Dr Andrew Whitelaw, Principal Specialist, National Health Laboratory Service
An 86 year old male patient was admitted to an orthopedic ward with a right hip fracture and a right sided pleural effusion. Co-morbidity included diabetes mellitus and hypertension and he was in chronic renal failure on hemodialysis. The patient underwent open reduction and internal fixation of the right hip and had a right sided thoracostomy for the pleural effusion and was subsequently admitted to a high care unit (HCU). Two weeks later the patient was discharged to a renal ward for ongoing hemodialysis. A few days later the patient became delirious with fever and had an increased C-reactive protein and white cell count. Blood cultures and urine cultures taken at the same time revealed no growth. Ten days later whilst on empiric meropenem and linezolid he became hypotensive and obtunded; one day later a urine MC&S grew a Klebsiella pneumoniae that, according to automated susceptibility testing (Vitek 2), was resistant to all commonly used antibiotics (i.e. amino-penicillin’s, β-lactam/β-lactamase inhibitors, aminoglycosides, fluoroquinolones, cephalosporins, tigecycline and carbapenems). Subsequent disc susceptibility testing, showed that fosfomycin and colistin were the only active agents. Based on MIC testing, colistin was the only agent active against this pathogen. The isolate was genotypically analyzed by the Ampath molecular laboratory in Pretoria, to detect the presence of carbapenemase genes and sequencing confirmed the presence of the NDM (blaNDM-1 ) gene. The patient demised however without having received colistin and prior to all the tests being completed.
During his prolonged hospitalization of 40 days the patient received multiple courses of antibiotics which included:
Question 1: How does carbapenem resistance spread?
Answer to Q1
It is important to remember that carbapenem resistance does not only arise as a result of carbapenemases (carbapenem hydrolyzing enzymes). Carbapenem resistance can also be the result of mutations in porin channels in the bacterial cell wall. However, much of the recent attention around carbapenem resistance has been associated with carbapenemase producing Enterobacteriaceae (especially Klebsiella pneumoniae). Thus much of the following discussion revolves around carbapenemase producing Enterobacteriaceae (CRE).
There are two ways in which carbapenem resistance can spread. The gene encoding the carbapenemase enzyme (of which there are a number) can be on a mobile genetic element (and the mobile genetic element may carry resistance genes for a variety of other antibiotics as well). This is not unique to carbapenem resistance – many antibiotic resistance genes are on mobile genetic elements and can thus be acquired by different organisms. These resistance genes can be transferred from one organism to another, and this gene transfer can occur either in the patient or in the environment. In further studies on the prevalence of organisms carrying the NDM-1 gene in environmental water samples in India, the NDM-1 gene was found in a large number of organisms (including recognized human pathogens such as Vibrio cholerae, Shigella boydii, Pseudomomas aeruginosa, K. pneumoniae and E. coli) isolated from environmental sources. The gene can thus be transferred both from one strain of a bacterial species (such as K. pneumonia) to another as well as to completely different genera. Interestingly, the plasmids on which the gene was found were more stable in the fermenting Gram negative bacilli than in the non-fermenters.
The other way in which carbapenem resistance can spread is by spread of the organism from one patient / person to another. This is likely to be the major means of transfer within a hospital setting. Spread is by contact - non-affected individuals must thus come into contact with the organism in order to become colonized and/or infected. This contact can either be by one patient directly touching another patient who is colonized with the resistant organism, or, more commonly, by the organism being carried on health care workers who move from patient to patient. Transfer can also be mediated by inanimate objects (stethoscopes, cell phones etc) which may move from patient to patient or be shared among patients.
It is difficult to quantify the relative contribution of each of the above methods to the overall dissemination of carbapenem resistance in areas of the world where they are now common, but each mechanism undoubtedly plays a role.
Question 2: What are transmission-based precautions, and how do they differ from standard precautions?
Answer to Q2
As defined in the CDC’s Guidline for Isolation Precautions, “Standard Precautions are intended to be applied to the care of all patients in all healthcare settings, regardless of the suspected or confirmed presence of an infectious agent. Implementation of Standard Precautions constitutes the primary strategy for the prevention of healthcare-associated transmission of infectious agents among patients and healthcare personnel”.
Standard precautions encompass practices such as hand hygiene, safe sharps disposal, waste segregation and disposal, wearing of appropriate personal protective equipment when coming into contact with blood and body fluids (and were discussed in a previous case of the month).
Transmission based precautions are additional practices applied to prevent the spread of certain micro-organisms based on their route of spread. Transmission based precautions are always applied in addition to standard precautions, never instead of. The three categories of transmission based precautions are: airborne, droplet and contact.
These are applied in cases where the pathogen is spread in small droplet nuclei that can remain airborne for hours and disseminate widely in a room depending on the air currents. Pathogens that spread by the airborne route are M. tuberculosis, Varicella (chickenpox), Rubeola (measles) and Variola (Smallpox – hopefully of historical interest only). Airborne precautions include isolation of the patient in a private room with negative pressure ventilation (ideally) and wearing of suitable respirators (N95 level or higher) whenever entering the patient’s room.
These are applied to pathogens which are spread via the respiratory route, but on larger droplets that would not remain circulating in the air for prolonged periods of time. Transmission thus occurs when individuals are in close contact with respiratory secretions. Organisms that are spread by the droplet route include rhinovirus, adenovirus, Haemophilus influenzae type B, Neisseria meningitidis, Bordetella pertussis.
Droplet precautions ideally include isolation of the patient in a sideroom (although not with the ventilation requirements of a room used for airborne isolation). If isolation is not possible, patients should be separated by at least 3 feet / 1 meter (and a curtain if available), and health care workers should wear surgical masks when coming into close contact with the patient.
