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1.3C: Immunization, Antiseptics, and Antibiotics - Biology

1.3C: Immunization, Antiseptics, and Antibiotics - Biology


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Understanding microbes gives us the ability to fight pathogens using immunization, antiseptics, and antibiotics.

Learning Objectives

  • Compare immunization, antiseptics and antibiotics, and how they are used to combat human pathogens

Key Points

  • Immunization is the fortification of our own immune system, priming it against potential future infections by specific microbes.
  • Antiseptics are broadly defined as substances we can use on our body or surfaces around us to slow or kill microbes that could potentially harm us.
  • Antibiotics, like antiseptics, can slow or kill microbes. However, unlike antiseptics, antibiotics can circulate in the human blood system and be used to fight microbial infections.

Key Terms

  • anaphylactic shock: A severe and rapid systemic allergic reaction to an allergen, constricting the trachea and preventing breathing.
  • immunogen: any substance that elicits a immune response; an antigen

Surprisingly, most microbes are not harmful to humans. In fact, they are all around us and even a part of us. However, some microbes are human pathogens; to combat these, we use immunization, antiseptics, and antibiotics.

Immunization is the process by which an individual’s immune system becomes fortified against an agent (known as the immunogen ).

When the immune system is exposed to molecules that are foreign to the body, it will orchestrate an immune response. It will also develop the ability to respond quickly to subsequent encounters with the same substance, a phenomenon known as immunological memory. Therefore, by exposing a person to an immunogen in a controlled way, the body can learn to protect itself: this is called active immunization.

Vaccines against microorganisms that cause diseases can prepare the body’s immune system, thus helping it fight or prevent an infection. The most important elements of the immune system that are improved by immunization are the T cells, the B cells, and the antibodies B cells produce. Memory B cells and memory T cells are responsible for the swift response to a second encounter with a foreign molecule. Through the use of immunizations, some infections and diseases have been almost completely eradicated throughout the United States and the world. For example, polio was eliminated in the U.S. in 1979. Active immunization and vaccination has been named one of the “Ten Great Public Health Achievements in the 20th Century. ”

By contrast, in passive immunization, pre-synthesized elements of the immune system are transferred to a human body so it does not need to produce these elements itself. Currently, antibodies can be used for passive immunization. This method of immunization starts to work very quickly; however, it is short-lasting because the antibodies are naturally broken down and will disappear altogether if there are no B cells to produce more of them. Passive immunization occurs physiologically, when antibodies are transferred from mother to fetus during pregnancy, to protect the fetus before and shortly after birth. The antibodies can be produced in animals, called ” serum therapy,” although there is a high chance of anaphylactic shock because of immunity against animal serum itself. Thus, humanized antibodies produced in vitro by cell culture are used instead if available.

In early inquiries before there was an understanding of microbes, much emphasis was given to the prevention of putrefaction. Procedures were carried out to determine the amount of agent that needed to be added to a given solution in order to prevent the development of pus and putrefaction. However, due to a lack of understanding of germ theory, this method was inaccurate. Today, an antiseptic is judged by its effect on pure cultures of a defined microbe or on their vegetative and spore forms.

Antiseptics are antimicrobial substances that are applied to living tissue to reduce the possibility of infection, sepsis, or putrefaction. Their earliest known systematic use was in the ancient practice of embalming the dead. Antiseptics are generally distinguished from antibiotics by the latter’s ability to be transported through the lymphatic system to destroy bacteria within the body, and from disinfectants, which destroy microorganisms found on non-living objects. Some antiseptics are true germicides, capable of destroying microbes (bacteriocidal), while others are bacteriostatic and only prevent or inhibit bacterial growth. Microbicides that destroy virus particles are called viricides or antivirals.

An antibacterial is a compound or substance that kills or slows down the growth of bacteria. The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, the term “antibiotic” has come to denote a broader range of antimicrobial compounds, including anti-fungal and other compounds.

The word “antibiotic” was first used in 1942 by Selman Waksman and his collaborators to describe any substance produced by a microorganism that is antagonistic to the growth of other microorganisms in high dilution. This definition excluded substances that kill bacteria but are not produced by microorganisms (such as gastric juices and hydrogen peroxide). It also excluded synthetic antibacterial compounds, such as the sulfonamides. Many antibacterial compounds are relatively small molecules with a molecular weight of less than 2000 amu. With advances in medicinal chemistry, most of today’s antibacterials are semisynthetic modifications of various natural compounds.


