An antibiotic is, in essence, a chemical weapon deployed against bacteria. It’s a substance designed to either obliterate these single-celled organisms or, at the very least, halt their relentless proliferation. This is, of course, the most crucial tool in our arsenal for combating bacterial infections, and these miraculous compounds are routinely employed for both the treatment and, in some cases, the prophylactic prevention of such maladies. [1] [2] Some antibiotics possess the rather specific ability to also wage war against protozoa, though this is a less common, albeit noteworthy, capability. [3] [4] Let’s be unequivocally clear, however: antibiotics are utterly useless against viruses. That nagging cough, the sniffles, the full-blown influenza – these are viral assaults, and antibiotics will do nothing to alleviate them. For those microscopic invaders, we require antiviral drugs, aptly named. Similarly, fungi, with their own unique biological machinations, are impervious to antibiotics. Antifungal drugs are the proper armamentarium for such fungal incursions.
The very name "antibiotic" itself hints at its function: "against life." From the ancient Greek roots anti (against) and bios (life), it’s a rather dramatic moniker for something that, in its purest form, is a natural product. These are substances produced by one microorganism to gain an advantage over another. Think of it as a microscopic arms race. However, the term is often used more broadly to encompass any substance that combats microbes. In the realm of medicine, while antibiotics like penicillin are naturally derived, synthetic antibacterials, such as sulfonamides and antiseptics, are also crucial players. Though their origins differ – one born of nature, the other of the laboratory – their ultimate effect is the same: to vanquish or inhibit microbial life. Both are integral to antimicrobial chemotherapy. [6] The distinction is important, though; "antibacterials" is a broader category that includes bactericides, bacteriostatics, antibacterial soaps, and chemical disinfectants. Antibiotics, on the other hand, are a specific, vital class within this group, primarily used in medicine and, regrettably, sometimes found in livestock feed, which raises its own set of concerning questions.
Early History
The annals of antibiotic use stretch back further than many realize. Evidence suggests that ancient societies in what is now northern Sudan, specifically around 350–550 CE, were already systematically incorporating antibiotics into their diets. Chemical analyses of Nubian skeletal remains have revealed consistently high levels of tetracycline, a potent antibiotic. The prevailing theory is that these ancient peoples brewed beverages from grains fermented with Streptomyces, a bacterium known for its natural production of tetracycline. This deliberate, dietary consumption of antibiotics marks a profoundly significant moment in the history of medicine, a foundational step that predates our modern understanding by millennia. [7] [8]
As the biological anthropologist George J. Armelagos aptly put it, regarding the substantial tetracycline levels found: "Given the amount of tetracycline there, they had to know what they were doing."
Beyond this remarkable discovery, evidence from other ancient civilizations – including Egypt, China, Serbia, Greece, and Rome – points to the topical application of moldy bread as a method for treating infections. [10]
The first documented instance of mold being used to treat infections comes from John Parkinson (1567–1650). However, it was in the 20th century that antibiotics truly revolutionized medicine. The scientific pursuit of synthetic antibiotic chemotherapy and the development of antibacterials began in earnest in Germany with Paul Ehrlich in the late 1880s. [11] Then, in 1928, Alexander Fleming (1881–1955) made his groundbreaking discovery of modern penicillin. Its widespread use proved invaluable, particularly during wartime. A parallel development occurred in 1932 or 1933 when a research team at the Bayer Laboratories, part of the IG Farben conglomerate in Germany, led by Gerhard Domagk, developed Prontosil. This was the first sulfonamide and the first systemically active antibacterial drug. [12] [13] [14]
Yet, the very success and accessibility of antibiotics have led to their unfortunate overuse, [15] fueling the evolution of resistance in bacterial populations. [1] [16] [17] [18] This phenomenon, known as antimicrobial resistance (AMR), is a natural evolutionary process, but it is now overwhelmingly driven by the inappropriate and excessive use of these agents. [19] [20] The irony is stark: while some parts of the world grapple with resistance, vast populations elsewhere still lack access to essential antimicrobials. [20] The World Health Organization has rightly classified AMR as a pervasive "serious threat," emphasizing that "it is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country." [21] The global toll is staggering, with nearly 5 million deaths annually linked to AMR, and 1.27 million directly attributable to it in 2019 alone. [20] [22]
Etymology
The term 'antibiosis,' meaning "against life," was first introduced by the French bacteriologist Jean Paul Vuillemin. He used it to describe the phenomenon observed with these nascent antibacterial drugs. [11] [23] [24] The concept of antibiosis in bacteria was scientifically documented in 1877 by Louis Pasteur and Robert Koch, who observed that an airborne bacillus could inhibit the growth of Bacillus anthracis. [23] [25] Later, in 1947, the American microbiologist Selman Waksman coined the term "antibiotics" for these substances. [26]
Waksman and his colleagues first used "antibiotic" in 1942 to denote any substance produced by a microorganism that, in high dilution, antagonizes the growth of other microorganisms. [23] [27] This definition explicitly excluded substances that kill bacteria but are not microbially produced (like gastric juices or hydrogen peroxide) and also excluded entirely synthetic antibacterial compounds like the sulfonamides. However, current medical usage has broadened the term to encompass any medication that kills or inhibits bacterial growth, irrespective of its origin. [28] [29]
The etymological roots of "antibiotic" are from the Greek anti (against) and biōtikos (fit for life, lively), which itself derives from biōsis (way of life) and ultimately bios (life). [30] [31] [32] The term "antibacterial," on the other hand, comes from the Greek anti (against) [34] and baktērion (staff, cane), a diminutive of baktēria (staff, cane), [35] so named because the first bacteria observed were rod-shaped. [36]
