Methicillin Resistant Staphylococcus Aureus (MRSA) and Extended Spectrum Beta-Lactamases (ESBL).

Methicillin Resistant Staphylococcus Aureus (MRSA) and Extended Spectrum Beta-Lactamases (ESBL)

Anak Agung Ayu Yuli Gayatri, Tuti Parwati Merati Division of Tropical and Infectious Disease

Department of Internal Medicine

Udayana University School of Medicine-Sanglah Hospital Denpasar

Introduction

Resistance of pathogenic organisms to countenance antibiotics has become a world wide problem with serious consequences on the treatment of infectious diseases. The heightened use or misuse of antibiotics in human medicine, agriculture and veterinary is primarily contributing to the phenomenon. There is an alarming increase of antibiotic resistance in bacteria that cause either community infections or hospital acquired infections. Resistance genes borne on chromosomal, and increasingly, on transmissible extrachromosomal elements. The resulting resistant clones e.g. Meticillin-resistant Staphylococcus aureus (MRSA) USA 300, Escherichia coli ST 131 and Klebsiella ST258 are disseminated rapidly worldwide.

This spread is fascilitated by interspecies gene transmission, poor sanitation and hygiene in communities and hospitals and the increasing frequency of global, travel, trade and disease transmission. (Alekshun et al. 2007)

The true prevalence of MRSA and ESBLs infections is not known and is probably underestimated because of difficulties encounters in their detection. In the USA, data reported to the Centers for Disease Control and Prevention (CDC) National Nosocomial Infection Surveillance System and the National Healthcare Safety Network reflect an increase over the past decade in rates of infections caused by some Multi Drug Resistant -Gram Negative Bacteria (MDR-GNB), defined as resistance to one or more tested antimicrobial s in three or more antimicrobial classes. Among Gram- negative organisms associated with central line-associated infections, catheter-associated urinary tract infections, ventilator- associated pneumonia and surgical site infections that were reported during 2009-20010 aproximately 15% of K pneumoaie or Klebsiella oxitoca, 2% of E coli and 65% of A baumannii isolate. In Asia, data of E coli resistance varied from 5% in Korea to 23.3 % in Indonesia. In 2010-2012, Sanglah hospital Denpasar Bali reported 32 affected MRSA infection patients, with SSTI was the most common clinical presentation followed by sepsis, osteomyelitis, UTI and pneumonia. All cases were more likely to be resistant to lactams but remain sensitive to vancomycin, linezolide and many non ß-lactam antibiotics (including clindamycin, erythromycin and trimethroprim-sulfamethoxazole). ( Sievert et al. 2013; Gayatri Y. 2013)

Treatment of these multiple drug resistant organisms, pose unique challenges to clinicians, clinical microbiologists, infection control professionals and antibacterial-discovery scienties. It is generally recognized that patients infected with MRSA and ESBL-producing organisms are at risk for poor outcome if they are treated with anti bacterials to which the organisms exhibits high level resistance. The mortality rate in these susceptibility/ mismatched patients has ranged from 42-100%. (Chong Yet al. 2011)

1. Methicillin- Resistant Staphylococcus Aureus (MRSA)

MRSA was first described in 1961, almost immediately after the agent was introduced into clinical practice. MRSA are a type of staphylococcus bacteria that are resistant to many antibiotics. MRSA bacteria are more likely to develop when antibiotics are used too often or are not used correctly. Staphylococcus bacteria only become a problem when they cause infection. For some people especially those who are weak or ill, these infections can become serious.

MRSA in an opportunistic bacterium which may colonize and grow readily on the skin and mucous membranes of a person without harm to that person. It competes with other microorganisms found on the skin surface and is commonly found in the nose, groin, perineum or any other warm, moist sites. The human skin is constantly shedding skin scales-MRSA is shed with the skin as it falls from the human body. The greater the number of MRSA colonies on a person, the greater the potential for contamination of the environment and the transmission of MRSA to others.

Infected and colonized patients are the reservoir of MRSA both in hospital and the community with transmission generally being via contact with health workers. Effective, rapid laboratory diagnosis and susceptibility testing is critical in treating, managing any preventing MRSA infections.

