infectious diseases issue - mpc · 2018. 4. 26. · pp-pna-zaf-0042 pfizer drug safety unit:...

Pfizer Drug safety unit: [email protected] or [email protected] Tel.: 0860 PFIZER (0860 734937)PP-PNA-ZAF-0042

Volume 9 No 2 - May 2018

CPD Accredited

Paediatric Newsletter

Infectious Diseases Issue

• Clostridium difficile in children – what do you need to know?• Antibiotic stewardship in state hospitals in South Africa• Staphylococcal Vaccines - going nowhere slowly? • Ethics: Vaccine refusal

Footprints and colours do not correspond to pneumococcal disease prevalence, Prevenar 13 (R) approval or use

3Volume 9 No 2 - May 2018

Publication in the interest of continuing medical education.

Editorial

Associate Professor Prakash Mohan JeenaHead of Paediatric Pulmonology and Critical CareUniversity of KwaZulu Natal, Durban

DisclAiMer

This is a Pfizer owned publication. Notwithstanding that it is a Pfizer publication, neither Pfizer nor its subsidiary or affiliated companies shall be liable for any damages, claims, liabilities, costs or obligations arising from the misuse of the information provided in this publication.

It is not the intention of this publication to provide specific medical advice or to substitute the advice of a health care practitioner but rather to provide readers with information to better understand health disorders. Readers are advised to consult their health care practitioner for specific information on personal health matters. Specific medical advice will not be provided by Pfizer, and Pfizer cannot make recommendations on the clinical management of patients or speak to patient’s healthcare professionals on their behalf. In this regard Pfizer does not support the use of products for off label indications, nor dosing which falls outside the approved label recommendations and readers must refer to the Package Insert of any product for full prescribing guidelines.

Should you want to report any adverse event or require further medical information, please contact the Pfizer Drug safety unit: Tel.: 0860 PFIZER (0860 734937) [email protected] or [email protected]

Editor: Prof Prakash Mohan JeenaProduction Editors: Ann Lake, Helen Gonçalves Design: Jane Gouveia Queries: Ann Lake Publications 011 802 8847, Email: [email protected]

The views expressed by the authors in this newsletter do not necessarily reflect those of the publishers, sponsor and editor. The sponsors, editor and publishers will not be liable for any damages, claims or liabilities arising from the use or misuse of the information provided in this publication and do not support the use of products for off-label indications.

ear Esteemed Readers

Welcome to this exciting edition of the Paediat-ric Focus Newsletter in 2018. While editing these manuscripts, I realised that the information provid-

ed in this bulletin has gone far beyond the level of a newsletter; it in fact surpasses the academic level of many peer reviewed manuscripts in SAPSE accredited scientific journals. For this, I as editor am indeed indebted to the extremely high standard of articles produced by our faculty, our esteemed authors.

This edition of the ‘mini-journal’ focuses on the new threats posed by infectious diseases and the responses of health care professionals to them. In 2014, reports from the World Health Assembly in New York highlighted the emerging global threat of antimicrobial resistance demonstrated by what society calls superbugs. As societies demand greater use of antibiotics for all illnesses and health care professionals continue to prescribe them irresponsibly, the human population is sitting on knife edge with the emergence of more and more resistant pathogens where no curative therapy is available. We are indeed fortunate to have an outstanding manuscript by paediatric infectious diseases specialists, Dr G Reubenson on emerging threats of old pathogens that are gaining prominence due to antibiotic abuse. He provides a clear approach to the emerging problem of Clostridium Difficile which is increasing in incidence due to excessive use of broad spectrum antibiotics. This is followed by an article by Dr E Hodgson, Chief Specialist in the Department of Anaesthesiology at Inkosi Albert Luthuli Hospital, Durban who expertly describes the issue of antibiotic stewardship in our state hospital as a means to limit antimicrobial resistance.

Both drug sensitive and resistant staphylococcal infections are currently on the increase. Dr A Pillay, a paediatric infectious diseases specialist from Durban, describes the pathogenesis of Staphylococcal infection and the challenges of finding a vaccine to reduce or eliminate its burden.

Finally, we have a wonderful philosophical review of the eth-ics of refusal of being vaccinated by certain persons within communities. Vaccinations have been the greatest advance in medical science. They have been the only medical intervention that has been able to eradicate a medical condition. And yet, some people, a minority are refusing to allow their children and themselves to be vaccinated. Prof K Bolton provides an expertly crafted article where he explains the risk these non-vaccinators are putting on all of society.

I hope you will have as much pleasure reading as I had putting this edition together. It will certainly add to your knowledge on current topics that are facing the medical fraternity.

God Bless and happy reading.Professor Jeena

Vaccinations have been the greatest advance in medical science. And yet, some people, a minority, are refusing to allow their children and themselves to be vaccinated.

4 Volume 9 No 2 - May 2018

than formula fed babies to be colonised. Colonisation rates beyond two years of age are similar to those observed in adults (± 3 %). Toxigenic as well as non-toxigenic strains can colonise the colon. Newborns and infants colonised with C. difficile do not appear to be at higher risk for symptomatic infection. Immature enterocytes seldom express receptors for toxin A and this likely explains the absent or limited pathogenicity of C. difficile in newborns, infants and young children. Asymptomatically colonised infants may be an important reservoir preceding transmission to more susceptible individuals. Colonisation is also more likely during hospitalisation, while receiving antibiotics and in people with acute diarrheal disease, rising to as high as 20 % in such patients. This has obvious implications for the interpretation of laboratory results.

CDAD may present with bloody or non-bloody diarrhoea, defined as passage of three or more stools in a 24 hour period that take the shape of their container.

Intestinal dysbiosis, in addition to antibiotic exposure, is believed to be important in CDAD pathogenesis and likely explains much of the progression from colonisation to symptomatic disease.