Prevention of infection among patients with cancer

Recognition of the alterations of host defense allows a rational approach to preventing associated infections. One of the most effective strategies for preventing infection in the granulocytopenic patient is the combined use of oral non-absorbable antibiotics, laminar air-flow room reverse isolation with strict housekeeping techniques, low microbial diet, sterile water, and topical antiseptics and antibiotics. The prohibitive cost, however, warrants that this system be restricted to research settings. The suppression of aerobic Gram-negative bacilli and fungi and the preservation of colonization resistance with such combinations as trimethoprim-sulfamethoxazole and nystatin show promise in preventing infection in the granulocytopenic patient. Prevention of infection in neutropenic patients also requires attention to simpler but very effective measures such as immunizations, antimicrobial prophylaxis against intracellular and nonbacterial pathogens in high-risk patients, limiting invasive diagnostic and monitoring procedures, hand-washing by all personnel between visiting patients, oral hygiene, low microbial diets, axillary and perianal swabbing, and care with venipunctures and marrow aspirates. Finally, while the recommendations for prevention of infection are likely to continue to change with resulting improvement in patient care [92, 93], a tabulation summarizing current practices can be established based on our current knowledge (Table 1).


What to know about antiseptics

Antiseptics, or skin disinfectants, are chemicals for cleaning the skin and wounds. They can kill or prevent the growth of microorganisms.

Although antiseptics can be very useful, there are some questions around their safety for topical use, especially in the long term.

Keep reading for more information about antiseptics, including the types available, their uses, and current safety concerns.

Share on Pinterest Antiseptics can help prevent the growth of microorganisms on the skin.

Antiseptics are chemicals that people apply to the skin. They can reduce the number of microorganisms living on the skin, in wounds, and in mucous membranes.

Different types of antiseptic vary in cost, effectiveness, uses, and potential side effects.

Healthcare workers often use antiseptics before carrying out medical procedures, such as drawing blood and performing surgery.

Antiseptics are also available over the counter for cleaning and treating minor cuts. Some may also be suitable as a substitute for soap.

People can use antiseptics to clean areas of broken skin, intact areas of skin, and mucous membranes.

Disinfectants, antibacterials, and antibiotics have similar but slightly different purposes. The sections below will outline these differences in more detail.

Disinfectants vs. antiseptics

People use antiseptics, such as peroxides, to kill microorganisms on the skin and mucous membranes. Whereas antiseptics destroy certain germs on the skin, disinfectants can remove them from objects.

Disinfectants and antiseptics are both made from chemicals. In fact, they often share similar active ingredients. However, disinfectants tend to have higher concentrations, which are not suitable for use on the skin or mucous membranes.

Antibacterials vs. antiseptics

Antibacterials are also chemicals that people can use to clean areas of the skin. Soaps and sprays often contain antibacterials.

Antibacterial sprays are effective in killing or slowing the growth of bacteria. They do not kill or prevent viruses from growing, however.

By contrast, antiseptics can kill or prevent the growth of viruses, bacteria, and fungi.

Antibiotics vs. antiseptics

Antibiotics are a type of prescription medication that can treat bacterial infections.

Both antiseptics and antibiotics can treat bacterial infections. People can apply both types to the skin or mucous membranes.

However, a person can also take antibiotics orally, to treat a variety of infections inside the body.


How Do Antibiotics And Vaccines Affect Nature?

What are the connections between the responses of nature to the ways humans have used vaccines and the ways they have used antibiotics? originally appeared on Quora: the place to gain and share knowledge, empowering people to learn from others and better understand the world.

Answer by Suzanne Sadedin, Ph.D. Evolutionary Biology, Monash University, on Quora:

Antibiotics and vaccines are in some ways opposites. Antibiotics kill indiscriminately, whereas vaccines are highly targeted. Antibiotics are used to treat severe infection, whereas vaccines prevent infections from ever becoming established. And antibiotics are based on defenses that evolved in microbes, to protect them from bacteria they are not a natural defense for us, and our bodies are not adapted to cope well with them. Vaccines, in contrast, simply invoke the human body’s natural long-term defense systems, and are therefore far less invasive.

How does nature respond to antibiotics?

