Bacteria and antibiotics – basic concepts
Infection occurs when microorganisms such as bacteria cause damage to body tissue. Infection can cause harm to a patient and may require treatment with antibiotics. Bacteria can grow on exposed body sites without causing infection, this is called colonisation. Colonisation is a normal process that begins when we are born and does not usually cause harm to a patient.
It is important to be aware of the different organisms that colonise different parts of the body to be able to predict what pathogens might be causing infection, and which empirical antibiotics to start if a patient presents with an active infection. For example, Staphylococcus aureus is a skin commensal (part of the skin microbiota) that can cause an infection when the skin barrier is broken.
Top tip: the normal flora of the body changes during hospital admission. This may prompt a change in choice of antimicrobials as some of these microorganisms are more likely to be resistant.
Antibiotics are broadly classified as either bacteriostatic (stop the reproduction and growth of bacteria) or bactericidal (kill the bacteria). Antimicrobial agents need to exhibit selective toxicity, where their target is not present or accessible in a human host.
Antibiotics and their targets.
Top tip: to overcome bacteria that produce beta-lactamase enzymes, some antibiotics that target the cell wall are often co-administered with beta-lactamase inhibitors, such as clavulanic acid or tazobactam.
Examples of combination antibiotics:
- Co-amoxiclav (Augmentin®) = amoxicillin + clavulanic acid
- Piptazobactam (Tazocin®) = piperacillin + tazobactam
- Co-trimoxazole (Septrin®) = sulfamethoxazole + trimethoprim
Author: Dr David McMaster
Starting an antibiotic
The diagnosis of infection is rarely certain. Instead, a patient should be considered as having a low, medium, or high probability of infection. In addition to a thorough history and relevant examination, diagnostic tests help improve the probability of a diagnosis and should be considered if they are indicated, and in relation to how easy, quick, expensive and practical they are to perform.
Common investigations that you will come across in clinical practice when diagnosing infection include haematology, biochemistry, radiology and microscopy, cultures and sensitivities (MC&S). Additional tests may be required in some circumstances, such as antigen detection, toxin detection and polymerase chain reaction (PCR) to detect nucleic acid.
Bacteria are unicellular microorganisms with key characteristics that allow them to be classified into groups, and with microscopy you can use a system of identifying the staining method, shape and growth requirements to help identify the pathogen before the culture results are available (usually 24-48 hours). This is particularly important in urgent life-threatening infections that require prompt antimicrobial treatment, such as meningitis and sepsis. Atypical bacteria cannot be stained or cultured in the normal way.
For example, a microbiological report of synovial fluid taken from an acutely hot, painful knee may report on microscopy ‘the cause is a Gram-positive cocci in clumps’. With this information, and the clinical findings you can begin to narrow down the likely organism and begin empiric antibiotic therapy (i.e., it is not suggestive of E. coli [Gram-negative] or Streptoccocus spp. [chain-forming]). Culture results will then confirm the diagnosis of Staphylococcus aureus, and the antibiotic sensitivities.
- Staining method
- Gram-positive: bacteria with a thick cell wall (made of peptidoglycan) that stains purple with crystal violet stain
- Gram negative: bacteria with a thin cell wall and a double membrane that stains red with a counterstain (e.g., safranin)
- Ziehl-Neelsen stain: bacteria with mycolic acid in the cell wall that stains red
- Bacillus: rod
- Coccus: sphere
- Growth requirements
- Aerobic: requires oxygen to grow
- Anaerobic: grows in absence of oxygen
- Facultative anaerobe: able to grow in presence or absence of oxygen
- Microaeorphilic: grows in presence of oxygen at lower concentrations that air
Bacterial classification of important clinical pathogens.
Selecting an antibiotic
Selecting the appropriate antibiotic is a step wise process:
- what is the working diagnosis?*
- which bacteria are likely to cause this infection?
- which antibiotics are effective against these bacteria? Antibiotic spectrum of activity
- which of these selected antibiotics have the right characteristics (e.g., can they be given orally; can the antibiotic get into the site of infection)?
- are there any contraindications or cautions for prescribing (e.g., allergy)?
*there is often time to make a diagnosis, however certain infections (e.g., sepsis, meningitis, encephalitis, epiglottitis) require urgent treatment, without waiting for investigation results.