InvestigationA variety of C. difficile diagnostic tests are available and clinicians should familiarise themselves with the particular tests being performed in their own laboratories. There is no perfect testing algorithm and debate is ongoing around the best approach to take. It is vital to correlate test results with clinical findings as both under- and over-diagnosis are common. If in any doubt, clinicians should discuss such patients with microbiology, gastro-enterology or infectious disease colleagues.

Culture-based testing has largely been superseded by immunoassays and nucleic acid amplification tests (NAATs). Testing focuses on two main aspects: Is C. difficile present in the stool and, if present, is it able to produce pathogenic toxins?

Laboratory testing is complicated by:• the fact that colonisation can occur with both non-

toxigenic and toxigenic strains• strains that carry the genes required to produce toxin

may not be expressing these genes and• C. difficile toxin is labile and so when present in small

quantities or when the specimen is not processed

Clostridium difficile in children – what do you need to know?

Dr Gary Reubenson MBBCh FCPaed DCH DTM&HPaediatrician (Infectious Diseases), Department of Paediatrics & Child Health, Empilweni Service & Research UnitRahima Moosa Mother & Child Hospital, University of the Witwatersrand

lostridium difficile is a spore-forming anaerobic Gram-positive bacterium. It was first isolated over 80 years ago from the stool of asympto-matic newborns and has recently been re-named Clostridioides difficile – this is of no clin-

ical relevance, but if readers encounter the new name it is helpful to know what is being referred to.

C. difficile is ubiquitous in nosocomial settings, but is also commonly found outside of the hospital. It has been detected in household pets, farm animals, waste water treatment plants, meat products, and in fresh produce. C. difficile predominantly causes diarrhoeal disease in predisposed individuals given antibiotics.

Overall, it is the most common infectious cause of nosocomial diarrhoea, although this is probably not true for children. Early in the 21st century rising incidence rates were reported from many sites globally; in addition, mortality rates were also higher than previously observed. Much of this increased incidence and greater severity is explained by the emergence of the NAP1/027 strain – initially identified in the 1980s but reached global prominence over the last few years. The heightened virulence of this strain appears to be predominantly related to increased production of toxins A & B, which are directly responsible for the clinical manifestations of C. difficile-associated diarrhoea (CDAD). Quinolone-resistance has also emerged within NAP1/027 strains, potentially conferring a survival advantage in the hospital setting where quinolone use is prevalent. Importantly, non-toxigenic strains do not cause CDAD.

Frail, elderly adults remain the highest risk group, but non-traditional patients, including children, may be affected. Community-associated CDAD has also been increasingly reported with NAP1/027 strains. Concerningly, CDAD can develop in some individuals without prior antibiotic use. This changing epidemiology has resulted in greater awareness of C. difficile in patients not previously considered to be at risk for CDAD. Children at higher risk for CDAD include those with cirrhosis, inflammatory bowel disease, haematological malignancies and solid organ transplant recipients. HIV infection does not appear to be a strong risk factor for CDAD.

Up to 70 % of infants may be colonised with C. difficile; colonisation declines over time but is not uncommon during the second year of life. Breast fed babies are less likely


timeously, false-negative toxin detection assays may occur.

An important component of C. difficile testing is ensuring that these tests are only performed in appropriate clinical settings. In particular, testing of stools from children less than one year of age, non-diarrheal stools and stools from patients receiving laxatives is considered inappropriate and many laboratories will decline to perform C. difficile testing on such samples. Certainly, C. difficile testing should not be performed routinely on patients with diarrheal illness and should not be done unless specifically requested by the treating clinician.

A number of studies have shown that clinicians are commonly unaware of baseline colonisation rates amongst young children, frequently investigate inappropriate patients and struggle to interpret C. difficile test results. Therefore, it is recommended to discuss such cases with microbiologists, gastroenterologists or infectious disease specialists with CDAD-related expertise with a view to limiting inappropriate testing and treatment.

By way of example, the NHLS laboratory in Johannesburg employs a two-step testing algorithm. Initial testing involves an enzyme immunoassay that can detect C. difficile glutamate dehydrogenase (GDH) and C. difficile toxin. Detection of both GDH and toxin in stool collected from an appropriate patient would be considered diagnostic for CDAD. If discrepant results are obtained (i.e. GDH positive, toxin negative) this may represent colonisation with a non-toxigenic strain or reflect CDAD with a false-negative test for toxin. Such samples are then subjected to a NAAT that can detect toxin-encoding genes; if negative, CDAD is highly unlikely; if positive, toxigenic C. difficile is present (although toxin production has not been confirmed) and appropriate infection control measures should be instituted. Such patients should be considered for CDAD treatment, although other causes for diarrhoea should also be considered.

Other laboratories will initiate testing with a C. difficile NAAT, if positive further testing for toxin and/or toxin-encoding genes will follow. Both approaches have advantages and disadvantages and there are ongoing efforts to improve commercially available tests and optimise testing algorithms.

Part of the increase in C. difficile detection over the last two decades relates to the widespread availability of more sensitive laboratory tests, detecting more clinically relevant isolates as well as previously undetected colonisation.

In the future, quantitative toxin assays will likely become available. The ability to quantify toxin will be useful in that larger amounts of free toxin have been closely linked to more severe illness and death, thus potentially allowing for more aggressive therapy in those at greatest risk.

Colonoscopy is seldom required but may be indicated in cases of diagnostic uncertainty and when concomitant pathology needs to be confirmed or excluded.

Prevention, including infection prevention and controlThe mainstay of CDAD prevention is the avoidance of inappropriate antibiotic use. Antibiotics that confer a higher risk for CDAD include clindamycin, amoxicillin, cephalosporins and fluoroquinolones. It was hoped that co-prescription of probiotics with antibiotics would reduce CDAD in susceptible patients. However, studies have shown mixed results and currently routine co-prescription of probiotics for prevention of CDAD is not recommended.