1.1. MRSA Infections in Hospital

MRSA that is acquired in a hospital or healthcare setting is called healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA). In most cases, a person who is already sick or who has a weakened immune system becomes infected with HA-MRSA. These infections can occur in wounds or skin, burns, and IV or other sites where tubes enter the body, as well as in the eyes, bones, heart or blood. Some patients harbor MRSA on their skin or nose without harm („colonised‟). However these patient may develop infections if the MRSA spread to other parts of the body (e.g. if MRSA spread from colonized nose to a wound). When this happens the resulting infection is described as „endogenous‟. Some patients are at increased risk of developing infection. They include those with breaks in their skin due to wounds or indwelling catheters which allow MRSA to enter the body, and those with certain types of deficiency in their immune system. This includes patients who: i. Are in hospital and long-term care fascilities for a long time, ii. Are

on hemodialysis, iii. Receive cancer treatment or medicines that weaken their immune system, iv. Inject illegal drugs, v. Had surgery in the past year.

The prevention of horizontal transmission of MRSA has become increasingly important as the prevalence of this pathogen increases. Oral carriage of MRSA may serve as a reservoir for re-colonization of other body sites or for cross-infection to other patients or health care workers. Therefore, it is important that consideration be given to the oral cavity if eradication of colonization by MRSA is clinically appropriate. Eradication of throat carriage of MRSA has been achieve with use of topical chlorhexidine (0.2%) in addition to normal control measures of patient isolation, nasal mupirocin and chlorhexidine body washes.

1.2. MRSA infection in the Community

MRSA infections can also occur in healthy people who have not recently been in the hospital. The strains were labeled community-associated MRSA (CA-MRSA) if they had been isolated within 48 hours of hospitalization from patients who had not been in any hospital for >1 year. CA-MRSA resistance is usually limited to β-lactams and the strains remain susceptible to clindamycin, gentamycin, sulfamethoxazole-trimethoprim, vancimycin, rifampin, tetracycline and linezolide. Most CA-MRSA strains characterized by carry the Panton-Valentine leukocidin genes, leading to leukocyte destruction, skin abcesses and necrotizing pneumonitis, and also presence of staphylococcal chromosome cassette mec (SCCmec) IVa, a novel smaller variant of the methicillin-resistant locus. Other S aureus strains that are not resistant to methicillin will be referred to as methicillin- sensitive Staphylococcus aureus (MSSA). Most of CA-MRSA infections are on the skin or less commonly lung infections. These infections can occur among people who are likely to have cuts or wounds and who have close contact with one another, such as members of sports teams. People who may be at risk are: i. Atlletes and other people who may share items such as towels or razors, ii. Children in day-care. iii. Members of military, iv. People who have gotten tattoos. In some cases these organisms can cause invasive infection such as septic arthritis, bacteriemia, or community-acquired necrotising pneumonia. An early skin infection often has the initial appearance of an insect bite. These infections often develop into cellulitis, furuncles, large boils or clusters of boils (up to 10 cm in diameter) and deep-seated abscesses often in the thighs or buttocks. If the bacteria gain access to the lungs, fortunately a rare event, a devastating pneumonia that kills more than 40% of patients can result.

The fundamental differences between HA-MRSA and CA-MRSA have been discussed and summarized in table1.

Table 1. Comparison between healthcare-associated and community-acquired Methicillin resistant Staphylococcus aureus. ( Sievert et al. 2013)

CA-MRSA HA-MRSA

Clinical spectrum

Skin and soft tissue infections Wound infections, urinary tarct infections and bacteraemia

Epidemiology Affected healthy people in the community

Mostly affects hospital patients Underlying

condition

Dernmatological Healthcare associated risk factors

Age group Younger older

Resistant pattern

Sensitive to multiple antibiotics Resistant to multiple antibiotic Toxin

production

May produce PVL toxin Not yet reported produce PVL toxin

1.3. MRSA testing

MRSA screening may be undertaken for the following reasons:

1. Screening requirement determined from the multidrug Resistant Organism (MDRO) Risk Assesment

2. If found positive after admission from a clinical sample 3. As part of Outbreak Management

MRSA specimens

A purple bacterial swab is use to sample the following sites: 1. Nasal swab (one swab for both nostrils)

2. Groin swab (one swab for both sides) 3. Perineum swab

4. Wound swab-including decubitus ulcer (pressure sore) or surgical wound and device insertion e.g. IV tracheostomy, drain, suprapubic

5. Additional site:

 Umbilicus in neonates

 Catheter urine specimen if patient for screening has an indwelling urinary catheter

 Sputum from patient with recent MRSA respiratory tract infection (not nasal colonization)

1.4. Care of patient with MRSA:

 Placement of patients in single room

 Treatment procedure applies to all patients and staff who may or may not be currently receiving systemic antibiotic treatment for MRSA infection