Antibiotics create selective pressure on a wide range of bacteria wherever they are used. Humans naturally host large numbers of bacteria. These are essential to our health and killing them off repeatedly risks many long-term health problems, including immune disorders, damage to the gut, and increased vulnerability to infections.

In addition, when you use antibiotics, you put all these bacteria under selection to resist antibiotics. Worse, since antibiotics are often excreted intact, low concentrations of antibiotics are now found in water supplies everywhere , creating a perfect environment for bacteria in general to evolve resistance. Bacteria exchange genetic material with other strains of bacteria, especially via plasmids. So once a mechanism to resist an antibiotic evolves in one strain, we can expect it to spread to many different strains — including those that cause severe disease.

In recent years, plasmids have been found in Africa that confer resistance both to multiple antibiotics and a common disinfectant. Salmonella bacteria with these plasmids are now a major cause of mortality among African children. As one expert commented : “It’s almost designed by nature to be the perfect solution to man’s attempt to treat with antibiotics.”

But resistance isn’t the only effect. Antibiotic treatments commonly kill almost all the bacteria, leaving only a few survivors. This is called an evolutionary bottleneck and its result is genetic drift. That is, the few survivors, apart from being resistant, may be quite random, so the genetic composition of the population can change rapidly, causing it to evolve in new and unpredictable directions — including increased pathogenicity.

So: the long term expected effect of antibiotics is that (1) antibiotics create resistant strains of pathogenic bacteria (2) antibiotics can create strains that are either more or less severe than the parent strain (3) by wiping out natural biota, antibiotics put us at risk of long-term health problems.

How does nature respond to vaccines?

Vaccines create selective pressure only on the specific infection they target. Due to herd immunity, even some people who cannot be vaccinated receive some protection from widespread use of vaccines (provided everybody else does the right thing). In addition, since vaccines prevent the target replicating at all in the host, they create no bottleneck. In fact, as hosts become more rare, the pathogen is under selection to lie low and avoid harming its host, because it may be a long time before it can spread to a new host. Also, the vaccine does no harm to normal human biota, and therefore does not significantly disrupt the gut, immune system or any other part of the body.

So: the long-term expected effect of vaccines is that (1) vaccines do not affect the evolution of non-targeted strains (2) vaccines cause the targeted strain to evolve to become less severe (3) vaccines are one of the safest medical interventions.

Comparison of long term expected effects on…

…evolution of resistant strains: Antibiotics — yes, including non-targeted strains. Vaccines — do not create resistance.

…evolution of disease severity: Antibiotics — unpredictable. Vaccines — make diseases less severe.

…health of treated people: Antibiotics — harmful (but hopefully less so than the infection they treated). Vaccines — harmless.

…health of untreated people: Antibiotics — none or harmful. Vaccines — beneficial.

Both antibiotics and vaccines are wonderful inventions. They have saved countless lives and spared humanity immense misery. I don’t think current generations can even imagine what life was like without them. Vaccines are vastly preferable to antibiotics we should use vaccines freely, and antibiotics only when necessary.

This question originally appeared on Quora - the place to gain and share knowledge, empowering people to learn from others and better understand the world. You can follow Quora on Twitter, Facebook, and Google+. More questions:

Quora: the place to gain and share knowledge, empowering people to learn from others and better understand the world.


Which Antibiotics Are Most Associated with Causing Clostridium difficile Diarrhea?

Clostridium difficile (C difficile) is responsible for 20-30% of antibiotic-associated diarrhea cases and is the most common cause of infectious diarrhea in the healthcare setting. 1 Over the past decade, the overall incidence rate of C difficile has increased, outbreaks of virulent strains have been identified (such as the NAP1/BI/027), and the risk of community-acquired C difficile has become more common. 2 Given that any antibiotic may theoretically increase the risk of C difficile infection, are certain antibiotics more associated with this risk than others?

Non-Modifiable Risk Factors for C difficile Infection

The Infectious Diseases Society of America (IDSA) guidelines clearly outline that the most significant risk factor for C difficile infection is older age, particularly in those 65 years of age and older. 1 In addition, hospitalization and duration of hospitalization are also 2 significant risk factors for C difficile infection. While it is important to recognize that age and hospitalization are risk factors, these cannot be modified to reduce a patient’s risk of infection.