Usage
Medical uses
Antibiotics are indispensable for treating or preventing bacterial infections, [37] and occasionally, protozoan infections, as with metronidazole, which is effective against a range of parasitic diseases. When the cause of an illness is suspected to be bacterial but the specific pathogen remains unidentified, empiric therapy is initiated. This involves administering a broad-spectrum antibiotic based on the observed signs and symptoms, pending laboratory results that can take several days to materialize. [37] [38]
Once the offending microorganism has been identified, definitive therapy can be commenced, typically employing a narrow-spectrum antibiotic. The selection process also considers cost-effectiveness and aims to minimize toxicity, which in turn reduces the risk of fostering antimicrobial resistance. [38] In cases of uncomplicated acute appendicitis, antibiotics may be used as an alternative to surgery. [39]
Antibiotics also serve a crucial role in preventive healthcare, particularly for individuals at higher risk. This includes those with weakened immune systems (especially in HIV cases to ward off pneumonia), patients undergoing immunosuppressive drug therapy, individuals undergoing cancer treatment, and those undergoing surgery. In surgical contexts, they are administered to prevent infections at the incision site. They are also vital in dental antibiotic prophylaxis to prevent bacteremia and subsequent infective endocarditis. Furthermore, antibiotics are employed to prevent infection in cases of neutropenia, particularly when it's cancer-related. [40] [41]
It's important to note that the scientific evidence does not support the use of antibiotics for the secondary prevention of coronary heart disease. In fact, such use may potentially increase the risk of cardiovascular mortality, all-cause mortality, and stroke. [42]
Routes of administration
Antibiotic treatment can be delivered through various routes of administration. Most commonly, antibiotics are taken by mouth. For more severe, deep-seated systemic infections, administration may be intravenously or via injection. [1] [38] When the site of infection is readily accessible, antibiotics can be applied topically. This includes eye drops for conjunctivitis or ear drops for ear infections and acute cases of swimmer's ear. Topical application is also a treatment option for certain skin conditions like acne and cellulitis. [43] The advantages of topical application are numerous: it allows for high and sustained concentrations of the antibiotic at the infection site, minimizes systemic absorption and potential toxicity, and requires smaller overall volumes of the drug, thereby reducing the risk of contributing to antibiotic misuse. [44] In some cases, topical antibiotics applied to surgical wounds have been shown to lower the incidence of surgical site infections. [45] However, there are considerations with topical antibiotic use: some systemic absorption can occur, accurate dosing can be challenging, and there's a possibility of local hypersensitivity reactions or contact dermatitis. [44] Prompt administration of antibiotics is generally recommended, especially in life-threatening infections, and many emergency departments maintain stocks for immediate use. [46]
Global consumption
Antibiotic consumption patterns vary dramatically across the globe. A WHO report analyzing 2015 data from 65 countries, measured in defined daily doses per 1,000 inhabitants per day, revealed significant disparities. Mongolia reported the highest consumption rate at 64.4, while Burundi had the lowest at 4.4. The most frequently consumed antibiotics were amoxicillin and amoxicillin/clavulanic acid. [47]
Side effects
While antibiotics undergo rigorous screening for adverse effects before approval, they are generally considered safe and well-tolerated. Nevertheless, certain antibiotics have been linked to a spectrum of side effects, ranging from mild to severe, depending on the specific drug, the targeted microbes, and individual patient factors. [48] [49] These effects can stem from the drug's inherent pharmacological or toxicological properties, or they may manifest as hypersensitivity or allergic reactions. [4] Adverse effects can include fever, nausea, and severe allergic responses like photodermatitis and anaphylaxis. [50]
Commonly observed side effects of oral antibiotics include diarrhea, which arises from the disruption of the normal intestinal flora. This imbalance can lead to the overgrowth of harmful bacteria, such as Clostridioides difficile. [51] The concurrent use of probiotics during antibiotic treatment may help mitigate antibiotic-associated diarrhea. [52] Antibacterials can also disrupt the vaginal flora, potentially causing an overgrowth of yeast species of the genus Candida in the vulvovaginal area. [53] Interactions with other medications can also lead to adverse effects; for instance, combining quinolone antibiotics with systemic corticosteroids has been associated with an increased risk of tendon damage. [54]
Some antibiotics have the potential to harm mitochondria, the organelles within eukaryotic cells (including human cells) that are thought to have originated from bacteria. [55] Mitochondrial damage can induce oxidative stress in cells, and this mechanism has been implicated in the side effects observed with fluoroquinolones. [56] These drugs can also affect chloroplasts. [57]
Interactions
Birth control pills
Evidence regarding the impact of antibiotics on the efficacy of oral contraceptive pills is not entirely conclusive, with few well-controlled studies. [58] The prevailing view, supported by the majority of research, is that most antibiotics do not significantly interfere with the effectiveness of birth control pills. [59] Clinical studies suggest the failure rate attributable to antibiotic use is very low, around 1%. [60] Factors that can increase the risk of contraceptive pill failure include non-compliance (missed pills), vomiting, or diarrhea, which can affect the absorption of the pill's active ingredients, such as ethinylestradiol serum levels. [58] Women experiencing menstrual irregularities may be at higher risk and should be advised to use backup contraception during antibiotic treatment and for a week afterward. If patient-specific factors suggest a reduced contraceptive efficacy, backup contraception is advisable. [58]