 Contact Precautions with own toilet facilities (if Ensuite not available, allocate own commode chair in room or dedicated toilet)

 Hand hygiene with antimicrobial liquid soap or alcohol- based hand rub

 Dedicated patient-care equipment or disinfect between use if shared with other patients e.g. blood pressure and oximetry equipment

 Remove unnecessary equipment from the isolation room and ensure supplies are not overstocked within the room

 If no Ensuite shower is available the patient showers last in the communal shower and the shower is disinfected after use

 Mupirocin (Bactroban) is to be applied to the anterior nasal nares three times a day

 Tridosan 1% is to be used for daily washing of skin and bathing. Cetrimide shampoo for hair washing twice weekly

 Treatment is to be for an initial period of seven days

 Visitors do not wear PPE but are encourage to perform hand hygiene after visiting the patient

 Where possible, permanent staff should be used Treatment

Patients who are severely ill or have a rapidly progressing infection should be referred to the hospital for consideration of intravenous antibiotics. Intravenous vancomycin is the most commonly used antibiotic for this indication. Vancomycin can have serious side effects, especially in elderly persons. These side effects could include ototoxicity (loss of hearing or other auditory damage), nephrotoxicity (damage to the kidneys or renal system), and allergic reactions such as fever and rash. Infusion of vancomycin, especially when to rapid, can result in flushing, hypotension, and tachycardia known as the “red man syndrome”. Vancomycin given by mouth is not absorbed and is not effective against MRSAEmergence of vancomycin-intermediate and vancomycin-resistant MRSA (VISA and VRSA, respectively) has been reported, but are uncommon (Moran. 2006)). Linezolid may offer an alternative to intravenous vancomycin. Recent studies have shown that the adverse event rate of linezolid is not significantly different than that for vancomycin and that linezolid is an effective agent for SSTIs including those caused by MRSA. Daptomycin has been used effectively in cases of complicated SSTI and for treatment of CA-MRSA bacteremia. Quinupristin/dalfopristin is active against MRSA, but is rarely used due to an adverse-effect profile and potential cross-resistance with clindamycin-resistant strains. Tigecycline is active against MRSA and it has FDA approval for the treatment of skin and soft tissue infections (Rybak. 2005; Moran.2006).

Patients with localized infection and without systemic toxicity may be managed as outpatients with oral medications. Oral antibiotic therapy should be continued until there is resolution of signs of acute inflammation; this typically occurs within 7-14 days. Options for oral antibiotics include trimethoprim-sulfamethoxazole, clindamycin, linezolid or tetracyclines (eg, minocycline or doxycycline ).(Moran, 2006; Rybak, 2005).

Access to oral linezolid may be limited due to formulary restrictions and other cost related issues. Some infectious disease specialists save linezolid for use in infections due to organisms resistant to other agents. This conservative approach is supported by reports of the emergence of linezolid-resistant organisms in healthcare settings (Kelly, 2006). Topical, rather than oral, antibiotics can be used to treat superficial lesions. For instance, topical mupirocin TID for ~7 days has been utilized for treatment of limited impetigo (Stevens, 2005; Swartz 2005). Of note, resistance to mupirocin may develop, but this usually occurs in the setting of prolonged usage. For multiple or larger CA-MRSA lesions, oral antibiotics are recommended.

These drugs generally have activity against CA-MRSA: 1. Vancomycin (Vancocyn®) 15 mg/kg IV q12 hours

2. Daptomycin (Cubicin®) 4 mg/kg IV daily (higher dosages are used for bacteremia/endocarditis) Intravenous or Oral Antibiotics

3. Linezolid (Zyvox®) 600 mg IV or PO twice daily

4. Clindamycin (Cleocin®) 900 mg IV q8 hours or 300–450 mg PO QID 5. Oral Antibiotics

• Tetracyclines

• Doxycycline (Vibramycin®) 100 mg PO twice daily • Minocycline (Minocin®) 100 mg PO twice daily

• Trimethoprim-sulfamethoxazole (Bactrim®, Septra®) 1 double-strength with 160 TMP/800 SMX tablet twice daily

6. Rifampin (Rifadin®) 300 mg PO twice daily 7. Topical Antibiotics

• Topical mupirocin (Bactroban®) apply to each nares twice daily

• Chlorhexidine body soaps, shower with soap daily (used for decolonization purposes, not treatment)

* Dosages listed assume normal kidney and liver function; for patients with abnormal values, drug dosage adjustments may be needed. Some antibiotics listed are not recommended in children or during pregnancy.