Antibiotics: the Most Important Modifiable Risk Factors for Infection

Nearly any antibiotic is capable of disrupting the normal gut microflora, which can allow for C difficile to flourish and produce toxin. 1 Surprisingly, even single doses of antibiotics for surgical prophylaxis have been associated with an increased risk of C difficile infection. In general, a longer antibiotic duration and multiple antibiotics (versus a single antibiotic) are 2 risk factors that increase the risk of antibiotic-associated C difficile diarrhea. Aside from these 2 standard antimicrobial stewardship principles, the IDSA guidelines are relatively silent regarding specific antibiotic drugs or drug classes that may carry a higher risk of C difficile infection.

Multiple studies have been conducted to assess the comparative risk of different antibiotics for C difficile infection. 3-5 Although there is heterogeneity in the studies available, multiple meta-analyses have concluded similar findings regarding which antibiotic classes are at the highest risk for C difficile infection.

Antibiotic Classes with Highest Risk of C difficile (odds ratio 5 or more)

Without a doubt, clindamycin carries the highest risk of C difficile infection with an odds ratio of about 17-20 compared to no antibiotic exposure. 3-5 Fluoroquinolones, cephalosporins, aztreonam, and carbapenems carry a fairly high risk, all of which being associated with an odds ratio of approximately 5 compared to no antibiotic exposure.

Antibiotic Classes with Moderate Risk of C difficile (odds ratio 1 to 5)

Macrolides, sulfonamides/trimethoprim, and penicillins are associated with a moderate risk of C difficile infection with odds ratios between about 1.8 and 3.3. 3-5 Within this group, penicillins are generally associated with a slightly higher risk (odds ratio about 50% higher) compared to macrolides and sulfonamides/trimethoprim.

Clinical Implications of C difficile Risk Data

On the basis of the available data, clindamycin should absolutely be avoided among patients who are at risk for C difficile infection, particularly in elderly patients and those with frequent antibiotic exposure or hospitalizations. Given the available data, it’s clear that clindamycin is a well-deserving candidate of its boxed warning specifically for C difficile risk. 6

For community-acquired pneumonia, it has been suggested that a tetracycline may be substituted in place of azithromycin (or another macrolide) among elderly patients at higher risk for C difficile infection. 7 In fact, data suggests that tetracyclines may NOT increased risk of C difficile infection at all, with a non-significant odd ratio of 0.9 versus no antibiotic exposure. 3,4

In patients hospitalized with severe infections who require anti-Pseudomonal coverage, the available data suggests that penicillins (such as piperacillin/tazobactam) may have a lower risk of C difficile infection versus cephalosporins (such as cefepime) or carbapenems (such as meropenem). While this risk is certainly relevant to the selection of antimicrobials, local resistance patterns should also be considered when selecting an agent.

Knowledge of high-risk and lower-risk antibiotics for C difficile infection is important, particularly in patients who are already at a higher risk for C difficile infection, such as elderly patients. Avoidance of these high-risk antibiotics when other first-line alternatives exist in certain patient populations should be an antimicrobial stewardship intervention for pharmacists to reduce the risk of C difficile infection both in the inpatient and outpatient settings.


Alternatives to Antibiotics: Why and How

The antibiotic resistance problem is caused by the evolution and transfer of genes that confer resistance to medically important antibiotics into human pathogens. The acquisition of such resistance genes by pathogens complicates disease treatment, increases health care costs, and increases morbidity and mortality in humans and animals. As antibiotic resistance continues to evolve, antibiotics of so-called last resort become even more precious. Reducing or preventing the dissemination of antibiotic resistance genes into human pathogens is currently of high international importance.

The complex factors that have led to the antibiotic resistance problem are revealed when examining potential solutions to reduce or prevent this problem. First, more than 70 years of antibiotic use have already selected for diverse and highly mobile antibiotic resistance genes in human pathogens and related bacteria. These resistant bacteria spread in the environment via water, air, wildlife, and humans, so targeted mitigation strategies are needed to decrease the environmental dissemination of antibiotic-resistant bacteria from “hot spots” of potential resistance development. Second, highly mobile resistance genes can be horizontally transferred from one bacterium to another. Resistance gene transfer events can be stimulated by antibiotics themselves. Therefore, prudent use of antibiotics is one potential mitigation strategy to slow the spread of resistance genes among bacteria. Finally, novel resistance genes that are not yet clinically relevant can emerge from the vast reservoirs of environmental and commensal bacteria due to selective pressure. Compared to anthropogenically selected resistance genes, these resistance genes are not commonly found on mobile genetic elements (MGEs), and so they face a multistep path of selection onto MGEs—such as integrons, transposons, and plasmids—before they will arrive in a human pathogen [1]. One example of this is the emergence of the clinically relevant and plasmid-borne CTX-M-5 extended-spectrum beta-lactamases from the chromosome of the commensal bacterium Kluyvera ascorbata [2]. Antibiotic prudency is also important to decrease the selective pressure for the eventual emergence of as yet unknown antibiotic-resistance genes.