Top tip: use your local empirical antimicrobial guidelines to select the most appropriate antibiotic, many of these guidelines can be found on the MicroGuide app.
Prescribing an antibiotic
- Antibiotic name (generic not specific product)
- Start date
- Frequency of dosing
- Stop date
- Signature/name/GMC number
Top tip: for children unable to swallow tablets, think about the taste of suspensions. Flucloxacillin is unpalatable so consider giving cefalexin!
Reviewing an antibiotic
All patients treated with antibiotics should have a daily review where you consider:
- is the patient improving?
- can you convert the antibiotics from IV to oral?*
- are microbiology results available, and can a broad to narrow switch be made?
- are antibiotic levels needed (and are they within range)? (e.g., vancomycin, gentamicin)
- are renal and liver function stable?
- can the antibiotics be stopped?
*Generally, all patients should be switched from IV to oral antibiotics within 48 hours if they can swallow and tolerate fluids. Switching to oral antibiotics reduces the risk of device related infection and length of hospital stay. Some conditions (e.g., meningitis) will require continuation of IV antibiotics, however, also consider the use of outpatient parenteral antimicrobial therapy (OPAT). These teams manage the delivery of IV antibiotics to patients who are medically stable, within their own homes.
Top tip: durations given in guidelines generally refer to the total intravenous plus oral treatment (see McMullan et al. Lancet Infectious Diseases; 2018).
Antibiotic prophylaxis may be required to prevent infection, this may be primary prophylaxis (e.g., before surgery) to prevent initial infection, or secondary prophylaxis (e.g., post-splenectomy) to prevent recurrent infection. Surgical antibiotic prophylaxis should be given within an hour before surgery. There is good evidence to suggest that surgical prophylaxis offers no benefit beyond a single dose given prior to ‘knife to skin’ for most surgical procedures.
Author: Dr David McMaster & Dr Sanjay Patel (Paediatric Infectious Diseases Consultant, Southampton)
Misuse of antibiotics leads to antibiotic resistance. Common mistakes include:
- Prescribing without evidence of infection
- Prescribing antibiotics that do not cover the infection
- Incorrect dosing/duration
- Not modifying prescriptions when microbiology results are available
Resistance to antimicrobials is an increasing problem worldwide. Exposure to antibiotics selects for resistant organisms, both in circulating pathogens and within the human microbiota. Resistance determinants, and genes for resistance to different antibiotics are often easily transmitted from normal flora to pathogenic bacteria on mobile genetic elements. Once resistance occurs, infections become very difficult to treat. Examples you may encounter include Methicillin-Resistant Staphylococcus Aureus (MRSA), Extended Spectrum Beta Lactamase (ESBLs) producing Gram-negative bacteria, Carbapenemase-Producing Enterobacterales (CPE) and Vancomycin-Resistant Enterococci (VRE).
MRSA is Staphylococcus aureus bacteria that has become resistant to beta-lactam antibiotics and is a widespread problem in many healthcare settings. Susceptibility testing is needed to diagnose MRSA, and treatment usually requires a glycopeptide (e.g., vancomycin).
ESBL producing Gram-negative bacteria have developed resistance to beta-lactam enzymes. ESBL producing bacteria include Klebsiella and E. coli, often causing urinary and respiratory tract infections. ESBLs confer resistance to 3rd generation cephalosporins (e.g., ceftriaxone) as well as piperacillin-tazobactam, and are frequently linked to resistance to other classes of antibiotics, making them very difficult to treat. They often require treatment with ultrabroad spectrum antibiotics such as carbapenems (e.g., meropenem).
Top tip: resistance rates vary markedly throughout the world, particularly in resource-scarce environments where with limited antibiotic formularies, options to treat multi-drug resistant bacteria quickly run out. Active surveillance for antibiotic resistance is essential to inform policy makers on how to prevent resistance rates from increasing. In Europe a number of organisations collect, collate and publish comparative resistance data: Surveillance Atlas of Infectious Diseases.
This animation has been funded by Merck Sharp & Dohme (MSD) but its content has been entirely produced by healthcare professionals with no input from the pharmaceutical industry.
Author: Dr David McMaster & Dr Sanjay Patel (Paediatric Infectious Diseases Consultant, Southampton)
Antimicrobial stewardship (AMS) is a set of actions which promote judicious use of antimicrobials (i.e., maximising their potential benefits whilst reducing risk from antimicrobial resistance (AMR), side effects and other adverse events such as development of healthcare associated infections). AMS is a key component in the global strategy to slow down the development of AMR, a major global health issue and a significant threat to human health.
