mask. T/F? Admission screening for MRSA encompasses the following specimens: Nares alone Nares, wounds, exit sites Nares, wounds Nares, exit sites ESBL genes are transmitted by plasmids and are restricted to Enterobacteriaceae. T/F? December 1, 2013 False B

International Federation of Infection Control IFIC’s mission is to facilitate international networking in order to improve the prevention and control of healthcare associated infections worldwide. It is an umbrella organisation of societies and associations of healthcare professionals in infection control and related fields across the globe . The goal of IFIC is to minimise the risk of infection within healthcare settings through development of a network of infection control organisations for communication, consensus building, education and sharing expertise. For more information go to http://theific.org/ December 1, 2013