C. difficile spores are ubiquitous in the healthcare setting and viable spores can be identified from almost any surface, including the hands, stethoscopes and pens of health care workers. Hand spraying with alcohol-containing hand-spray provides equivalent disinfection to hand-washing of unsoiled hands against almost all other nosocomial pathogens, but an important exception to this is C. difficile spores which are resistant to hand-spraying and better removed with effective hand-washing.

Patients with known or suspected toxigenic C. difficile infection or colonisation should be isolated. Health care workers in contact with such patients should wear gloves and gown and wash their hands with antiseptic soap and water. Post-discharge room disinfection is also recommended.

A number of C. difficile vaccines are undergoing Phase II and III evaluation in high risk patient groups.

A number of studies have shown that clinicians are commonly unaware of baseline colonisation rates amongst young children, frequently investigate inappropriate patients and struggle to interpret C. difficile test results.


TreatmentMost cases of CDAD respond well to first line treatment. However, recurrence may occur and treatment failures are not uncommon. In general, antibiotics should be stopped and supportive therapy provided. Mild and moderate cases can be treated with oral metronidazole (30mg/kg/day in 4 divided doses, max 2g/day) for 10-14 days, while more severe cases should receive oral vancomycin (40mg/kg/day in 4 divided doses, max 2g/day) for 10-14 days. There is some evidence to support the use of oral vancomycin ahead of metronidazole even in mild and moderate cases of CDAD. However, most guidelines continue to recommend metronidazole for such patients. The goal of therapy is resolution of symptoms and so repeat stool testing in an effort to document clearance of C. difficile is strongly discouraged. If CDAD recurs (defined as within 60 days of completion of primary treatment), retreatment with oral vancomycin is recommended, regardless of whether metronidazole or vancomycin was used initially, but for a longer duration including pulsed/intermittent dosing. The rationale for a longer, pulsed treatment course is to allow for killing of newly germinated bacteria as spores are resistant to antimicrobial therapy.

A number of novel treatments are under investigation. These include nitazoxanide, rifaximin, fidaxomicin, probiotics, immunotherapy, and bacteriotherapy.

Fidaxomicin is licenced in many countries for the treatment of CDAD, but is currently very expensive and should only be considered in patients with repeated recurrences following discussion with an appropriate expert.

Immunotherapy with monoclonal antibodies e.g. bezlotoxumab (against toxin B) when combined with antibiotic therapy reduces CDAD recurrence and has recently been licenced in some developed countries.

Bacteriotherapy, which includes faecal transplantation, has an emerging evidence base and will likely be available in palatable, commercially produced formulations within the next few years.

ConclusionPaediatricians should be aware that C. difficile is an important pathogen that is potentially underdiagnosed in children. However, overdiagnosis related to unnecessary treatment of colonised children is also common. Clinicians should be aware of available laboratory tests, their value and limitations. With appropriate treatment and attention to adequate infection control measures excellent outcomes can be expected. In the future, improved diagnostics, better treatment options and effective vaccines have the potential to further reduce CDAD morbidity and mortality.

References available on request.

Further Reading1. Leffler DA, Lamont JT. Clostridium difficile infection. N

Engl J Med. 2015 Apr 16;372(16):1539-48.2. Sammons JS, Toltzis P, Zaoutis TE. Clostridium

difficile Infection in children. JAMA Pediatr. 2013 Jun;167(6):567-73.

3. Sammons JS, Toltzis P. Recent trends in the epidemiology and treatment of C. difficile infection in children. Curr Opin Pediatr. 2013 Feb;25(1):116-21.

Take home messages

1. Do not routinely test for C. difficile in children with diarrhoea

2. Infants are commonly colonised with C. difficile and so testing them is discouraged as positive results predominantly reflect colonisation, even with toxigenic strains

3. Older children may also be colonised and so testing should be reserved for specific cases with a higher pre-test likelihood of CDAD

4. Non-toxigenic strains do not cause CDAD and should not be treated

5. Probiotics should not be routinely co-prescribed with antibiotics with a view to decreasing CDAD

6. In children infected or colonised with C. difficile, infection prevention and control measures are vital and include patient isolation, gloves, gowns and hand washing

7. Oral treatment with metronidazole (mild and moderate cases) or vancomycin (severe and recurrent cases) is highly effective

8. The goal of therapy is symptom resolution, so repeat testing to document clearance is discouraged

9. Novel and future therapies include fidoxamicin, rifaximin, immunotherapy, bacteriotherapy, and possibly probiotics

10. When assistance is required for diagnosis and treatment of CDAD involve microbiology, gastroenterology and/or infectious diseases colleagues to optimise outcomes


Antibiotic stewardship in state hospitals in South Africa

Dr Eric HodgsonAnaesthesiologist and Pain Practitioner, Chief Specialist, Dept. of Anaesthesia, Inkosi Albert Luthuli Central HospitalHonorary Clinical Associate, Dept. of Anaesthesia, Critical Care & Pain Management, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, KwaZulu-Natal

ntibiotics, introduced into medical practice in the 1950s, revolution-ised the management of infectious diseases.1 Excessive and inappro-priate use of antibiotics has result-

ed in the proliferation of antibiotic resistant “su-perbugs”, typified by the ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter bauman-nii, Pseudomonas aeruginosa, and Enterobacter species).2 Development of new antibiotics will not be a solution to this crisis as there are very few new antibiotics being researched and even fewer with new, unique mechanisms of action.3

Antibiotic stewardship is an attempt to preserve the efficacy of currently available antibiotics through promotion of appropriate use and limitation of inappropriate practice.4

Stewardship is largely externally applied in State health services by strict control over antibiotics allowed on the State Essential Medicines List (EML). However, there is still potential for misuse of this limited formulary that can be addressed by antibiotic stewardship programs.

