Antibiotic resistance, innovative treatment for heart failure, the role of the microbiome and novel approaches in cancer treatment were all topics addressed at the German Hospital Pharmacists’ (ADKA) Congress held in Mannheim in May 2015
Christine Clark PhD FRPharmS FCPP(Hon)
Politicians need help from hospital pharmacists in tackling the growing problem of antibiotic resistance and the German government supports the antibiotic stewardship initiative, Ingrid Fischbach (Secretary of State in the Ministry of Health) told pharmacists in her opening address to the conference. In addition, the government recognises that hospital pharmacists have an essential role in the preparation of individual doses, in promoting and ensuring medicines safety and in tackling the problems of counterfeit drugs, she said.
Hospital-acquired infections (HAIs) are a Europe-wide problem but many are avoidable and we should focus on “avoiding the avoidable”, according to Alexander Friedrich (Professor of Hygiene and Microbiology, University of Groningen, The Netherlands). Young patients, the elderly, pregnant and immunosuppressed patients are particularly vulnerable, he continued. The big five groups of facultative pathogens account for most HAIs. The five groups are methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), Clostridium difficile (C. diff) and multi-resistant gram-negative bacteria (MRGN), which are sub-divided into those that are resistant to four (4MRGN) and three (3MRGN) groups of antibiotics.
MRGNs pose a particular problem, said Professor Friedrich. Klebsiella pneumoniae is now resistant to third-generation cephalosporins, fluoroquinolones and aminoglycosides. Spread of the organisms results from colonisation of some individuals who have no evidence of disease. Some ‘supershedders’ have been identified, he said. The two most critical control measures are strict adherence to antibiotic usage guidelines to reduce selection pressure, and hand hygiene. Furthermore, in the current situation, specialist knowledge alone is not enough; what is now needed is the meta-competence of ‘theragnostics’ – a combination of therapeutics, diagnostic stewardship and infection prevention, he argued. Treatment must be personalised, real-time and targeted.
One element of proactive antibiotic stewardship is reducing the number of options on a sensitivity report. In his hospital, only six antibiotics are now reported, in place of the 21 reported in the past. Only the antibiotic team (‘A-team’) – comprising a pharmacist, an infectious disease specialist and microbiologist – has access to other agents, explained Professor Friedrich. An automatic email alert is sent after 48 hours of treatment to check whether an antibiotic prescription needs to be continued, changed or stopped. About a quarter continue and three quarters are changed or discontinued, said Professor Friedrich. It has been calculated that the return on investment for an A-team is about six – meaning that for every Euro spent about six Euros are saved.
Turning to the question of infection control, Professor Friedrich explained that this is not something that can be tackled on a single-hospital basis. Studies have shown that inter-institutional referrals of patients occur within wider healthcare networks and that, as a result, nosocomial pathogens tend to spread throughout the network. This means that infection control measures need to be implemented on regional basis, including all the centres in a network.
Rational antibiotic use
Antibiotic surveillance only provides top-line information but does not solve any problems – what is needed is local action, Winfried von Kern (Professor of Infectious Disease, University of Freiburg, Germany) told the audience. However, antibiotic stewardship, as defined in 2005 by MacDougall and Polk, improves patient outcomes, is cost-effective, reduces adverse reactions, and reduces antimicrobial resistance. It is not an activity that is confined to hospitals but applies to the country as a whole. In 2013, the German Society of Infectious Disease in conjunction with other bodies, including the German Society for Hospital Pharmacists (ADKA), published guidelines for achieving rational antibiotic use in hospitals. The document sets out the strategies for effective antibiotic stewardship and identifies the implications for practice. The most critical component is people with the required education and time to do the job, said Professor von Kern. The minimum requirement is one position for 500 beds; at this level, extra funding is not required because improving antibiotic use saves a great deal of money, he explained.