Antibiotic prudency is the use of antibiotics only when they are expressly needed and at the most appropriate dose for disease treatment. This is a nebulous concept that is difficult to define—particularly in cases of human health when the health of the individual, not the population, is of immediate importance. Nonetheless, central to executing antibiotic prudency is the availability of efficacious alternatives to antibiotics. The use of antibiotic alternatives to promote health and reduce disease will decrease antibiotic use, thereby decreasing selective pressure for the emergence and transmission of antibiotic-resistance genes.

Antibiotics are used for disease treatment and prevention in both humans and animals. Historically, antibiotics have also been used for improving growth promotion in food-producing animals, although this practice is no longer allowed in the United States. These multiple uses can be attended to by various alternatives, some of which are presented in Table 1 [3].

Numerous alternatives to antibiotics exist for treating specific diseases, including bacteriophage therapy [4], predatory bacteria [5], bacteriocins [6], and competitive exclusion of pathogens [7]. Unfortunately, none have consistently demonstrated efficacy comparable to antibiotic treatment. The advantage to these approaches, however, is that only the disease-causing bacterium is targeted by the treatment, and not the other members of the host’s commensal, beneficial microbial communities. This is in contrast to most antibiotics, which generally have collateral effects on commensal bacteria in addition to the pathogenic target. Further development of these specific approaches for disease treatment is warranted to improve deliverability, potency, and reliability as antibiotic alternatives.

Bacteriophage, or phage, therapy is among the most heavily researched of the alternatives to antibiotics for disease treatment. Phage viruses infect bacteria, and the use of phages to treat bacterial diseases has been investigated for over a century. Several phage therapeutic products are available and in use in Eastern Europe, but variable efficacy tends to prevent phage therapeutic products from the market in the United States [8]. Advantages of phage therapy include specificity for a target bacterial population and efficacy on topical or mucosal infections. Among the disadvantages: the therapy requires knowledge of the target bacterium and sufficiently high populations of the target bacterium, and resistance can develop. So the therapeutic phage would need to be updated.

Although disease treatment is the most obvious use of antibiotics, a great deal of antibiotics are used for disease prevention. In swine, roughly half of all antibiotic usage is for disease prevention [9, 10]. Disease prevention in both humans and animals has been advanced by contemporary knowledge of sanitation and nutrition. Continued improvements in sanitation and nutrition, particularly in animal husbandry, will contribute to decreased antibiotic use. In addition to these seemingly primitive interventions, molecular developments such as vaccination have been instrumental in reducing primary and secondary bacterial infections that would have necessitated antibiotic use. Vaccines continue to be one of the most important ways to prevent infections.

Another promising intervention is the use of immunotherapeutics, which are molecules that boost the host immune system to generally prevent disease at infection-prone times. One successful immunotherapeutic in human health is pegfilgrastim, a granulocyte colony-stimulating factor (G-CSF) that is used to induce neutrophil production in chemotherapeutic patients with low neutrophil counts [11]. Maintaining appropriate neutrophil numbers in the blood helps the immune system to prevent infections. Immunotherapeutics have also been exploited for agricultural purposes with pegbovigrastim, a bovine G-CSF that is administered to cattle prior to parturition to boost the immune system and decrease the incidence of mastitis. The advantage of these immunotherapeutics is that they generally boost the immune system to prevent infectious disease. The disadvantage is that the timing of delivery needs to be precise, which is a potential challenge for on-farm applications.

Finally, the use of pro-, pre-, or synbiotics to modulate the gut microbial community toward health has demonstrated inconsistent efficacy [12]. Probiotics are living organisms that are intentionally fed to a host and are typically known as “good” bacteria, prebiotics are molecular precursors to expand the presence of the existing “good” gut microbiota of a host, and synbiotics are a combination of both. All of these “-biotics” are designed to affect the gut microbiota in a way that improves health. However, the gut microbial community of mammals is a complex consortium of more than 500 different bacterial species, and researchers currently lack knowledge of the precise mechanism of how each member contributes to host health. This lack of understanding likely contributes to the variable results with modulating the gut microbial community as an alternative to antibiotics. Investigations of how gut bacteria interact with each other and with their animal hosts is currently an active area of research worldwide.