The organisation that has taken the lead in antibiotic stewardship in South Africa is the Federation of Infectious Diseases Societies of South Africa (FIDSSA). The initiative launched by FIDSSA is the South African Antibiotic Stewardship Programme (SAASP - http://www.fidssa.co.za/SAASP). The SAASP app is available free on Google Play (Android) or the iStore (Apple). The app provides extensive information, including:• A pocket guide to available antibiotics• Online training courses including:

https://www.openlearning.com/courses/clinical-antibiotic-stewarship-for-south-africa

• Contact details for experts in the field• Links to local, national and international courses and

congresses in antibiotic stewardship

The effectiveness of antibiotic stewardship programmes, especially in hospitals with limited resources has been questioned.5 Fortunately there is robust data demonstrating the effectiveness of stewardship programmes in South Africa.6 The principles are demonstrated in Figure 1.

The most important “who” of any antibiotic stewardship programme are the nursing staff as well as the cleaning and portering staff. With appropriate training and explanation, simple interventions such as handwashing can have a major impact on the rate of infections in a unit.7 Input from the clinical microbiologist is vital.8

“Outbreaks” involving a single organism are inevitably linked to inadequate infection control with spread of organisms between patients by staff. A simple, cheap and effective counter to such “outbreaks” is to colour code beds. Each bed is assigned a colour. Equipment (e.g. stethoscopes) and disposables (e.g. plastic aprons) are supplied in that colour. No-one may enter the bed-space without disinfection and changing into that bed-space’s colour.

The presence of multiple resistant organisms in a unit is a good indicator of antibiotic misuse as resistant mutants are being selected from individual patients by the use of inappropriate antibiotics.

The clinical pharmacist also has an essential role.9 After antibiotic selection by the clinicians in consultation with microbiology, the clinical pharmacist can advise on:• Drug interactions with the other drugs the patient

may be taking.

Why?Reduce resistance

Reduce AB side effectsImprove patient outcome

Reduce costs

How?Study baseline data

Know barriersChoose interventions

Develop a plan

What?Focus on early diagnosis

Appropriate empirical therapyOptimise PKStop early

Who?Intensivist

Microbiologist/IDClinical pharmacist

Antibiotic stewardship

in icU

Figure 1.7 AB = antibiotic, ID = infectious diseases,PK = pharmacokinetics


• Prescription of antibiotics with similar modes of action e.g. two beta-lactams

After their intervention, Brink et al were able to demonstrate substantial improvement in all these indicators and could move on to further interventions.

Antibiotic stewardship can be implemented in most clinical scenarios where antibiotics are prescribed. The major limiting factor in State practice is availability of staff but modest audit with limited goals can provide great benefit.5

Essential resource1. http://www.fidssa.co.za/SAASP

References1. Mendelson M, Whitelaw A, Nical M, Brink A. Wake up,

South Africa! The antibiotic ‘horse’ has bolted. South Afr Med J 2012; 102(7):607-8.

2. Santajit S, Indrawattana N. Mechanisms of antimicrobial resistance in ESKAPE pathogens. BioMed Res Int 2016; Article ID 2475067

3. Cooper MA, Shlaes D. Fix the antibiotics pipeline. Nature 2011; 472: 32.

4. Diane Ashiru-Oredope D, Sharland M, Charani E, et al. Improving the quality of antibiotic prescribing in the NHS by developing a new Antimicrobial Stewardship Programme: Start Smart—Then Focus. J Antimicrob Chemother 2012; 67 Suppl 1: i51–i63.

5. Ramsamy Y, Muckart DJJ, Mlisana KP. Antimicrobial stewardship in South Africa: a fruitful endeavour. Lancet 2016; S1473-3099(16): 30052-4

6. Brink AJ, Messina AP, Feldman C. Antimicrobial stewardship across 47 South African hospitals: an implementation study. Lancet Infect Dis 2016; 16: 1017–25.

7. Schouten J. Antimicrobial stewardship in the ICU. Intens Care Management J 2017; 16(1). http://www.healthmanagement.org.

8. Chunnilall D, Peer AK, Naidoo I, Essack SY. An evaluation of antibiotic prescribing patterns in adult intensive care units in a private hospital in KwaZulu-Natal. South Afr J Infect Dis 2015; 30(1): 17-22.

9. Pakyz AL, Moczygemba LR, VanderWielen LM, et al. Facilitators and barriers to implementing antimicrobial stewardship strategies: Results from a qualitative study. Am J Infect Control 2014; 42: S257-S263

10. Rello J. Antibiotic Stewardship in Hospital-Acquired Pneumonia. Chest 2013; 143(5): 1195-6.

11. Davey P, Brown E, Charani E, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients (Review). Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database of Systematic Reviews 2013; 4: CD003543.

This article was originally published in Infectious Diseases Update Vol 6 No 3 August 2017 and is reprinted here with permission.

• Dose adjustment based on co-existing organ dysfunction to assure appropriate levels are achieved.

• Advice on stopping antibiotics. Resistance increases with duration of antibiotic therapy. A very effective intervention to reduce antibiotic exposure is a separate prescribing chart for antibiotics with an automatic stop at 5 days to facilitate re-evaluation of the therapy.

The essence of antibiotic stewardship has been described by Rello10 in terms of rights: The right patient, given the right drug at the right time for the right indication and the right duration.

This may be achieved in clinical practice by two broad groups of intervention:11

• Restrictive: Limited antibiotic formulary, telephonic authorisation of antibiotic therapy.

• Persuasive: Provision of teaching and learning opportunities with feedback on effectiveness, monetary incentives.