Antibiotics should be avoided unless there are clear clinical indications for their use. Broad-spectrum antibiotics (e.g., cephalosporins, fluoroquinolones, co-amoxiclav, piperacillin-tazobactam) have been most associated with the selection of antimicrobial resistant bacteria, including extended-spectrum beta-lactamase (ESBL)-producing Gram-negative bacteria, Methicillin resistant Staphylococcus aureus (MRSA) and the induction of Clostridioides difficile (C. diff) infection.
In practice, when deciding whether or not to prescribe an antimicrobial, take into account the risk of antimicrobial resistance for individual patients and the population as a whole.
- If immediate antimicrobial prescribing is not the most appropriate option, consider:
- self-care with over-the-counter preparations of the narrowest spectrum antimicrobials
- back-up (delayed) prescribing
- other non-pharmacological interventions (e.g., draining site of infection)
- If an antimicrobial is needed (antibiotics should be started when the benefits of starting are greater than the disadvantages), follow local (where available) or national guidelines on:
- prescribing the shortest effective course
- the most appropriate dose
- route of administration*
*intravenous (IV) antimicrobial prescriptions should be reviewed at 48-72 hours in all healthcare settings. Include response to treatment and microbiological results in any review to determine if antimicrobial needs to be continued and, if so, whether it can be switched to an oral administration. Due to advances in rapid diagnostics, it may be possible to review prior to 48 hours after first dose.
AMS Treatment Algorithm – Start Smart Then Focus. Available at: https://www.gov.uk/government/publications/antimicrobial-stewardship-start-smart-then-focus
National toolkits that support the implementation of antimicrobial stewardship include the Royal College of General Practitioners’ TARGET Antibiotics Toolkit for primary care, and Public Health England’s Start Smart – Then Focus for secondary care. The World Health Organisation has also developed a framework based on three different categories for antibiotics – Access, Watch and Reserve – which together forms the AWaRe tool.
Author: Keep Antimicrobials Working steering group
Targeted laboratory investigations will help narrow your differentials for a patient with suspected infection. If investigations are performed promptly at the initial presentation, results will likely be available 24-72 hours later, allowing you to review and amend the management as appropriate (Start Smart then Focus).
Top tip: treat the patient, not investigation results, especially if they don’t fit the clinical picture. When interpreting results, ask yourself, is this consistent with the diagnosis? Investigations can support a diagnosis but should never make the diagnosis.
Full blood count
- White blood cell (WBC) count
- Neutrophils usually increase in bacterial infections – but beware of low neutrophil count in severe sepsis
- Lymphocytes may increase in viral infections
- Eosinophils may increase in parasitic infection
- Platelets – acute phase reactant, may rise in infection – but beware of low platelet count in severe sepsis
- International Normalised Ratio (INR) – may increase in sepsis and invasive group A Beta-haemolytic Streptococcus infection
- Erythrocyte sedimentation rate (ESR) may rise in inflammatory conditions (however not specific for infection)
Urea and electrolyte profile
- Raised urea is a prognostic marker in severe pneumonia (CURB-65 score)
- Rises in inflammation – peak 24-48 hours after onset and fall in response to antibiotics takes a minimum 24-48 hours
- Rises in bacterial infection – peak after 12 hours
Top tip: no laboratory marker is uniquely specific to infection, interpret results in the context of the patient.
Example clinical pathology report of suspected bacterial infection. Reference ranges for tests vary, you should refer to the ranges your laboratory provides when interpreting results.
Samples should be taken from the affected body site (e.g., sputum, urine, synovial fluid, cerebrospinal fluid) for the best chance of identifying a causative organism before starting antimicrobials. During the request, state any antimicrobial therapy that patient is on or which you intend to start, and the laboratory can ensure the appropriate antibiotic sensitivities are released.
- Identifies appearances of microorganism, see Starting an antibiotic tab – beware that prior antibiotic use may alter Gram stain appearance
Culture and sensitivity
- Identifies microorganisms that have grown and susceptibilities of antibiotics, see Starting an antibiotic tab
- Biochemical tests help identify cultured organisms by assessing an organism’s ability to use different substrates, or the presence of certain enzymes (e.g., coagulase/catalase/oxidase)
Example microbiology report of a suspected septic arthritis.