Pharmacists play a key role in antibiotic stewardship but overall there is a deficit of ‘experts’ in this field. Better education in the topic is required and a formal training course has now been developed and more than 200 experts were trained in the first phase. More have now been trained and a quarter of participants are pharmacists, Professor von Kern noted. The network of experts will need updates and refresher courses as times goes on, he added.
ARNI for heart failure
Currently heart failure is managed with ACE inhibitors, beta-blockers and diuretics but a recent trial using an angiotensin receptor-neprilysin inhibitor (ARNI), code-named LCZ696, appears to offer better outcomes. Martin Hug (Director of Pharmacy, University Hospital, Freiburg, Germany) presented the study as part of the Top Papers session. LCZ696 is a combination molecule made up of valsartan chemically combined with sacubitril. Valsartan is an ARB and sacubitril is a neprilysin inhibitor that increases the effects of natriuretic peptide. The multicentre trial, PARADIGM-HF,1 compared LCZ696 with an ACE inhibitor (enalapril) in 1000 centres in 47 countries. By 1260 days, approximately 40% of patients had reached the endpoint of cardiovascular death or hospitalisation for CCF. The results showed that LCZ696 reduced cardiovascular mortality and death to a greater extent than enalapril. In addition, there was less symptomatic hypotension with LCZ696 than with enalapril.
Another study of interest examined the evidence for effectiveness of cardiac glycosides in reducing mortality.2 A meta-analysis including more than 300,000 patients showed that among patients with atrial fibrillation and heart failure who are taking digoxin, the risk of mortality is always increased. As yet there is still no randomised, controlled trial that shows a beneficial effect of cardiac glycosides in atrial fibrillation, said Dr Hug.
Intimate kissing and the microbiome
Matthias Fellhauer (Director of Pharmacy, Schwarzwald-Baar Hospital, Villingen-Schwenningen, Germany) described how a study designed to answer the question, “Does the kiss profile influence the oral microbiota?” involved 21 sets of partners.3 One partner of each pair took a probiotic yoghurt containing streptococci, lactobacilli and bifidobacteria. Kiss frequency was recorded and saliva samples were collected. The results showed that the salivary microbiome is influenced by intimate kissing and the magnitude of effect declines rapidly. In order to have shared salivary organisms, a kiss frequency of more than eight per day is required or a time of less than one and a half hours after the last kiss, explained Dr Fellhauer. The researchers calculated that the rate of transfer of microorganisms during intimate kissing was 0.8 x 108 every 10 seconds.
Two important papers examined the outcomes of treatment for Clostridium difficile infection (CDI). A retrospective, case-control study compared the outcomes in patients who had been treated according to Infectious Disease Society of America (IDSA) guidelines and those who had been treated in a guideline-discordant manner.4 The results showed that patients who received guideline-directed treatment had significantly better outcomes with fewer complications and lower rates of reinfection and mortality. A systematic review and meta-analysis sought to quantify the effect of antibiotic stewardship on the incidence of CDI.5 The results showed that ABS programmes can reduce the risk of CDI by 52%. Beneficial positive effects were associated with restriction of usage of cephalosporins and fluoroquinolones and the effects were particularly marked for geriatric patients.
BiTE and ALL
BiTE technology could be the last hope for patents with refractory acute lymphoblastic leukaemia (ALL), according to Hans-Peter Lipp (Chief Pharmacist, University Hospital of Tübingen, Germany). BiTE stands for bi-specific T-cell engaging antibodies. An example is the drug blinatumomab – a monoclonal antibody that combines an anti-CD3 fragment with an anti-CD19 fragment. The anti-CD3 fragment binds to specific T-cells and the anti-CD19 fragment binds to tumour-specific CD19. Dr Lipp noted that CD19 is expressed earlier than CD20 during B-cell differentiation. When a tumour cell and a T-cell are linked in this way, the T-cell is activated to release cytotoxic proteins and the tumour cell is destroyed. A trial in patients with refractory ALL has produced better results than previous treatments. However, the use of the drug presents some challenges, explained Dr Lipp. It has to be given by continuous infusion over 28 days and costs more than €60,000 per cycle. The preparation of blinatumomab infusion involves adding a solution stabiliser to the carrier solution bag before adding the reconstituted drug.