Certain antibiotics, like the broad-spectrum antibiotic rifampicin, have been anecdotally linked to reduced oral contraceptive effectiveness, possibly due to increased activity of hepatic liver enzymes, which accelerate the breakdown of the pill's active components. [59] Effects on the intestinal flora, potentially leading to reduced absorption of estrogens in the colon, have also been proposed, but these findings remain inconclusive and debated. [61] [62] Clinicians often recommend the use of additional contraceptive measures when patients are on antibiotics suspected of interacting with oral [contraceptives]. [59] Further research is needed to definitively clarify potential interactions between antibiotics and oral contraceptives, alongside careful assessment of individual patient risk factors for contraceptive failure before dismissing the need for backup contraception. [58]
Alcohol
Interactions between alcohol and certain antibiotics can occur, potentially leading to side effects and diminished effectiveness of the antibiotic therapy. [63] [64] While moderate alcohol consumption is unlikely to interfere with many common antibiotics, specific types of antibiotics can cause serious adverse reactions when combined with alcohol. [65] Therefore, the potential risks are highly dependent on the specific antibiotic being used. [66]
Antibiotics such as metronidazole, tinidazole, cephamandole, latamoxef, cefoperazone, cefmenoxime, and furazolidone can trigger a disulfiram-like reaction when consumed with alcohol. This occurs because they inhibit the breakdown of alcohol by acetaldehyde dehydrogenase, leading to symptoms like vomiting, nausea, and shortness of breath. [65] Additionally, the efficacy of doxycycline and erythromycin succinate might be reduced by alcohol consumption. [67] Alcohol can also influence the liver enzymes responsible for metabolizing antibiotics, altering their activity. [32]
Pharmacodynamics
The success of antimicrobial therapy hinges on several factors, including the host defense mechanisms, the specific location of the infection, and the pharmacokinetic and pharmacodynamic properties of the antibacterial agent. [68] The bactericidal effect of antibacterials can be influenced by the bacterial growth phase; often, it requires active metabolic processes and cell division. [69] While these observations are primarily derived from laboratory studies, they have also been shown to correlate with successful elimination of bacterial infections in clinical settings. [68] [70] Given that the activity of many antibacterials is concentration-dependent, [71] in vitro characterization typically involves determining the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of an agent. [68] [72] To predict clinical outcomes, the antimicrobial activity of an antibacterial is usually integrated with its pharmacokinetic profile, and various pharmacological parameters serve as indicators of drug efficacy. [73]
Combination therapy
In critical infectious diseases, such as tuberculosis, combination therapy – the simultaneous use of two or more antibiotics – is employed to delay or prevent the development of resistance. For acute bacterial infections, antibiotics are often prescribed in combination for their synergistic effects, aiming for a treatment outcome superior to that achieved with individual agents. [74] [75] Fosfomycin, for instance, exhibits the highest number of synergistic combinations and is frequently used as a partner drug. [76] Combination therapy also broadens the antimicrobial spectrum, increasing the likelihood that at least one antibiotic in the regimen will be effective against the pathogen, which is particularly crucial when the causative agent is unknown. [77] Methicillin-resistant Staphylococcus aureus (MRSA) infections, for example, can be treated with a combination of fusidic acid and rifampicin. [74] However, it's important to acknowledge that antibiotic combinations can sometimes be antagonistic, resulting in a combined effect that is less potent than monotherapy. [74] For example, chloramphenicol and tetracyclines can antagonize penicillins, although this effect can vary depending on the bacterial species. [78] Generally, combining a bacteriostatic antibiotic with a bactericidal one tends to be antagonistic. [74] [75]
Beyond combining antibiotics with each other, antibiotics are sometimes co-administered with resistance-modifying agents. A prime example is the use of β-lactam antibiotics in conjunction with β-lactamase inhibitors, such as clavulanic acid or sulbactam, to combat infections caused by β-lactamase-producing bacterial strains. [79]
Classes
Antibiotics are typically categorized by their mechanism of action, chemical structure, or their spectrum of activity. Most target fundamental bacterial processes or growth mechanisms. [11] Those that target the bacterial cell wall (like penicillins and cephalosporins) or the cell membrane (polymyxins), or interfere with essential bacterial enzymes (rifamycins, lipiarmycins, quinolones, and sulfonamides), exhibit bactericidal activity, meaning they kill bacteria. Protein synthesis inhibitors, such as macrolides, lincosamides, and tetracyclines, are usually bacteriostatic, inhibiting further growth, with the notable exception of the bactericidal aminoglycosides. [80] Further classification is based on target specificity: "narrow-spectrum" antibiotics are effective against particular types of bacteria (e.g., gram-negative or gram-positive), while broad-spectrum antibiotics act against a wider range. After a 40-year hiatus in discovering new classes of antibacterial compounds, four new classes emerged in clinical use between the late 2000s and early 2010s: cyclic lipopeptides (e.g., daptomycin), glycylcyclines (e.g., tigecycline), oxazolidinones (e.g., linezolid), and lipiarmycins (e.g., fidaxomicin). [81] [82]
Production
With advancements in medicinal chemistry, many contemporary antibacterials are semisynthetic modifications of naturally occurring compounds. [83] This includes the beta-lactam antibiotics, such as the penicillins (originally derived from fungi of the genus Penicillium), cephalosporins, and carbapenems. Other antibacterials, like the aminoglycosides, are still isolated directly from living organisms. Conversely, antibacterials such as the sulfonamides, quinolones, and oxazolidinones are produced entirely through chemical synthesis. [83] Many antibacterial compounds are relatively small molecules, with molecular weights typically under 1000 daltons. [84]