In summary, solutions to the antibiotic-resistance problem are multifaceted and include reducing the use of antibiotics via the use of alternative products. No one alternative will replace all uses of antibiotics, because a variety of specific and general methods are needed to both prevent and treat disease. Immunotherapeutics, vaccines, and gut microbiota modulation could be among the most promising approaches.

Join the conversation!

Tweet this! As antibiotic resistance continues to evolve, solutions are more important than ever. A look at alternatives: http://bit.ly/2uAHzZ7

Tweet this! No one alternative will replace all uses of antibiotics to reduce antibiotic resistance. Here are some options: http://bit.ly/2uAHzZ7

Tweet this! New paper from @theNAMedicine identifies several alternatives to antibiotics in treating/preventing diseases: http://bit.ly/2uAHzZ7


Antibiotic content in vaccines licensed for use in the United States

mg = milligrams ppm = parts per million ppb = parts per billion

Measles, mumps, rubella (MMR®)

Quantity Neomycin (per dose): 0.025 mg

Measles, mumps, rubella, varicella (ProQuad®)

Quantity Neomycin (per dose): .005 mg to < 0.016 mg (depending on storage requirements)

Meningococcal B Vaccine (Bexsero®)

Quantity Kanamycin (per dose): < 0.00001 mg

Varicella [chickenpox] (Varivax®)

Quantity Neomycin (per dose): Trace quantities

Rabies (Imovax®, RabAvert®)

Imovax

RabAvert

  • Quantity Neomycin (per dose): < 0.001 mg
  • Quantity Chlortetracycline (per dose): 0.0002 mg
  • Quantity Amphotericin B (per dose): 0.00002 mg

Influenza

Some influenza vaccines contain no antibiotics and others contain one or more of the following:

  • Quantity Neomycin (per dose): < 0.00002 mg – 0.000062mg
  • Quantity Polymyxin B (per dose): < 0.011mg
  • Kanamycin (per dose): < 0.00003 mg
  • Gentamicin (per dose): < 0.00015 mg

Polio (IPOL®)

  • Quantity Neomycin (per dose): 0.000005 mg
  • Quantity Streptomycin (per dose): 0.0002 mg
  • Quantity Polymyxin B (per dose): 0.000025 mg

Diphtheria, tetanus, pertussis, polio (Kinrix®, Pentacel®, Quadracel®)

Kinrix

Pentacel and Quadracel

  • Quantity Neomycin (per dose): < 0.000000004 mg
  • Quantity Polymyxin B (per dose): < 0.000000004 mg

Diphtheria, tetanus, pertussis, hepatitis B, polio (Pediarix®)

Hepatitis A (Havrix®, Vaqta®)

Havrix

Quantity Neomycin (per dose): < 0.00004 mg

Vaqta

Quantity Neomycin (per dose): < 10 ppb

Hepatitis A, hepatitis B (Twinrix®)

Quantity Neomycin (per dose): < 0.00002 mg


Introduction

Staphylococcus aureus (S. aureus) is an opportunistic bacterial pathogen that is responsible for a variety of superficial and invasive infectious diseases in human, including soft tissue infection, bacteremia, endocarditis, pneumonia, sepsis and general wound infections 1 . Such infections are associated with considerable morbidity and mortality, both in hospitals and the greater community, thereby posing a major global health challenge 2 . In addition, the emergence of drug-resistance strains, such as methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA), make it increasingly difficult to cure the infection 3 .

Immunotherapy represents a promising strategy to prevent S. aureus related infectious diseases 4,5 . Efforts to develop an effective vaccine against S. aureus infection have been ongoing, with extensive studies currently underway 6 . A wide variety of proteins from S. aureus were identified as promising candidate antigens, including capsular polysaccharides 7 , secreted toxins 8 and out membrane proteins 9 . In previous studies, we reported three proteins that exhibited protective immunity against S. aureus infection, including a genetically detoxified staphylococcal alpha-toxin mutant H35L (mHla) 10 , staphylococcal enterotoxin B mutant L45R/Y89A/Y94A (mSEB) 11 and wild-type manganese transport protein C (MntC) (submitted). Active immunization with either of these proteins was able to induce specific antibodies and cellular immune responses, resulting in reduced bacterial loads and inflammation reaction, as well as improved survival time and rate in mice.