A study showing that coffee consumption was associated with a reduction in the number of DNA strand breaks in leucocytes raised the possibility that components of roasted coffee could increase DNA repair capacity and therefore reduce the risk of certain cancers.6 A Norwegian study showed that there is an inverse relationship between the consumption of boiled coffee (but not non-boiled coffee) and the risk of prostate cancer.7
Handling of toxic drugs
Training and retraining of staff who manipulate cytotoxic drugs is essential because there are still people who do not understand the toxicity of cytotoxic drugs, according to Paul Sessink (CEO, Exposure Control AB, Sweden).
Cytotoxic drugs are spread in the environment during preparation, administration, patient care and waste handling. Studies in North America, Europe and Japan consistently identify environmental contamination. Now that sensitive analytical techniques have been developed that can identify picogram quantities, contamination is almost always found and the question of acceptable levels of contamination has arisen. Cyclophosphamide has been used a marker because it is highly toxic and penetrates skin easily. If cyclophosphamide solution is splashed on the skin, 80% of the drug will be absorbed within five minutes – there is no point in washing 10 minutes after a splash, said Dr Sessink. Studies have shown that if surface contamination with cyclophosphamide is below 0.1 nanograms/cm2, then no traces of cyclophosphamide can be detected in the urine samples taken from healthcare workers. In The Netherlands, reference values have been defined as follows: contamination (with cyclophosphamide) of less than 0.1 nanograms/cm2 is acceptable and annual monitoring is sufficient; levels between 0.1 and 10 nanograms/cm2 should be investigated and measures should be implemented to reduce contamination. If the level is above 10 nanograms/cm2, then work should stop until suitable measures to reduce contamination have been introduced.
Patients themselves can be serious sources of cytotoxic contamination. One study in Dutch hospitals found high levels of cyclophosphamide contamination in patients’ toilets and two studies had found high urine levels of cyclophosphamide in members of patients’ families. Dr Sessink suggested that patients (at home) should always use separate toilets, if possible, urinate in the seated position and flush toilets several times. They should also receive written guidance about minimising environmental contamination with cytotoxic drugs, he said.
Contamination of the working environment can be significantly reduced by the use of validated closed system transfer devices (CSTDs) such as BD PhaSeal, said Dr Sessink. Such devices need to be airtight and leak-proof and should prevent the escape of droplets and vapours. Once traces of cytotoxic drugs are in the environment they can be spread and so effective cleaning procedures are needed. Unfortunately, there is, as yet, no standard method. Wiping with alcohol is ineffective, emphasised Dr Sessink. Although it can disinfect surfaces it does not remove cytotoxic drugs.
Commercial products such Surface Safe (only available in the US and Canada) remove some, but not all, agents. Dr Sessink recommends the following procedure: wash with an alkaline detergent, rinse with water, wash with acidic detergent, rinse with water and then wipe with alcohol to disinfect.
McMurray JJ et al. Prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure. N Engl J Med 2014;371:993–1004.
Vamos M et al. Digoxin-associated mortality: a systematic review and meta-analysis of the literature. Eur Heart J 2015;36(28):1831–8.
Kort R et al. Shaping the oral microbiota through intimate kissing. Microbiome 2014;2:41.
Brown AT, Seifert CF. Effect of treatment variation on outcomes in patients with Clostridium difficile. Am J Med 2014;127:865–70.
Feazel LM et al. Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis. J Antimicrob Chemother 2014;69(7):1748–54.
Bakuradze T et al . Consumption of dark roast coffee decreases the level of spontaneous DNA strand breaks: a randomized, controlled trial. Eur J Nutr 2015;54:149–56.
Tverdal A. Boiled coffee consumption and the risk of prostate cancer: follow up of 224,234 Norwegian men 20–69 years. Br J Cancer 2015;112:576–9.