Despite the expectation that persuasive interventions would be more durable, both are equally effective after 6 months.

Implementation of an antibiotic stewardship programme should follow the same cycle as other clinical interventions typified by the audit cycle in Figure 2:

Audit will identify specific problems unique to a particular unit.8 In the study by Brink et al6 on implementation of antibiotic stewardship in 47 South African private hospitals, the following were identified as problems resulting in increased unnecessary antibiotic exposure:• Cultures not taken prior to starting antibiotics• Antibiotics given for >7 or >14 days• Prescription of > 4 antibiotics

Figure 2. Audit cycle


Staphylococcal Vaccines - going nowhere slowly?

Dr Ashendri Pillay MBBCH (WITS) FCPaed (SA) Paeds ID (SA) Paediatric Infectious Diseases Specialist King Edward VIII Hospital, University of KwaZulu Natal

symptomatic Staphylococcus aureus coloni-sation is common in humans. Children have been shown to have higher colonisation rates when compared to adults. The nasal cavity is considered to be the predominant

site for asymptomatic colonisation, with the most fre-quent area of colonisation being the posterior regions of the vestibule. The skin, nails, pharynx, axillae, perine-um, throat, rectum and vagina may also be asymptomat-ically colonised. Nasal carriage is thought to be a risk factor predisposing to invasive disease. When these commensals breach the skin and/or epithelial barriers and become pathogenic, they have the potential to cause life threatening hospital and community-acquired infections.

EpidemiologyS. aureus is the most common human pathogen causing community and hospital-associated infections. It can infect people of all age groups, but the severity of disease may be increased in children, the elderly and immunocompromised individuals. A previous infection with S. aureus does not provide immunity against subsequent infections; however it would seem that infections in colonised individuals may be less severe. This supports a theory that some immunity may develop in individuals with prolonged colonisation. Studies have shown that the mortality rate from staphylococcal infections in neonates and children up to one year of age, in low income countries may be as high as 50%.

The increasing incidence of hospital acquired methicillin resistant S. aureus strains (HA-MRSA), the emergence of community acquired MRSA (CA-MRSA) infections together with reduced susceptibility to vancomycin and linezolid, have prompted public health concern globally. Hospital and community acquired S. aureus infections are becoming progressively resistant to previously susceptible antibiotics like vancomycin and linezolid.

In light of progressively increasing resistance to current antibiotics, several approaches trying to elicit active and passive immunisation to S. aureus have been explored. Also, the dampened enthusiasm for the development of new more expensive antibiotics has forced researchers to optimise efforts to create a staphylococcus vaccine and therapeutic antibodies.

PathogenesisS. aureus is a member of the Staphylococcal genus, it is a gram-positive coccus. It has a number of virulence factors, classified according to function. S. aureus adheres to and colonises the host tissue using surface proteins. It then spreads in the host tissue via invasins. S. aureus avoids opsonisation and phagocytosis. It lyses host cells and can secrete toxins which result in disease progression. Prior S. aureus infections do not protect individuals against recurrent disease.

Initially thought to be un-encapsulated or having a limited capsule, further evaluation of most clinical S. aureus isolates confirms a polysaccharide capsule. Although 11 serotypes have been described, capsular polysaccharide types 5 and 8 (CP5 and 8) have been implicated in pathogenesis.

The cell wall is made up of peptidoglycan, capsular polysaccharide, ribitol teichoic acid, lipotechoic acid and surface proteins. Surface protein A (SpA) binds to immunoglobulin G (IgG) thereby reducing efficient opsonisation and phagocytosis. Other surface proteins implicated in pathogenesis include adhesions, fibrinogen and fibronectin binding proteins, and clumping factors A and B (ClfA, ClfB) and IsdA, an iron acquisition factor. Invasins (leukocidins, kinases, hyaluronidase) enhance bacterial spread in host tissue.

S. aureus also secretes:• membrane damaging toxins (α, β, γ and δ haemolysins,

leukocidins and leukocidins) that form part of phages i.e. Panton-Valentine leucocidin (PVL)

• toxins that interfere with receptor function but are not membrane damaging (enterotoxins A-G, toxic shock syndrome toxin-1 (TSST-1))

• secretory enzymes (staphylocoagulase, von Willebrand protein and staphylokinase)

The arsenal of virulence factors deployed by S.aureus play a vital role in its pathogenesis and development of antibiotic resistance. They have also been the target of development of vaccines and antibody-based therapeutics.

Clinical spectrum The clinical spectrum of disease may range from skin and soft tissue infections, invasive systematic and life-


enhancing neutrophil function and promoting bacterial clearance.

Trials using live whole-cell vaccination in mice did not elicit protective immunity, similarly killed whole-cell vaccines prepared from clinical S. aureus isolates did not show vaccine efficacy in rabbits.

There are currently two vaccines in Phase II clinical testing, both vaccines target surface antigens. Vaccine SA4Ag (S. aureus 4-Antigen vaccine) sponsored by Pfizer, is expected to produce antibodies to induce opsonophagocytosis and inhibit adhesion of S. aureus. It has 4 target antigens, capsular polysaccharide conjugates of serotypes 5 and 8 (CP5 and CP8), recombinant surface protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (rMntC). It is currently undergoing Phase IIB efficacy trials in adults having elective spinal fusion to assess the ability of SA4Ag to prevent postoperative S. aureus invasive surgical site and bloodstream infections.

Vaccine NDV 3A has a target antigen that is a recombinant protein derived from the Candida Als3 adhesion protein, this is homologous to surface proteins on S aureus. It is expected that the vaccine sponsored by Novadigm, will result in an induction of a protective T cell response. It is currently in Phase II clinical trials in patients with autosomal dominant hyper-IgE syndrome in the United States of America.