However, S. aureus usually causes an acute infection with rapid progression and 60% of patients with invasive infections die within 7 days of culturing positive for MRSA 12 , indicating that active immunization is not the best choice for the prevention of such acute infections. Contrastingly, passive immunization is able to provide immediate and effective protection, as previous studies have demonstrated that antibody responses play a major protective role in specific immunity against MRSA 13 and passive immunization with antigen specific antibody is able to provide partial protection against S. aureus infections 14,15 . Thus, in this study, we have systematically evaluated the protective efficacy of passive immunization with rabbit-generated polyclonal antibodies against mHla, mSEB and MntC (termed “SAvac-pcAb”) in a murine sepsis model and further investigated the possible mechanisms that might contribute to its protective immunity.


Impact of AMR on COVID-19 clinical care

Patients with COVID-19 may receive antimicrobial therapy for two main reasons. First, COVID-19 symptoms can resemble bacterial pneumonia. Diagnostics used to distinguish viral from bacterial pneumonia may prove ineffective or have turnaround times of hours or days when immediate treatment is needed. For example, faster tests, such as diagnostics measuring C-reactive protein – a biomarker that is elevated in bacterial infections but typically not in viral ones – may in fact be increased in patients with COVID-19 (Sproston and Ashworth, 2018). As a result, many patients hospitalised with COVID-19 will be prescribed empiric antibiotics, often in the absence of a microbiological confirmation of the diagnosis (Langford et al., 2021).

Second, patients with COVID-19 may acquire secondary co-infections which require antimicrobial treatment. Several evidence reviews suggest that the secondary bacterial infection rates are low (㰠%) (Langford et al., 2020 Lansbury et al., 2020 Rawson et al., 2020b), but more, better data are needed to provide a better understanding of the occurrence of co-infections and pathogens involved, alongside the impact of underlying patient risk factors. In many of these studies, secondary infections were subsidiary endpoints and hence, moving forward, standardised definitions and diagnostic criteria should be used to perform more in-depth analysis of microbiological, resistance and antimicrobial usage data, where diagnostic laboratory infrastructure exists.

Local stewardship guidance, often based on local antimicrobial susceptibility data where available, influences a clinician’s choice of antimicrobial for their patients. Empiric treatment intends to cover a wide range of suspected organisms. Hence, AMR will influence the choice of antimicrobials prescribed to those with COVID-19. Clinicians are therefore challenged with competing priorities: prescribing a broad enough spectrum antimicrobial to ensure the organism is sensitive, while at the same time avoiding the unnecessary use of antimicrobials, particularly those of last resort, when a more commonly used or narrower-spectrum antimicrobial would suffice. Inappropriate treatment in either direction has been associated with increased risk of mortality (Gutiérrez-Gutiérrez et al., 2017 Paul et al., 2010).

Concern about potential infections with resistant pathogens could lead to unnecessary empiric prescribing of last resort antimicrobials to patients with COVID-19. For example, in areas where carbapenem resistance is high, antibiotics with less favourable safety profiles such as colistin may be recommended as a first-line treatment for suspected Gram-negative infections (Torres et al., 2017). This may result in more frequent adverse events and worse clinical outcomes in patients with COVID-19. Conversely, if recommendations for empiric treatment are not tailored to the local AMR prevalence, patients with co-infections may receive ineffective treatment which may in turn result in increased mortality and healthcare costs.


Glossary

Actinomycetes: Soil bacteria that produce the majority of currently identified natural product antibiotics. In particular, the genus Streptomyces has historically been a prolific source of antibacterial agents.

Aerobic Bacteria: All aerobic bacteria require oxygen for growth. Microaerophiles require some oxygen for growth, however they are harmed by high concentrations of it.

Anaerobic Bacteria: Bacteria that do not require oxygen for growth. Obligate anaerobes are incapable of growing in oxygenated environments. Aerotolerant anaerobes can grow in oxygenated environments, but are incapable of utilizing oxygen. Facultative anaerobes are capable of utilizing oxygen for growth, but are also capable of surviving in oxygen free environments.

Bactericidal Agent: An agent that is capable of killing bacteria. These can be antiseptics, disinfectants, or antibiotics.