Since the pioneering work of Howard Florey and Ernst Chain in 1939, the immense importance of antibiotics to medicine has spurred extensive research into large-scale production. Following screening against a broad range of bacteria, the active compounds are typically manufactured via fermentation, often under strongly aerobic conditions. [85]
Resistance
Antimicrobial resistance (AMR), a naturally occurring evolutionary process, is now primarily exacerbated by the misuse and overuse of antimicrobials. [19] [20] Simultaneously, access to essential antimicrobials remains a critical issue for many globally. [20] The emergence of antibiotic-resistant bacteria is a widespread phenomenon, predominantly caused by the overuse and misuse of antibiotics, posing a significant global health threat. [86] [87] Annually, AMR is associated with nearly 5 million deaths worldwide. [20]
The development of resistance often reflects evolutionary pressures during antibiotic treatment. The drug can select for bacterial strains possessing inherent or acquired mechanisms to survive high concentrations, leading to their preferential growth while susceptible bacteria are eliminated. [88] For instance, the Luria–Delbrück experiment in 1943 demonstrated how antibacterial selection could favor strains that had already acquired resistance genes. [89] Antibiotics like penicillin and erythromycin, once highly effective against numerous bacterial species, have seen their efficacy diminish due to widespread resistance. [90]
Resistance can manifest through the biodegradation of pharmaceuticals, as seen with soil bacteria that degrade sulfamethazine after exposure through medicated pig feces. [91] Bacterial survival frequently relies on inheritable resistance, [92] but resistance can also spread through horizontal gene transfer, a process more likely to occur in environments with frequent antibiotic use. [93]
Antibacterial resistance may impose a fitness cost on bacteria, potentially limiting the spread of resistant strains in the absence of antibiotics. However, compensatory mutations can arise, aiding their survival. [94] Paleontological data indicate that both antibiotics and resistance mechanisms are ancient phenomena. [95] Antibiotic targets that negatively impact bacterial reproduction or viability are considered the most useful. [96]
Several molecular mechanisms underlie antibacterial resistance. Intrinsic resistance is part of a bacterium's inherent genetic makeup, [97] [98] for example, if an antibiotic's target is absent from its genome. Acquired resistance arises either through mutations in the bacterial chromosome or the acquisition of foreign DNA. [97] Bacteria that produce antibiotics have evolved resistance mechanisms that bear similarities to those found in resistant strains, suggesting potential gene transfer. [99] [100] The spread of antibacterial resistance is often facilitated by vertical transmission of mutations during bacterial growth and by genetic recombination through horizontal genetic exchange. [92] For instance, resistance genes can be transferred between strains or species via plasmids. [92] [101] Plasmids carrying multiple resistance genes can confer resistance to numerous antibacterials. [101] Cross-resistance, where a single resistance mechanism confers resistance to multiple antibiotics, can also occur. [101]
Antibacterial-resistant strains and species, often termed "superbugs," are now contributing to the resurgence of diseases that were once well-controlled. For example, multidrug-resistant tuberculosis (MDR-TB) presents significant therapeutic challenges, with an estimated half a million new cases globally each year. [102] A notable example is the enzyme NDM-1, which confers resistance to a broad spectrum of beta-lactam antibacterials. [103] The UK's Health Protection Agency has noted that "most isolates with NDM-1 enzyme are resistant to all standard intravenous antibiotics for treatment of severe infections." [104] In 2016, an E. coli "superbug" was identified in the United States that was resistant to colistin, an antibiotic often considered a "last line of defence." [105] [106] Even anaerobic bacteria, historically less concerning regarding resistance, have shown high rates of resistance, particularly Bacteroides species, with penicillin resistance rates reportedly exceeding 90%. [107]
Misuse
The principle of antibiotic use, as articulated in The ICU Book, is stark: "The first rule of antibiotics is to try not to use them, and the second rule is try not to use too many of them." [108] Inappropriate and excessive antibiotic treatment has undeniably contributed to the rise of antibiotic-resistant bacteria. Beyond this, the overuse of antibiotics can also lead to direct harm to patients, most evident in critically ill individuals in Intensive care units. [109] Self-prescribing antibiotics is a common form of misuse. [110] Many antibiotics are prescribed for conditions that do not respond to them or are likely to resolve spontaneously. Furthermore, incorrect or suboptimal antibiotics are sometimes chosen for specific bacterial infections. [48] [110] The widespread use of antibiotics, including penicillin and erythromycin, has been linked to emerging antibiotic resistance since the 1950s. [90] [111] The extensive use of antibiotics in hospitals has also correlated with an increase in bacterial strains and species that no longer respond to conventional treatments. [111]
Common instances of antibiotic misuse include the excessive use of prophylactic antibiotics for travelers and a failure by medical professionals to prescribe appropriate dosages based on patient weight and prior use history. Other forms of misuse involve not completing the full prescribed course of antibiotics, incorrect dosage or administration, or inadequate rest for recovery. A prevalent example of inappropriate treatment is prescribing antibiotics for viral infections like the common cold. One study on respiratory tract infections found that "physicians were more likely to prescribe antibiotics to patients who appeared to expect them." [112] Multifaceted interventions targeting both physicians and patients have demonstrated success in reducing inappropriate antibiotic prescriptions. [113] [114] The absence of rapid point-of-care diagnostic tests, particularly in resource-limited settings, is considered a significant driver of antibiotic misuse. [115]