To test how susceptible bacteria is to an antibiotic, we determine the minimum amount of antibiotic that stops the bacteria from growing, the Minimum Inhibitory Concentration (MIC). This can be done by culturing the bacteria in the presence of an antibiotic and determining whether the MIC is above a predetermined ‘breakpoint’ level. Above a certain MIC, bacteria is labelled as resistant (R) to an antibiotic, below a certain MIC value bacteria is labelled as sensitive (S) to an antibiotic.
Susceptibility testing allows us to switch to narrow spectrum agents, and also helps provide epidemiological data to inform local antibiotic and infection prevention and control policies, as well as public health surveillance.
Top tip: most microbiology laboratories will now identify organisms using matrix-assisted laser desorption ionization-time of flight (MALDI-TOF). This uses mass spectroscopy to detect proteins of different masses in a culture specimen to create a signature which is then compared to reference libraries of bacteria and fungi. This improves time from sampling to identification in many cases.
If culture methods are not appropriate, for example where the organism cannot be easily grown in culture (e.g., Rickettsia, mycoplasma, viruses) serology can be used to look for evidence of infection by detecting antibodies.
- Rapid result detecting small parts of infecting microorganism, or molecules from infected cells
- Rapid result detecting patient’s response to infection. Interpretation can be complex, but broadly IgM suggests acute/recent infection (however may be present in other conditions that stimulate the immune system), whereas IgG suggests immunity/past infection
- Beware cross reactivity, for example infection with one virus causing a low-level positive IgM in another (e.g., HIV/EBV/CMV). Other inflammatory conditions (and pregnancy) may also cause false positive results
- Rapid result detecting small parts of infecting microorganism, or molecules from infected cells
Top tip: Enzyme immunoassays (e.g., ELISA – enzyme-linked immunosorbent assay) use antibodies linked to enzymes to detect bacterial antigens or antibacterial antibodies.
Molecular tests – Nucleic acid detection
- Most commonly done using polymerase chain reaction (PCR) to detect microorganism by multiplying DNA or RNA allowing for detection of minute traces of microorganism
- Quantitative methods for nucleic acid detection for an increasing number of infections are now being used including hepatitis B, hepatitis C, CMV and HIV. These allow measurement of viral load and can be used to monitor disease progression/response to treatment
- As well as viruses/fastidious organisms, PCR using targets from bacterial (16S) and fungal (18S) ribosomes can be used to try to detect infection in samples which are culture negative, for example where sampling has occurred post antibiotic administration
Top tip: whole-genome sequencing (WGS) provides information into the genetic basis of bacteria, resistance mechanisms and pathogen evolution. WGS is now being used to develop novel antibiotics, and support surveillance of antimicrobial resistance. The WHO’s Global Antimicrobial Resistance and Use Surveillance System (GLASS) was set up to manage this surveillance and monitors several ‘priority pathogens’ to provide information on early emergence and spread of resistance.
Rapid diagnostic tests
Rapid diagnostic testing may include any of the above techniques, employed in a novel way where the result is delivered more quickly than traditional methods. This may be within the laboratory or in the clinical/near-patient setting (point-of-care). Examples you may encounter include rapid PCR platforms which can deliver results from sampling in often less than an hour, and point-of-care lateral flow testing devices (e.g., for COVID-19).
Top tip: the Xpert® MTB/RIF assay for the detection of Mycobacterium tuberculosis uses an integrated miniature PCR system to obtain results from unprocessed sputum samples within 90 mins, dramatically reducing time to diagnosis when compared to culture based techniques.
As an antimicrobial stewardship intervention, key questions that rapid diagnostics could help answer at the point-of-contact include:
- Differentiating between bacterial or viral infections and reducing antibiotic prescriptions
- Rapidly identifying causative bacteria to allow focused antibiotic therapy
- Identifying bacterial resistance mechanisms to give predicted sensitivity profiles
Knowing these answers allows a clinician to reach the optimal treatment quickly, reducing the risk of misuse of antimicrobials, and as a result rapid diagnostic tests at the point-of-care are becoming more widely used.