1.5. MRSA Treatment in the Setting of Highly Active Antiretroviral Therapy (HAART) Although several oral agents are available, co-infection with HIV and the use of antiretroviral therapy may limit treatment options in some patients. TMP-SMX use may be limited in HIV patients due to pre-existing drug allergy. Clindamycin may be associated with Clostridium difficile _{colitis, a potentially vexing issue among HIV-patients. Linezolid} use may be limited by thrombocytopenia necessitating weekly monitoring of complete blood counts. Linezolid may also interact with psychotropic medications such as monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). Ideally patients should be titrated off of SSRIs prior to taking linezolid, but in many clinical situations this may not be possible. In those situations, patients should be

warned to watch for and report any signs or symptoms suggestive of the serotonin syndrome which include hyperthermia, agitation, tremors, myoclonus, altered mental status, and/or diaphoresis (Rybak, 2006).

Drug-drug interactions limit the co-administration of rifampin with several antiretroviral agents including protease inhibitors and non-nucleoside reverse transcriptase inhibitors. Rifampin is a powerful inducer of the cytochrome P450 enzyme system, leading to a decrease in antiretroviral plasma levels below the inhibitory concentration of 50% (IC50) of the latter and potentially leading to viral rebound. Rifampin should be avoided in patients receiving protease inhibitors and an alternate antibiotic, such as clindamycin, linezolid or tetracycline should be selected.

2. Extende Spectrum β-Lactamase (ESBL)

There is no consensus of the precise definition of ESBLs. β-lactamases are bacterial enzymes that ineffective β-lactam antibiotics by hydrolysis, which results in ineffective compounds. One group of β-lactamases, extended-spectrum β-lactamases (ESBLs) have the ability to hydrolyse and cause resistance to various types of the newer β-lactam antibiotics, including the expanded-spectrum (or third generation) cephalosporins (eg, cefotaxime, ceftriaxone, ceftazidime) and monobactams (eg, aztreonam), but not the cephamycins (eg, cefoxitin and cefotetan) and carbapenem (eg, imipenem, meropenem and ertapenem). ESBL has generally been defined as transmissible β- lactamases that can be inhibited by clavulanic acid, tazobactam or sulbactam, and or which are encoded by genes that can be exchanged between bacteria. Most ESBLs can be devided into three groups: TEM, SVH and CTX-M types. The currently most common genetic variant of ESBL is CTX-M.( Paterson DL et al. 2005)

2.1. Mechanisms of Transmission

A review of the literature on mechanism of transmission of MDR-GNB was problematic for three main reasons; the low number of studies; the low availability of high quality studies and the high heterogeneity of definitions, settings and pathogens. Patient-to patient transmission was frequently thought to be the most important route of transmission whenever several patients shared clonally related isolates. This is based on the hypothesis that colonized or infected patients are the only reservoir for the microorganism. However, intermediate vectors for spread between patients, including contaminated hands of healthcare workers (HCWs), environment, and visitors should also be taken into consideration for the prevention and control of healthcare-associated MDR-GNB transmission.

2.2. Extended Spectrum β- lactamase Escherichia coli (ESBL E-coli)

ESBL producing E coli are antibiotic resistant strains. In most respect they are no different from other strains of E coli in that can harbored as part of the normal flora and can cause urinary tract infections, bacteraemia and meningitis in susceptible individuals. A key

feature of these strains is that they carry specific genes that enable them to produce enzymes that destroy a large number of common antibiotics, making the infection they cause very difficult to treat. In many instances, only two oral and a very limited group of intravenous antibiotics remain effective. ESBL-producing strains E coli were first noted in 2003 when East and West Midlands region of England reported.

E. coli as the constant influx of community isolates colonizing patients at hospital admission is highly significant in the epidemiology of these organisms within hospitals, understanding the complex epidemiological behavior of E. coli in the community is a key to adequate interpretation of studies addressing the epidemiology of E. coli in hospitalized patients. The extra-intestinal pathogenic strain are the predominant strains in 20% of individual and harbor the typical virulence factors causing extra-intestinal infections when reaching the appropriate site from the bowel, which serve as their primary reservoir. Transmission of extra-intestinal pathogenic E. coli in the community is thought to occur by person to person transmission, either through direct contact or by means of faecal-oral route through or by contaminated food and/or water. (Johnson JR et al. 2010)

2.3. Klebsiella species

There have been several rescent studies of the epidemiology of K. pneumonia as a nosocomial pathogen. Cross-transmission via HCWs‟hands seems to be important in the nosocomial spread of K pneumonia strains. However in a recent study, an outbreak caused by contaminated food was described, indicating that transmission may also occur via the food chain.