Numerous organizations dedicated to combating antimicrobial resistance are advocating for the elimination of unnecessary antibiotic use. [110] The US Interagency Task Force on Antimicrobial Resistance, coordinated by the US Centers for Disease Control and Prevention, the Food and Drug Administration (FDA), and the National Institutes of Health, is actively addressing antimicrobial resistance. [116] A non-governmental organization, Keep Antibiotics Working, is also a prominent advocate. [117] In France, a government campaign launched in 2002, titled "Antibiotics are not automatic," led to a significant reduction in unnecessary antibiotic prescriptions, especially for children. [118]
The escalating issue of antibiotic resistance prompted restrictions on antibiotic use in the UK in 1970 (following the Swann report) and led the European Union to ban the use of antibiotics as growth-promoting agents in animal feed starting in 2003. [119] Furthermore, several organizations, including the World Health Organization, the National Academy of Sciences, and the U.S. Food and Drug Administration, have called for limiting antibiotic use in food animal production. [120] However, regulatory and legislative actions to curb antibiotic use often face delays, partly due to industry resistance and the time required for research to establish causal links between use and resistance. Two federal bills (S.742 [121] and H.R. 2562 [122]) proposed in the US to phase out non-therapeutic antibiotic use in food animals have not yet passed. These bills garnered support from public health and medical organizations, including the American Medical Association and the American Public Health Association. [123] [124]
Despite commitments from food companies and restaurants to reduce or eliminate meat sourced from animals treated with antibiotics, the actual purchase of antibiotics for use in farm animals has continued to increase annually. [125]
Antibiotic use in animal husbandry has been extensive. In the United States, the FDA raised concerns about the emergence of antibiotic-resistant bacterial strains due to antibiotic use in livestock as early as 1977. In March 2012, a ruling by the United States District Court for the Southern District of New York, in a lawsuit brought by the Natural Resources Defense Council and others, ordered the FDA to revoke approvals for antibiotic use in livestock that violated FDA regulations. [126]
Studies indicate that common misconceptions about the effectiveness and necessity of antibiotics for treating mild illnesses contribute significantly to their overuse. [127] [128]
Beyond resistance, antibiotic-associated harm can include anaphylaxis, drug toxicity (particularly kidney and liver damage), and superinfections with resistant organisms. Antibiotics are also known to impact mitochondrial function, [129] which may contribute to the bioenergetic failure observed in immune cells during sepsis. [130] They also alter the microbiome of the gut, lungs, and skin, [131] potentially leading to adverse effects such as *Clostridioides difficile* associated diarrhoea. While antibiotics are undeniably life-saving for bacterial infections, their overuse, especially in challenging diagnostic scenarios, can cause harm through multiple pathways. [109]
History
Before the advent of modern medicine in the early 20th century, treatments for infections were largely rooted in medicinal folklore. Compounds with antimicrobial properties were described and used over 2,000 years ago. [132] Ancient cultures, including the ancient Egyptians and ancient Greeks, utilized specific molds and plant materials to treat infections. [133] [134] Notably, Nubian mummies studied in the 1990s showed significant levels of tetracycline, believed to have originated from the beer they consumed. [135]
The era of antibiotics in modern medicine began with the discovery of synthetic antibiotics derived from dyes. [11] [136] [14] [137] [12] Various essential oils have demonstrated antimicrobial properties, [138] and the plants from which they are derived can also serve as niche antimicrobial agents. [139]
Synthetic antibiotics derived from dyes
The scientific pursuit of synthetic antibiotic chemotherapy and the development of antibacterials commenced in Germany with Paul Ehrlich in the late 1880s. [11] Ehrlich observed that certain dyes selectively stained different types of cells – human, animal, or bacterial – while others did not. This led him to hypothesize the possibility of creating chemicals that could act as selective drugs, targeting and killing bacteria without harming the host. After systematically screening hundreds of dyes against various organisms, he discovered a medicinally significant compound in 1907: the first synthetic antibacterial, an organoarsenic compound called salvarsan, later known as arsphenamine. [11] [136] [14]
This discovery heralded the dawn of the antibacterial treatment era, initiated by a series of arsenic-derived synthetic antibiotics developed by both Alfred Bertheim and Ehrlich in 1907. [137] [12] Their experiments, involving various dye-derived chemicals, aimed to treat trypanosomiasis in mice and spirochaeta infections in rabbits. While early compounds proved too toxic, Ehrlich, working alongside Japanese bacteriologist Sahachiro Hata, achieved a breakthrough with the 606th compound in their series, which proved effective against syphilis. In 1910, Ehrlich and Hata announced their discovery, designated "drug 606," at the Congress for Internal Medicine in Wiesbaden. [140] The Hoechst company began marketing the compound as Salvarsan, now known as [arsphenamine], towards the end of 1910. [140] This drug was a primary treatment for syphilis for the first half of the 20th century. Ehrlich was awarded the Nobel Prize in Physiology or Medicine in 1908 for his contributions to immunology. [141] Hata was subsequently nominated for the Nobel Prize in Chemistry in 1911 and for the Nobel Prize in Physiology or Medicine in 1912 and 1913. [142]
The first sulfonamide and the first systemically active antibacterial drug, Prontosil, was developed around 1932 or 1933 by a research team led by Gerhard Domagk at the Bayer Laboratories of the IG Farben conglomerate in Germany. [12] [13] [14] For this achievement, Domagk received the 1939 Nobel Prize in Physiology or Medicine. [143] Sulfanilamide, the active component of Prontosil, was not patentable as it had already been in use within the dye industry for some time. [13] Prontosil demonstrated relatively broad efficacy against gram-positive cocci but was less effective against enterobacteria. Its success spurred significant research, effectively opening the era of antibacterials. [144] [145]
Penicillin and other natural antibiotics