Top tip: it is important that quality assurance remains in place to ensure the result is not only quick, but accurate. This can be challenging when testing is taken outside of the controlled laboratory setting. There may be a degree to which accuracy is knowingly compromised for a faster result, and this must be factored into any decision making. For example, when non-molecular rapid tests (e.g., lateral flow for SARS-CoV-2) are used, be aware of the sensitivity and specificity of the test you are using when interpreting the result!
Author: Dr David McMaster & Dr Owen Seddon (Consultant in Microbiology and Infectious Diseases, Public Health Wales)
Infection prevention and control
The World Health Organisation (WHO) defines infection prevention and control (IPC) as a practical, evidence-based approach which prevents patients and health workers from being harmed by avoidable infection and as a result of antimicrobial resistance. Good infection control can reduce and prevent hospital acquired infections; in hospitals in England between 2006 and 2014 there was an 18-fold reduction of MRSA bloodstream infections (from 1.2% to <0.1%) due to increased awareness and implementation of infection control procedures.
1. Hand hygiene is the most effective way to prevent the spread of infection. Decontamination of hands involves the appropriate use of soap and water, antiseptic wash or alcohol hand rub solution. Hands must be decontaminated at critical points before, during and after patient care. This includes on arrival and when leaving a ward (and isolation cubicle), before and after touching a patient and their surroundings, before and after aseptic non-touch technique (ANTT) and after removing personal protective equipment.
World Health Organisation (WHO) 5 moments for hand hygiene. Available at: https://www.who.int/gpsc/5may/Your_5_Moments_For_Hand_Hygiene_Poster.pdf
Top tip: when caring for patients with known infectious diarrhoea (e.g., C. difficile/norovirus) and/or visibly soiled hands, alcohol hand rub alone is not sufficient, hand washing with liquid soap is essential.
2. Dress code is standard practice across most healthcare settings. At a minimum, to prevent the spread of infection healthcare workers should be bare below elbow (e.g., no watches), have short clean nails and not wear stoned rings.
3. Personal protective equipment (PPE)
Apron, non-sterile gloves and mask must be worn when within 2 metres of a patient with a respiratory tract infection, or in contact with respiratory secretions or other infectious material of contaminated surfaces. In addition,
- Gloves and apron are for single patient use, remove as soon as clinical activity is completed
- Use FFP3 mask (fit-tested) if performing an aerosol generating procedure (e.g., intubation) on a patient with a respiratory tract infection, *or with patient with known/suspected COVID-19 infection*
- Use eye protection when there is an increased risk of splashing body fluids, or with a patient with persistent coughing and/or sneezing
- Use sterile gloves (and gown) for ANTT if touching key sites/key parts (e.g., urinary catherisation/central line)
4. Aseptic Non-touch technique (ANTT) is the procedure to ensure that devices, sterile areas and wounds are not contaminated. It is important to wash hands, use gloves and to identify ’key parts’ that must not be contaminated in a procedure.
ANTT procedure guidelines. Available at: https://link.springer.com/chapter/10.1007/978-3-030-03149-7_11
5. Urinary catheters
Urinary infections account for 17.2% of all hospital acquired infections, the majority of these are associated with urinary catheterisation. The following should be considered in all patients with/needing a urinary catheter:
- Does the patient need a catheter? Many can be removed and documentation is key if it remains to ensure that it is reviewed
- Hand hygiene is critical before touching a catheter and gloves must be worn
- During insertion, clean the meatus according to local guidance and use a lubricant from a single use container
- Avoid breaking the connection between the catheter and the collecting system, do not let the collecting system touch the floor and empty if the bag is full
6. Vascular access
Cannulas are very commonly the source of MSSA and MRSA bacteraemia. Always wash hands before inserting or accessing a medical device. Use gloves. On insertion decontaminate the skin with 2% chlorhexidine in 70% alcohol for 30 seconds and allow to dry for 30 seconds. On access, decontaminate an access port or hub with a 2% chlorhexidine in 70% alcohol single use applicant.
Top tip: review the need for vascular access daily.
Infection control prevents the spread of infections within healthcare environments, and isolation of patients is essential to preventing outbreaks of infectious diseases. Isolation refers to both protective isolation to prevent vulnerable patients from contracting infection, and source isolation to prevent other patients and staff from spreading/contracting infection. If there are not enough cubicles, prioritise the most easily transmissible and pathogenic infections. If unsure, consult with your Infection Prevention and Control Team (IPCT).