Staphylococcal antibodies Antibodies are able to exert their actions immediately, they do not require the priming effect needed with vaccination and can be administered as an emergency intervention or in patients with immune-deficiencies. Three of the four antibody-based biologics currently in phase II clinical testing, target the α-haemolysin antigen with the aim to neutralise the toxicity associated with Hla.

MEDI4893 (MedImmune) is one of the human monoclonal antibodies (mAb) that targets Hla. The primary outcome measure will evaluate efficacy of MEDI4893 by clinical symptoms of pneumonia and other staphylococcus serious infections and secondary outcome measures will look at the incidence of Staphylococcus aureus pneumonia on mechanical ventilated patients, measured by clinical symptoms of pneumonia and other staphylococcus serious infection.

ASN100 (Arsanis) is a combination of two human monoclonal antibodies ASN-1 and ASN-2, they neutralise six cytolysins. ASN-1 targets Hla and cross reacts with leukocidins (HlgAB, HlgCB, LukED and LukSF). ASN-2 neutralises LukAB. ASN100 is currently being tested in a phase 2 clinical trial, evaluating the prevention of S. aureus pneumonia in heavily colonised, mechanically ventilated patients.

threatening infections such as osteomyelitis, pneumonia, meningitis and blood stream infections. S. aureus is also responsible for certain toxin mediated syndromes, namely staphylococcal food poisoning, staphylococcal scalded skin syndrome and toxic shock syndrome.

Staphylococcal vaccinesA staphylococcal vaccine like most other bacterial vaccines will need time and repeated dosage schedules to prime the cell mediated immune system. Because S. aureus uses many different pathogenic pathways, vaccines that targeted single antigens, toxins and/or capsular polysaccharides combined with adjuvants that stimulate cell mediated immunity, have been investigated.

Both a T-cell and B-cell vaccine-induced response is required to induce adaptive immunity. Although the precise mechanisms of humoral and cell mediated responses to staphylococcal colonisation and infection have eluded researchers for years, it is now thought that antigen-specific T-helper cells are responsible for generating antibody responses, with Th17 cells

In light of progressively increasing resistance to current antibiotics, several approaches trying to elicit active and passive immunisation to S. aureus have been explored. Also, the dampened enthusiasm for the development of new more expensive antibiotics has forced researchers to optimise efforts to create a staphylococcal vaccine and therapeutic antibodies.


Human mAb AR-301(Aridis) is an IgG1 antibody that specifically targets S. aureus Hla. It is currently being evaluated in phase I/II trials as an adjunctive therapy in combination with standard of care antibiotics for hospital-acquired pneumonia and ventilator-associated pneumonia.

Human mAb 514G3 (Xbiotech) targets staphylococcal SpA. It is expected to induce “antibodies to block SpA mediated immune evasion and induce opsonophagocytosis”. Hospitalised patients with S. aureus blood stream infections were randomised to either receive a dose of 514G3 in addition to standard of care antibiotics versus placebo and antibiotics.

ConclusionDespite ongoing trials, to date, there are no licensed S. aureus vaccines nor therapeutic antibody based therapies.

References1. Bagnoli, Fabio(2017): Staphylococcus aureus toxin an-

tibodies: Good companions of antibiotics and vaccines, Virulence, DOI: 10.1080/21505594.2017.1295205

2. Becker, Karsten. Staphylococcal aureus, Chapter 2,Pathogenesis of staphylococcus aureus, ttp://dx.doi.org/10.1016/B978-0-12-809671-0.00002-4

3. DeLeo Frank, R, Diep Binh An, and Otto Michael, Infectious Diseases Clinics North America. 2009 March; 23(1): 17–34.

4. Francois, B. Barraud, O. Jafri, H.S. Clinical Micribiology and Infection 23 (2017)219-221

5. Daum Robert S., Principles and Practice of Pediatric In-fectious Diseases, Staphylococcal aureus, 2018. Pages 692-706.e4.

6. Daum Robert, S. Plotkin's Vaccines, Staphylococcal aureus Vaccines, chapter 55, 1031-1038.e4

7. Fowler Jr V.G, and Proctor R.A Where does a Staphylo-coccus aureus vaccine stand? Clinical Microbiology and Infection 2014; 20 (Suppl. 5): 66–75

8. Giersing, Birgitte K. Dastgheyb , Sana S. Modjarrad, Kayvon. Moorthy, Vasee. Status of vaccine research and development of vaccines for Staphylococcus

aureus, Vaccine 34 (2016) 2962–2966 9. Haghighat Setareh, Siadat Seyed Davar, Sorkhabadi

Seyed Mehdi Rezayat, Sepahi Abbas Akhavan Sepahi, Sadat Seyed Mehdi, Yazdi Mohammad Hossein, Mahdavi Mehdi.

10. Recombinant PBP2a as a vaccine candidate against methicillin-resistant Staphylococcus aureus: Immuno-genicity and protectivity. Microbial Pathogenesis 108 (2017) 32e39

11. Jansen Kathrin, U. Girgenti Douglous Q. Scully Ingrid, L. S. Anderson Annaliesa, S. Vaccine review: “Staphyloccocus aureus vaccines: Problems and prospects” Vaccine 31 (2013) 2723–2730

12. Dominique Missiakas and Olaf Schneewind , Staphylococcus aureus vaccines: Deviating from the carol, Journal of Experimental Medicine (2016)

13. Knut Ohlsen, Udo Lorenz, Immunotherapeutic strate-gies to combat staphylococcal infections, International Journal of Medical Microbiology 300 (2010) 402–410

14. Procter, Richard A., Is there a future for a Staphylococcus aureus vaccine? Vaccine 30 (2012) 2921–2927

15. Que, Yok-Ai; Moreillon, Philippe. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Updated Edition. Published January 1, 2015. Pages 2237-2271.e9.