Observations regarding the inhibitory effect of certain microorganisms on the growth of others date back to the late 19th century. These observations of antibiosis between microorganisms ultimately led to the discovery of natural antibacterials. As Louis Pasteur once remarked, "if we could intervene in the antagonism observed between some bacteria, it would offer perhaps the greatest hopes for therapeutics." [146]
In 1874, physician Sir William Roberts noted that cultures of the mold Penicillium glaucum, famously used in the production of certain blue cheeses, were notably free from bacterial contamination. [147]
Later, in 1895, Italian physician Vincenzo Tiberio published research detailing the antibacterial power of specific mold extracts. [148]
In 1897, doctoral student Ernest Duchesne submitted a dissertation titled "Contribution à l'étude de la concurrence vitale chez les micro-organismes: antagonisme entre les moisissures et les microbes" (Contribution to the study of vital competition in micro-organisms: antagonism between molds and microbes). [149] This work is considered the first scholarly exploration of the therapeutic potential of molds derived from their antimicrobial activity. Duchesne posited that bacteria and molds were locked in a constant struggle for survival. He observed that E. coli was eliminated by Penicillium glaucum when cultured together. Furthermore, he found that laboratory animals inoculated with lethal doses of typhoid bacilli alongside Penicillium glaucum did not contract typhoid. Unfortunately, Duchesne's subsequent military service prevented him from pursuing this research further. [150] He tragically died of tuberculosis, a disease now treatable with antibiotics. [150]
The pivotal moment came in 1928 when Sir Alexander Fleming theorized the existence of penicillin, a substance produced by certain molds that could kill or inhibit the growth of specific bacteria. Fleming's discovery was serendipitous: while working with cultures of disease-causing bacteria, he noticed the presence of spores from a green mold, identified as Penicillium rubens, [151] on one of his culture plates. Crucially, he observed that the mold inhibited the growth of the surrounding bacteria. [152] Fleming hypothesized that this mold secreted an antibacterial substance, which he named penicillin in 1928. He recognized its potential for chemotherapy and conducted initial characterizations of its biological properties, even attempting to treat some infections with a crude preparation. However, he lacked the chemical expertise to further develop it. [153] [154]
It wasn't until 1942 that Ernst Chain, Howard Florey, and Edward Abraham successfully isolated and purified the first penicillin, penicillin G. Its widespread availability beyond Allied military use, however, wouldn't occur until 1945. [Norman Heatley] later developed the back-extraction technique, enabling the efficient purification of penicillin on a large scale. Abraham first proposed the chemical structure of penicillin in 1942, [155] which was later confirmed by Dorothy Crowfoot Hodgkin in 1945. Purified penicillin demonstrated potent antibacterial activity against a broad range of bacteria and exhibited low toxicity in humans. Significantly, unlike synthetic sulfonamides, its activity was not diminished by biological components like pus. The success of penicillin spurred renewed interest in the search for similar efficacious and safe antibiotic compounds. [156] For their collective efforts in developing penicillin into a therapeutic drug, Chain and Florey shared the 1945 Nobel Prize in Medicine with Fleming. [157]
Florey credited René Dubos with pioneering a systematic approach to discovering antibacterial compounds, which had led to the identification of gramicidin and rekindled Florey's own research into penicillin. [158] In 1939, at the onset of World War II, Dubos reported the discovery of tyrothricin, the first naturally derived antibiotic. Composed of 20% gramicidin and 80% tyrocidine, it was isolated from Bacillus brevis. Tyrothricin was one of the first commercially produced antibiotics and proved highly effective in treating wounds during the war. [158] However, gramicidin's systemic use was limited by toxicity, as was that of tyrocidine. Notably, research findings were not shared between the Axis and Allied powers during the war, and access was further restricted during the Cold War. [159]
Late 20th century
The mid-20th century witnessed a significant increase in the introduction of new antibiotic substances for medical use, with 12 new classes launched between 1935 and 1968. However, this pace slowed dramatically, with only two new classes introduced between 1969 and 2003. [160]
Antibiotic pipeline
Both the WHO and the Infectious Disease Society of America have expressed concern over the dwindling antibiotic pipeline, which fails to keep pace with the increasing rate of bacterial resistance development. [161] [162] The Infectious Disease Society of America's report highlighted a decline in the number of new antibiotics approved annually and identified only seven antibiotics targeting gram-negative bacilli in phase 2 or phase 3 clinical trials, none of which covered the full spectrum of resistance. [163] [164] As of May 2017, the WHO reported 51 new therapeutic entities – including antibiotics and combinations – in phases 1–3 clinical trials. [161] The development of antibiotics targeting multidrug-resistant Gram-positive pathogens remains a high priority. [165] [161]
In recent years, several antibiotics have received marketing authorization. These include the cephalosporin ceftaroline and the lipoglycopeptides oritavancin and telavancin, approved for treating acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. The lipoglycopeptide dalbavancin and the oxazolidinone tedizolid have also been approved for acute bacterial skin and skin structure infections. Fidaxomicin, the first in a new class of narrow-spectrum macrocyclic antibiotics, has been approved for treating C. difficile colitis. Additionally, new cephalosporin-lactamase inhibitor combinations, such as ceftazidime-avibactam and ceftolozane-avibactam, have been approved for complicated urinary tract and intra-abdominal infections. [166]
- Ceftolozane/tazobactam (CXA-201; CXA-101/tazobactam): An antipseudomonal cephalosporin/β-lactamase inhibitor combination targeting cell wall synthesis. Approved by the FDA on December 19, 2014. [167]
- Ceftazidime/avibactam (ceftazidime/NXL104): An antipseudomonal cephalosporin/β-lactamase inhibitor combination targeting cell wall synthesis. [168] Approved by the FDA on February 25, 2015.