Top tip: some patients with transmissible infectious diseases require negative-pressure rooms to prevent airborne microorganisms leaving the area, whereas some vulnerable patients (e.g., immunodeficient) require positive-pressure rooms to prevent airborne microorganisms entering the room.
8. Outbreak is defined as two (or more) cases of infection linked in time or place, or a single case for certain rare diseases (e.g., viral haemorrhagic fevers). Outbreaks may result from a break down in infection control procedures
Top tip: when outbreaks occur pathogens may commonly be found in places of high contact (e.g., door handles and computer keyboards) often denoting a breakdown in hand hygiene.
9. Root cause analysis (RCA) is the process an event can be evaluated to generate recommendations and learning points to avoid the event happening again. You may encounter RCA in practice following cases of MRSA bacteraemia and C. difficile associated disease or outbreaks.
Author: Dr David McMaster & Dr Ashley Price (Consultant in Infectious Diseases, Newcastle)
Vaccines have saved millions of lives worldwide by preventing deadly infections. They also play an important role in preventing the development and spread of AMR and reducing antibiotic use. Like infection prevention and control, vaccination is a preventative approach to AMR. The UK government has included the development of, and access to, vaccines as part of the UK’s five-year national action plan against AMR.
Vaccines contribute to fighting AMR by:
- Directly preventing the infection, colonisation, and transmission of drug-resistant organisms
- Reducing the occurrence of symptomatic infections that result in antibiotic use
- Preventing secondary infections
Vaccines can prevent drug-resistant infections which are harder-to-treat and may require longer hospitalisation time, longer duration on antibiotics, and the use of second-line antibiotics classed within the ‘Watch’ or ‘Reserve’ categories, as per the WHO AWaRe (Access, Watch and Reserve) categorisation. Vaccines recognise antigens on the pathogens that are independent from the genetic determinants of resistance, so vaccines are generally equally effective against sensitive and resistant forms of the target pathogen. Herd immunity will further reduce transmission of drug-resistant pathogens within the population.
Vaccines also reduce the demand for, and use of, antibiotics. This is true for vaccines against bacteria, and for vaccines against pathogens that are not resistant themselves, such as viruses. Any pathogen (bacterial, fungal, or viral) that causes symptoms such as fever, cough or diarrhoea could lead the patient or their guardian to present to a healthcare professional. When faced with such symptoms, clinicians can find it challenging to distinguish a viral from a bacterial aetiology, and as a result patients may unnecessarily receive antibiotics, especially when stringent antimicrobial stewardship approaches are not followed. This misuse of antibiotics will unfortunately select for resistant organisms, both in circulating pathogens and within the human microbiota.
Secondary infections with bacterial pathogens are common following viral infections such as influenza. Secondary infections can be avoided when the patient has been vaccinated against the cause of the primary infection, or the common causes of secondary bacterial infections such as pneumococcus. Notably, there are currently no vaccines available against the other common causes of secondary bacterial infections, such as Staphylococcus aureus and non-typeable Haemophilus influenzae.
Top tip: frontline healthcare workers are recommended to get a yearly influenza vaccine. This will help fight AMR by reducing the spread of influenza to patients who may develop symptomatic infections, seek antibiotics, or develop secondary infections that may be drug-resistant and/or require antibiotics.
Vaccines for Haemophilus influenzae type b (Hib), pneumococcal disease, influenza, rotavirus, measles, and typhoid are all thought to be important in preventing the development and spread of AMR. Studies have shown that use of the pneumococcal vaccine (PCV10 and PCV13) reduces the incidence of drug-resistant invasive pneumococcal disease and other diseases such as otitis media that require antibiotic treatment. Studies have also shown that the influenza vaccine can reduce the number of healthcare visits and antibiotic prescriptions. However, vaccines only work when they are given to patients and the uptake of vaccines could be improved in the UK, especially for older adults.
Top tip: it is important that patients receive all recommended vaccines throughout their life-course to protect themselves and the population from infection and antimicrobial resistance. The UK immunisation schedule can be found in The Green Book. Older adults (65 years and older) should be routinely offered the influenza vaccine every year and the pneumococcal vaccine if they have not previously received it.
Dr Elizabeth Klemm (Senior Research Advisor – vaccines group, Wellcome Trust)