16. Reddy Prakash Narayana, Srirama Krupanidhi and Dirisala Vijaya R., An Update on Clinical Burden, Diagnostic Tools, and Therapeutic Options of Staphylococcus aureus Infectious Diseases: Research and Treatment Volume 10: 1–15 2017

17. Adam C. Schaffer, Jean C. Lee, Staphylococcal Vaccines and Immunotherapies, Infectious Diseases Clinics of North America 23 (2009) 153–171

18. Shuping, Liliwe L. Kuonza, Lazarus Musekiwa Alfred, Iyaloo Samantha, Perovic Olga . Hospital-associated methicillin-resistant Staphylococcus aureus: A cross-sectional analysis of risk factors in South African tertiary public hospitals, Plos One, November 2017 https://doi.org/10.1371/journal.pone.0188216


Ethics

Vaccine refusal

Prof Keith Bolton MBBCh DCH FCPaeds MSc Med (Bioethics & Health Law)Rahima Moosa Mother and Child Hospital, Johannesburg

accination is arguably, the greatest all-time achievement in public health and has contributed to massive declines in morbidity and mortality caused by vaccine-preventable diseases (VPD). “Old” vaccines were

responsible for the global elimination of smallpox and we sit on the cusp of polio elimination. Diphtheria and tetanus are rarely seen. “Newer” vaccines, such as those against measles, pneumococcal infection and rotavirus have proved to be equally effective. Over the last decade it is estimated that more than 2.5million deaths from measles have been prevented. In RSA, since 2009, there has been a 70% reduction in pneumococcal pneumonia and meningitis in infants and more recently, a dramatic decrease in dehydrating gastroenteritis has been seen.

Despite these gains with vaccines, South Africa has sub-optimal vaccine coverage in our childhood population with progressive decrease in uptake from birth through childhood. Different authorities vary in their assessment of our deficit but all would agree that we have a problem. In our relatively well-resourced country, we are outshone by our poorer neighbours as regards vaccination. Recent local outbreaks of measles, with the attendant morbidity and mortality give testimony to this. Much of the problem can be laid at the door of a dysfunctional healthcare system but this article concerns another important cause for poor coverage, that is, vaccine refusals.

To some extent, the falling-off in vaccine uptake is a product of the success of the intervention. As vaccine coverage increases, VPD are less commonly seen by healthcare workers (HCWs), patients and their families alike. Most recently qualified HCWs have never seen a new case of paralytic polio or even diphtheria or tetanus. However, the adverse-effects attributed to the vaccine now become a focus of attention. The medical and especially the electronic media become the source of both “true” scientific information but, increasingly, a source of pseudo-scientific fake-news and scaremongering.

As you would expect, anti-vaccine websites originated and blossomed in developed countries where VPDs were rarely seen. The USA, with its high regard for individual autonomy and wide-spread internet access, became a fertile environment for anti-vaccine websites. The world today is truly a village with regard to the dissemination of information and disinformation but not only do South Africans have access to international websites, we have

our very own local brands. A search for anti-vaccine websites showed that 12/67 (17.9%) were of South African origin.1

It is useful to consider that parents’ acceptance or rejection of vaccination are not the only two diametrically opposed positions possible but that there is a continuum between these extremes: Hence the concept of vaccine “hesitancy”. A useful model of this concept has been published where individual decision-making depends on trust existing between the role-players.2 The parents should be considered in the broader concept as displaying of historical, political and cultural characteristics. On the “other side” are the public health authorities with their vaccine policies and the health professional’s recommendations. Stirring the pot, are sources of information; the media.

Before considering the nature of the vaccine hesitant population, we should address the inescapable breakdown of trust between the role-players. This is probably part-and parcel of a general lack of trust seen in many aspects of our postmodern era. Here, “Modernity” refers to societies that have capitalistic economies and democratic political structures, and are highly industrialised and divided into social classes based on economic status. These characteristics include regular patterns of everyday life, urbanisation, influx of women at all levels of employment and business, secular outlook, sexual freedom, sharp reduction in birth rate and death rate, centralised democratic but bureaucratic government, standardised education system, and pervasive use of technology especially in communications. Health systems flourished in the modern society as did vaccination. There was a trust between government and the people and a hope for a better life for all. Paternalism was the order of the day.

Enter “Postmodernity”. Around the 70’s or 80’s it became apparent that the better life was not being realised by most. This evoked a radical reappraisal of modern assumptions about culture, identity, history, language, science and medicine. Postmodernism is characterised by relativism where there are no such things as objective facts and truth is elusive, polymorphous, inward and subjective. And who can blame a move from paternalism where the political “fathers” are corrupt and elite with little evidence in promoting the best interests of all. Within the medical sphere, there has been a turn from trust in scientific realm


numbers are excessive, herd immunity collapses, putting all at risk. Considering the above dynamics, what should be our ethical response to poor vaccination uptake by “refuseniks”, whether religious, ideological, misguided or simply, cowardly?

The strongest weapon against pseudo-science, scaremongering and fake-news is surely education. The veracity of the information should be impeccable. Education campaigns have had varying success in improving uptake. Generally, vaccine education is best given prior to the vaccine event and pregnancy offers a useful opportunity. Vaccine refusers are often resistant to education attempts and these attempts might even harden resistance. What is apparent is that ‘refuseniks’ uniformly display a lack of trust in healthcare authorities. They are apparently much less resistant to information provided by their usual caregivers (such as obstetricians, GPs & paediatricians) than information obtained from public health authorities and government. Targeted information campaigns have been useful where education of religious leaders may lead to changed attitudes in their “flock”. This recognises the importance of communalistic principles where the community takes charge of policies that affect the herd.