- Ceftaroline/avibactam (CPT-avibactam; ceftaroline/NXL104): An anti-MRSA cephalosporin/β-lactamase inhibitor combination targeting cell wall synthesis. [ citation needed ]
- Cefiderocol: A cephalosporin siderophore. [168] Approved by the FDA on November 14, 2019.
- Imipenem/relebactam: A carbapenem/β-lactamase inhibitor combination targeting cell wall synthesis. [168] Approved by the FDA on July 16, 2019.
- Meropenem/vaborbactam: A carbapenem/β-lactamase inhibitor combination targeting cell wall synthesis. [168] Approved by the FDA on August 29, 2017.
- Delafloxacin: A quinolone targeting DNA synthesis. [168] Approved by the FDA on June 19, 2017.
- Plazomicin (ACHN-490): A semi-synthetic aminoglycoside derivative targeting protein synthesis. [168] Approved by the FDA on June 25, 2018.
- Eravacycline (TP-434): A synthetic tetracycline derivative targeting protein synthesis by binding to bacterial ribosomes. [168] Approved by the FDA on August 27, 2018.
- Omadacycline: A semi-synthetic tetracycline derivative targeting protein synthesis by binding to bacterial ribosomes. [168] Approved by the FDA on October 2, 2018.
- Lefamulin: A pleuromutilin antibiotic. [168] Approved by the FDA on August 19, 2019.
- Brilacidin (PMX-30063): A peptide defense protein mimetic disrupting the cell membrane. Currently in phase 2 trials. [169]
- Zosurabalpin (RG-6006): A lipopolysaccharide transport inhibitor. Currently in phase 1 trials. [170] [171]
Potential improvements include clearer clinical trial regulations from the FDA and economic incentives to encourage pharmaceutical companies to invest in antibiotic development. [164] In the US, the Antibiotic Development to Advance Patient Treatment (ADAPT) Act was proposed to expedite the drug development of antibiotics against "superbugs." This act would allow the FDA to approve antibiotics and antifungals for life-threatening infections based on smaller clinical trials, while the CDC would monitor usage and resistance patterns, publishing the data. The FDA's 'breakpoints' system for antibiotic labeling would provide healthcare professionals with precise data. According to Allan Coukell, senior director for health programs at The Pew Charitable Trusts, "By allowing drug developers to rely on smaller datasets, and clarifying FDA's authority to tolerate a higher level of uncertainty for these drugs when making a risk/benefit calculation, ADAPT would make the clinical trials more feasible." [173]
Replenishing the antibiotic pipeline and developing other new therapies
The continuous emergence and spread of antibiotic-resistant bacterial strains necessitate the ongoing development of new antibacterial treatments. Current strategies encompass traditional chemistry-based approaches like natural product-based [drug discovery], [174] [175] more advanced chemistry methods such as [drug design], [176] [177] as well as biology-based approaches including immunoglobulin therapy, [178] [179] and experimental methods like [phage therapy], [180] [181] [fecal microbiota transplants], [178] [182] antisense RNA-based treatments, [178] [179] and CRISPR-Cas9-based therapies. [178] [179] [183]
Natural product-based antibiotic discovery
The vast majority of antibiotics currently in use are either natural products or derived from them. [175] [184] Extracts from bacteria, [185] [186] [fungi], [174] [187] [plants], [188] [189] [190] [191] and animals [174] [192] are being screened for novel antibiotic compounds. Organisms are selected for testing based on various criteria, including ecological, ethnomedical, genomic, or historical rationale. [175] For instance, medicinal plants are screened due to their traditional use in treating infections, suggesting the presence of antibacterial compounds. [193] [194] Similarly, soil bacteria are a focus of research, as they have historically been a prolific source of antibiotics, accounting for 70-80% of those currently in use, primarily from actinomycetes. [175] [195]
Beyond direct antibacterial activity, natural products are also screened for their ability to counteract antibiotic resistance and antibiotic tolerance. [194] [196] For example, certain secondary metabolites can inhibit bacterial drug efflux pumps, thereby increasing intracellular antibiotic concentrations and reducing resistance. [194] [197] Natural products known to inhibit efflux pumps include the alkaloid [lysergol], [198] the carotenoids capsanthin and [capsorubin], [199] and the flavonoids rotenone and [chrysin]. [199] Other natural products, specifically [primary metabolites], have been shown to eradicate antibiotic tolerance. For instance, glucose, mannitol, and fructose have been observed to reduce antibiotic tolerance in Escherichia coli and Staphylococcus aureus, making them more susceptible to killing by aminoglycoside antibiotics. [196]
Natural products are also investigated for their potential to suppress bacterial virulence factors. These factors are molecules, structures, or regulatory systems that enable bacteria to evade host immune defenses (e.g., urease, staphyloxanthin), adhere to or invade host cells (e.g., type IV pili, adhesins, internalins), coordinate virulence gene expression (e.g., quorum sensing), and ultimately cause disease (e.g., exotoxins). [178] [191] [200] [201] [202] Examples of natural products with antivirulence activity include the flavonoid [epigallocatechin gallate] (which inhibits listeriolysin O), [200] the quinone tetrangomycin (which inhibits staphyloxanthin), [201] and the sesquiterpene zerumbone (which inhibits motility in Acinetobacter baumannii). [203]
Immunoglobulin therapy
Antibodies, such as anti-tetanus immunoglobulin, have been used for tetanus treatment and prevention since the 1910s, [204] and this approach remains valuable for controlling bacterial diseases. The monoclonal antibody [bezlotoxumab] has received approval from the US FDA and EMA for treating recurrent *Clostridioides difficile* infection. Other monoclonal antibodies are under development, such as AR-301 for adjunctive treatment of S. aureus ventilator-associated pneumonia. Antibody treatments function by binding to and neutralizing bacterial exotoxins and other virulence factors. [178] [179]