2.4. Detection

The clinical laboratory acts as an early warning system, alerting the medical community to new resistance mechanism present in clinically important bacteria. The methods for detection of ESBLs can be broadly devided into two groups: phenotypic methods that use non-molecular techniques, which detect the ability of the ESBL enzymes to hydrolyse different cephalosporins and genotypic method, which use molecular techniques to detect the gene responsible for the production of the ESBL. Clinical diagnostic laboratories use mostly phenotypic methods because these tests are easy to do, are cost effective and have been incorporated in most automated susceptibility systems, making them widely accessible.

2.5. Treatment

This multiple drug resistance has major implications for the selection of adequate empirical therapy regimens. Empirical therapy is prescribed at the time when an infection is clinically diagnosed, while the results of cultures and antimicrobial susceptibility profiles are awaited. Multiple studies in a wide range settings, clinical syndromes, and organisms have shown that failure or delay in adequate therapy results in an adverse mortality outcome, which is also true of infections cause by ESBL-producing bacteria. A major challenge

when selecting an empirical regimen is to choose an agent that has adequate activity against the infecting organism(s). Empirical antibiotic choices should be individualized based on institutional antibiograms, which tend to be quite different from hospital to hospital, from city to city, and from country to country. ( Pitout J.D., et al. 2008)

The next issue surrounding the therapy of ESBL-producing infections is that even if an agent is selected that has activity against the bacteria in vitro, clinical efficacy in patients is not always guaranteed. Although in vitro tests ESBLs are inhibited by ß-lactamase inhibitors such as clavulanic acid, other study has shown the activity of ß-lactam/ß-lactamase inhibitor combination agent (e.g. piperacillin-tazobactam) is influenced by the bacterial inoculums, dose administration regimen and specific type of ESBL present. The other consideration treatment of ESBL-producing bacteria are cephamycins (e.g. cefoxitin, cefotetan) and Cefepime. This is widely believe to occur as a result of the so-called inoculums effect that occurs when the minimum inhibitory concentration of the antibiotic rises (i.e. the antibiotic looses activity) with the increasing size of the inoculums (or number) of bacteria tested. This effect has been described for cephalosporins, β-lactam-β lactamase inhibitor combinations (piperacillin, tazobactam) and to a lesser extent with the quinolones. Tigecycline is also one of the drugs in the pipeline which can be considered for treatment. (Pitout J.D., et al. 2008; Perez et al. 2007)

The carbapenems ( imipenem, meropenem, ertapenem, doripenem) are still the first choice of treatment for serious infections with ESBL-producing E coli and K pneumonia. It has been reported that >98% of the ESBL-producing E coli, K pneumonia and P. mirabilis are still susceptible to these drugs. This agents are highly stable to hydrolysis by ESBLs, are distributed into body tissues in high concentration and there is no inoculums effect. (Perez et al, 2007; Pitout J.D., et al. 2008). But with the emergence of the carbapenem – resistant Enterobateriaceae, the “magic bullet” is actually difficult to find. There are some older drugs which can be used to treat the ESBL-producing E. coli or K. pneumonia infections. Fosfomycin was reported of having admirable in vitro activity against the ESBL-producing E. coli or K. pneumonia. In HongKong, most of the ESBL-ESBL-producing E coli isolates were reported to be sensitive to fosfomycin. ( Ho et al., 2010). Colistin is another choice which we can consider for the treatment of these organisms. Although once considered as quite a toxic antibiotic, it is a last resort that we can consider at the present moment as there is no new anti gram negative antibiotics available for the treatment of these multidrug resistant organisms. ( Perz et al. 2007)

To reduced the problem of antimicrobial resistance, action should be taken along to tracks; promotion of prudent use of antibiotics and prevention of the spread of resistant bacteria. Improving antibiotic use can be achieved by changing the prescribing behavior of doctors, education, guideline and clinical pathway, antimicrobial cycling, antimicrobial order form, combination therapy streamlining or de-escalation, dose optimization, intravenous or oral therapy.

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BIDS-7 dan BAMHOI-3, Widhya Sabha, Denpasar 21 November 2015

BIDS-7 dan BAMHOI-3, Widhya Sabha, Denpasar 21 November 2015