While the major pillar of principlism is autonomy, this too must be seen to have its limitations as succinctly noted by Oliver Wendell Holmes; “The right to swing my fist ends where the other man’s nose begins.” Various policies have developed around the world where incentives and

towards alternate answers to health problems. With regard to vaccines, there has been suspicion and hesitancy in uptake.

Those with vaccine hesitancy are not a uniform bunch but are influenced to varying degrees by the following: Knowledge and information, past experiences, perceptions of the importance of vaccination, perceptions of risk, social norms and religious and moral convictions. What unifies all these considerations is a strong adherence to consider what is good for me and mine (autonomy) and much less concern with the well-being and justice for the masses. Vaccine coverage can be considered to offer benefits to the individual, the community (or herd) and even the world (when we consider eradication of a disease). The ethical principles pertaining to these may be different and even oppose each other. The diagram above depicts, albeit simplistically, these positions.

The “beauty” of herd immunity is that if there are adequate numbers of immune individuals (? >90%), then a minority of unimmunised individuals can reasonably safely “hide in the herd”. This may be ethically ideal, if it allows some vulnerable immune-impaired individuals to be protected. This caring attitude may even be extended to a few children whose devout religious parents are incapable of giving consent. Surely, this privilege cannot be extended to so-called “free-loaders” who are not prepared to take the risks of immunisation but want to share in the benefits. It is also important to remember that relatively few individuals can “hide in the herd”. If the

By involving the community in decisions regarding their well-

being, it becomes possible that they “police” vaccine policy.

Appropriate non-recipients can then be condoned to

“hide in the herd”

Paternalism is the system most favoured by public

health authorities and could be entrenched by legal

compulsion. It denies the rights of individual

autonomy but is best for global eradication.

Autonomy guarantees individual rights but at the expense of community rights. It also

allows free-loaders to “hide in the herd”.

Autonomy

Public policy

Communalism Paternalism


or disincentives are applied so as to improve vaccine uptake. It makes absolute sense to separate the various vaccines in this regard, as each vaccine has unique features in administration, efficacy and adverse events. Australia provides an example of “positive” coercion where families are rewarded with cash payments during and after completion of the EPI. However, the quantum of these rewards is of necessity, relatively modest and can be disregarded by the wealthy. Other countries use “negative” coercion. Many states in the USA have legislation banning unvaccinated children from attending state schools or requiring that they do not attend when there are cases of VPDs. Some require that unvaccinated children must be home-schooled.

Compulsory vaccination can be ethically justified on the grounds that it is wrong to harm others by transmitting an infectious disease, especially if that disease is serious and potentially lethal. In France currently, vaccination against polio, tetanus and diphtheria are compulsory but by 2018 a total of 11 vaccines will be obligatory. The government of Italy approved making 12 vaccines mandatory, including measles, rubella and chickenpox, starting September 2017 for children attending Italian pre-schools through the second year of high school. Other required vaccines include tetanus, diphtheria, polio and hepatitis B. A firmer stance against ‘refuseniks’ has been implemented following measles outbreaks.

Finally, it is important to consider the response of caregivers to those patients who, despite education and encouragement, refuse vaccination. Nationally-representative surveys of paediatric providers in the USA indicate that 29% would dismiss a family who refused some vaccines and 40% would dismiss a family who refused all vaccines.3 But is this an ethical response? On the face of it, in simple deontological terms, the ethical response of the practitioner should always be to do what is right, regardless of the outcome. On the other hand, should a practitioner be complicit with an action by a surrogate towards and incompetent child, which may result in harm? Primum non nocere.

References1. Burnett RJ, von Gogh LJ, Moloi MH et al. A profile

of anti-vaccination lobbying on the South African internet, 2011-2013. SAMJ 2015; 105(11): 922-926.

2. Dube E, Laberge C, Guay M et al. Vaccine hesitancy; An overview. Hum Vaccin Immunother 2013; 9(8): 1763-1773

3. Buttenheim AM, Cherng ST & Asch DA. Provider dismissal policies and clustering of vaccine-hesitant families. Hum Vaccin Immunother 2013; 9(8): 1819-1824.

As a healthcare professional (HCP), you can effortlessly complete all your CPD compliance requirements on the SAMA accredited, Medical Practice Consulting (MPC) Online Education System, without having to leave the comfort of your own home or practice.

The MPC System provides a comprehensive CPD compliance solution that offers accredited CPD events, journals and courses, as well as industry leading CPD management services such as automatic issuing and secure storage of all your CPD certificates within the MPC CPD Manager.

What sets the MPC CPD Manager apart is its unique functionality that enables HCPs to elec-tronically submit your CPD activity records directly to the HPCSA at the click of the button when audited.

All this functionality is available at no cost on MPC.

Healthcare professionals can acquire CPD points with this newsletter by completing an online multiple-choice questionnaire on www.mpconsulting.co.za. All queries should be directed at [email protected] | 012 001 0452.

Register today on www.mpconsulting.co.za.


Event/Congress Date Venue Contact

3rd ICPCN Conference: Inspiration, Innovation, Integration

30 May - 2 June

Southern Sun Elangeni Hotel, Durban www.icpcnconference.org/en/home/

7th ICAN Congress 2018 8-11 July Century City Conference Centre, Cape Town www.icancongress.org/

ALLPAEDS 2018 29 August - 2 September

Century City Conference Centre, Cape Town

Claries [email protected] or 011 954 5753

34th World Congress of Internal Medicine (WCIM 2018) 18-21 October

Cape Town International Convention Centre, Cape Town

www.wcim2018.com

World Congress Of Audiology 2018 27-30 October

Cape Town International Convention Centre, Cape Town

www.wca2018.co.za

This congress calendar has been compiled from various sources and dates, venues and contact details are subject to change without notice. Please consult the relevant contact links to confirm all events.

Congress Calendar 2018

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