Phage therapy
Phage therapy is being investigated as a strategy for treating antibiotic-resistant bacterial strains. This therapy involves using viruses that specifically infect bacterial pathogens. Bacteriophages, or phages, are highly specific to certain bacteria, meaning they do not disrupt the host organism's intestinal microbiota, unlike broad-spectrum antibiotics. [206] Bacteriophages primarily kill bacteria through lytic cycles, where they inject their genetic material into the bacterium. [206] [205] The phage's DNA is then transcribed and used to produce new phages, ultimately leading to the lysis of the bacterial cell and the release of new phages capable of infecting and destroying more bacteria of the same strain. [205] This high specificity protects beneficial bacteria. [207]
However, bacteriophage use also presents challenges. Phages can carry virulence factors or toxic genes, necessitating genomic sequencing to identify such elements before use. Oral and IV administration of phages carries a higher safety risk than topical application, and potential immune responses to these complex biological agents are also a concern. [208] Significant regulatory hurdles must be overcome for these therapies to gain widespread acceptance. Despite these challenges, bacteriophages remain an attractive option as a potential alternative to conventional antibiotics for treating multidrug-resistant (MDR) pathogens. [206] [209]
Fecal microbiota transplants
Fecal microbiota transplants (FMT) are an experimental treatment primarily for C. difficile infection. [178] This procedure involves transferring the complete intestinal microbiota from a healthy human donor, in the form of stool, to patients with C. difficile infection. Although not yet officially approved by the US FDA, FMT is permitted under specific conditions for patients with antibiotic-resistant C. difficile infection. Cure rates approach 90%, and efforts are underway to establish stool banks, standardize products, and develop methods for oral delivery. [178] FMT has also been explored more recently for the treatment of inflammatory bowel diseases. [210]
Antisense RNA-based treatments
Antisense RNA-based treatment, also known as gene silencing therapy, involves several steps: (a) identifying bacterial genes that encode essential [proteins] (e.g., the Pseudomonas aeruginosa genes acpP, lpxC, and rpsJ), (b) synthesizing single-stranded RNA complementary to the mRNA encoding these proteins, and (c) delivering this antisense RNA to the infection site using cell-penetrating peptides or liposomes. The antisense RNA then binds to the bacterial mRNA, preventing its translation into the essential protein. This approach has demonstrated efficacy in in vivo models of P. aeruginosa pneumonia. [178] [179]
In addition to silencing essential bacterial genes, antisense RNA can be used to target genes responsible for antibiotic resistance. [178] [179] For example, antisense RNA has been developed to silence the S. aureus mecA gene, which encodes a modified penicillin-binding protein 2a and confers methicillin resistance. Antisense RNA targeting mecA mRNA has successfully restored susceptibility of methicillin-resistant staphylococci to oxacillin in both in vitro and in vivo studies. [179]
CRISPR-Cas9-based treatments
In the early 2000s, a defense system used by bacteria against invading viruses was discovered, known as CRISPR-Cas9. This system comprises an enzyme that degrades DNA (the nuclease Cas9) and DNA sequences of previously encountered viral invaders (CRISPR). These viral DNA sequences guide the nuclease to target foreign DNA, distinguishing it from the bacterium's own DNA. [211]
While CRISPR-Cas9 naturally protects bacteria, the DNA sequences within the CRISPR component can be modified to direct the Cas9 nuclease to target bacterial resistance or virulence genes instead of viral ones. This modified CRISPR-Cas9 system can then be delivered to bacterial pathogens using plasmids or bacteriophages. [178] [179] This approach has been successfully employed to silence antibiotic resistance genes and reduce the virulence of enterohemorrhagic E. coli in an in vivo infection model. [179]
Reducing the selection pressure for antibiotic resistance
Beyond developing new antibacterial treatments, mitigating the selection pressure that drives the emergence and spread of antimicrobial resistance (AMR), including antibiotic resistance, is paramount. Established infection control measures play a vital role, encompassing infrastructure improvements (e.g., less crowded housing), [213] [214] enhanced sanitation (e.g., safe drinking water and food), [215] [216] optimized use of vaccines and continued vaccine development, [20] [181] along with strategies like [antibiotic stewardship], [217] [218] and experimental approaches such as the use of prebiotics and probiotics for infection prevention. [219] [220] [221] [222] While antibiotic cycling (alternating antibiotics) has been proposed, recent studies suggest it is ineffective against antibiotic resistance. [223] [224]
Vaccines
Vaccines are a cornerstone in the strategy to reduce AMR, as they prevent infections, thereby decreasing the need for and overuse of antimicrobials, and consequently slowing the emergence and spread of drug-resistant pathogens. [20] Vaccination stimulates or bolsters the host's immune system to combat infection, activating macrophages, prompting antibody production, and initiating inflammation, among other immune responses. Antibacterial vaccines have been instrumental in drastically reducing the global burden of bacterial diseases. [225]