Bacteriostatic Agent: An agent that stops bacteria from reproducing while not harming them otherwise. Unlike bactericidal agents they are not capable of killing bacteria on their own.

Biofilm: A sessile community of microorganisms that adhere to a surface. Some biofilm forming bacteria produce exopolysaccharide sheaths that make them dramatically less susceptible to antibiotics and other environmental toxins.

Center for Disease Control and Prevention (CDC): An agency of the United States Department of Health and Human Services that is in charge of monitoring and maintaining the health safety of its residents in regard to both noncommunicable and communicable disease.

Commensal Bacteria: Bacteria that benefit from their host environment without causing harm to the host. These bacteria are non-pathogenic.

Cytotoxin: Substances that are toxic to cells. They can induce cell death through apoptosis or necrosis or they can simply reduce cell viability.

Efflux Pump: Protein or glycoprotein complexes located in the cell membrane that are responsible for energy-dependent, active transport of toxins out of cells. These structures play a major role in bacterial antibiotic resistance. Bacterial efflux pumps are categorized by five sub-families: Major facilitator superfamily (MFS), ATP-binding cassette superfamily (ABC), small multi-drug resistance family (SMR), resistance-nodulation cell-division superfamily (RND), and multi-antimicrobial extrusion protein family (MATE).

Endotoxin: Toxins that are not secreted by bacteria, but rather are a part of their cellular membrane and are released only upon its degradation. These toxins are most often lipopolysaccharides.

Enterobacteriaceae: A family of gram-negative bacteria that includes many non-pathogenic species as well as many problem pathogens including Klebsiella, Shiegella, Enterobacter, Salmonella, E. coli, and Y. pestis.

Enterotoxin: Protein exotoxins that target the intestines.

Exotoxin: A broad term referring to any toxin that is secreted by the bacteria. Many exotoxins are highly potent and can be potentially lethal to humans.

Food and Drug Administration (FDA): An agency of the United States Department of Health and Human Services that regulates food, drugs, and cosmetic products. One of the duties of the FDA within the context of pharmaceuticals is the approval of new drugs for public consumption.

Gram-negative Bacteria: Bacteria that have a lipopolysaccharide / protein outer cell membrane and an inner cell membrane with a peptidoglycan layer sandwiched between the two. Their outer cell membrane does not retain Gram stain allowing them to be differentiated from gram-positive bacteria.

Gram-positive Bacteria: Bacteria that have a thick peptidoglycan cell wall surrounding their cell membrane which is capable of retaining Gram stain.

Infectious Diseases Society of America (IDSA): An association based in the United States that represents health care professionals and scientists from around the world that specialize in infectious diseases. The society promotes research, education, and initiatives related to this field.

Methylase: Otherwise known as methyltransferases, these enzymes are highly relevant in many aspects of biology and medicine. In the context of antibiotics they are a common bacterial resistance mechanism. Bacteria utilize them to modify drug targets with methyl groups thereby decreasing the affinity of the antibiotic.

Nosocomial Infection: Also referred to as hospital acquired infections (HAIs), these infections occur in hospital associated environments.

Opportunistic Pathogen: A microorganism that is normally commensal, but can become pathogenic in hosts with compromised immune systems.

Penicillin-binding Proteins: A large group of proteins essential for cell wall biogenesis that are all characterized by their ability to irreversibly bind β-lactam antibiotics.

Peptidoglycan: A polymeric saccharide and amino acid structure. In a cross linked form it is the primary constituent of the cell wall of bacteria. Gram positive bacteria have a thick peptidoglycan layer outside of their cell membrane. Gram negative bacteria have a much thinner peptidoglycan layer located between an inner and an outer cell membrane.

Porin: Beta-barrel, transmembrane, transport proteins that allow small to medium sized molecules to pass through cell membranes.

Structure-activity Relationship (SAR): The relationship between the chemical structure of a molecule and its biological activity. Medicinal chemists probe this relationship by manipulating functional groups or even larger portions of a molecule and then observing the changes to biological activity that result.

World Health Organization (WHO): An agency of the United Nations with a focus on international public health. The WHO monitors and advises on all aspects of public health including trends in communicable diseases.

Zoonotic Infection: A disease transmitted from animals to humans. These infections can occur via contact with living animals or through the consumption of foods that are either products of animals or have been contaminated by animals.



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