These are applied to patients infected / colonised with pathogens that are spread by direct contact, and that have clinical and/or epidemiological importance. This included multi-drug resistant organisms, C. difficile, Hepatitis A (in babies or incontinent patients), severe Herpes simplex. In addition, patients with extensively draining sinuses, abscesses, faecal incontinence etc should be placed on contact precautions as there is potential for environmental contamination.
The decision of what degree of antibiotic resistance warrants implementation of contact precautions will vary from centre to centre, but methicillin-resistant Staphylococcus aureus, ESBL producing Enterobacteriaceae, carbapenem resistant Acinetobacter baumannii and vancomycin resistant Enterococci are examples of resistant organisms that usually warrant contact precautions.
Contact precautions include isolating patients in single cubicle rooms if possible; alternatively cohorting patients with the same organism may be a more practical solution. Adequate spacing between patients (at least 1 metre) is important to limit sharing of equipment. Health care workers must wear gloves and gowns (or aprons) when coming into contact with the patient or their environment, and remove the gowns and gloves when finished. Hand hygiene before and after patient care is still mandatory even when gloves are being worn, as hands can become contaminated when removing gloves.
Question 3: What infection control precautions would be appropriate for carbapenemase producing Enterobacteriaceae (CPE)?
Answer to Q3
As discussed above, the Enterobacteriaceae are spread by contact, regardless of the resistance mechanism they may carry. This also applies to non-fermenters such as Acinetobacter and Pseudomonas species. The resistance mechanism does not thus change the nature of the infection control precautions being applied. There have been a number of publications describing infection control measures for CPE, with varying degrees of success. Both the CDC and the European Society of Clinical Microbiology have published guidelines for infection control in the face of carbapenemase producing K. pneumoniae, and the same principles would apply to all CRE. Although the principles are the same, there may be some differences depending on whether the organism is well established, or relatively uncommon in the health care setting.
Since CPE are (for now) relatively rare in South Africa, it may be appropriate to institute more rigorous contact precautions when trying to control these organisms. Unlike MRSA and ESBL-producing Enterobacteriaceae which are now well entrenched in health care settings, CPE are relative newcomers, and a “search and destroy” strategy (as has been suggested in settings in Europe) may be able to limit the threat these organisms pose. However, this is only possible if sufficient resources are made available.
Adequate laboratory support is vital to ensure early and reliable detection of these organisms, as well as timely notification of health care personnel and infection control personnel. Health care facilities should have plans in place to implement an infection control plan if CPE are identified in the facility.
The infection control plan should include isolating patients where possible, although due to space limitations most centres have used cohorting of patients and this seems to have been effective where instituted properly. When cohorting is carried out, nursing staff should be dedicated to looking after the cohorted patients – which is likely to require additional staff resources. If and when CPE become established in a health care setting, implementation of this degree of staffing may become unsustainable.
Rigorous adherence to contact precautions (gloves and aprons – single use – ie one per patient) is required of any staff coming into contact with the patients, and must be enforced by the nursing staff and infection control practitioners. Hand hygiene remains crucial, and again must be enforced by the nursing staff and infection control practitioners. Other suggestions include the “bare below the elbows” policy which facilitates hand hygiene, and not wearing elaborate jewellery on fingers or neckties. Education is important component of successful control. HCWs need to be aware of the significance of CPE, of how these organisms are spread, as well as how they are not spread.
If possible, patient records should be flagged so that patients with a previous CPE who have been discharged and are subsequently readmitted can be easily identified, and placed on presumptive contact precautions – at least until screening cultures are negative. It is not known how long carriage may persist, but some studies have demonstrated faecal carriage of resistant organisms for up to 6 months after discharge.
If cases are identified in hospitals, any patients with epidemiological links to the index case should be screened, by means of rectal swabs or stool samples. Rectal swabs / stool samples are currently regarded as the most reliable specimens to take for screening of otherwise asymptomatic patients.
Question 4: What is the role of routine screening of patients for carbapenem resistant organisms?
Answer to Q4
In South Africa, where CPE are still uncommon, it is probably not cost effective to screen every patient entering a health care facility. However, targeted screening may be valuable, although this will probably vary from facility to facility, depending on documented risk factors for CPE infection / carriage. Previously described risk factors (from studies in other parts of the world) include prior antibiotic exposure, ICU admission, prolonged hospitalization and use of indwelling devices. In one study in Israel (where CPKP has become a major problem), all contacts of a patient known to be a CPKP carrier were screened, as well as patients being admitted to ICU, and patients who had recently been in a long term care facility. The yield from screening was relatively low (1,5-2,0%), and did not change much over the course of the study, although the overall incidence in CPKP cases did decrease as a result of an infection control intervention. Thus the benefit of screening itself as part of the infection control strategy is difficult to judge.
In South Africa, it would be prudent to screen any patient known to have been in contact with a patient with confirmed CPE. In addition, if patients are admitted from facilities with a known CPE outbreak, screening and isolation of the patient until proven negative should be performed.
Reliable laboratory detection of CPE is crucial, both to identify patients infected colonized with the organism, as well as to identify carriers if screening is undertaken. A number of strategies have been suggested, and it is beyond the scope of this discussion to go into all of them in detail. However, any member of the Enterobacteriaceae with reduced susceptibility to carbapenems (ertapenem, meropenem, imipenem or doripenem) should raise suspicion and be a trigger for laboratories to discuss the cases with clinical and infection control staff (or vice versa).
While the emergence of carbapenem resistant Klebsiella pneumoniae is of concern, and poses an infection control challenge, by implementing early and appropriate infection control precautions, it may be possible to control the spread of these organisms. However, to achieve this, there must be a well co-ordinated response involving laboratory services, clinicians, nursing personnel, infection control specialists and hospital administration.
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