their use does carry risks. They can adversely affect patients by eliciting allergic reactions, causing direct toxicity, or altering the normal bacterial flora, leading to superinfections with other organisms. Antibiotic use is the primary driving force in the development of antibiotic resistance, which can affect not only the treated patients but other patients by transmission of resistant organisms. It is important to keep in mind all of these potential adverse consequences when using antibiotics. Antibiotic Allergy Through formation of complexes with human proteins, antibiotics can trigger immunologic reactions. These reactions may manifest immediately (such as anaphylaxis or hives) or be delayed (rashes, serum sickness, drug fever). Because of their highly reactive chemical structure and frequent use, beta- lactam drugs are the most notorious group of drugs for causing allergic reactions. It is difficult to determine how likely it is that a patient with an allergy to a particular antibiotic agent will have a similar reaction to another agent within that class. While some (highly debated) estimates of the degree of cross-reactivity are available for beta-lactam drugs, estimates for cross- reactivity within other classes (e.g., between fluoroquinolones) are essentially nonexistent. Because labeling a patient with an allergy to a particular antibiotic can limit future treatment options severely and possibly lead to the selection of inferior drugs, every effort should be made to clarify the exact nature of a reported allergy. Antibiotic Toxicities www.allmedicalbooks.com Antibiotic Toxicities Despite being designed to affect the physiology of microorganisms rather than humans, antibiotics can have direct toxic effects on patients. In some cases, this is an extension of their mechanism of action when selectivity for microorganisms is not perfect. For example, the hematologic adverse effects of trimethoprim stem from its inhibition of folate metabolism in humans, which is also its mechanism of antibiotic effect. In other cases, antibiotics display toxicity through unintended physiologic interactions, such as when vancomycin stimulates histamine release, leading to its characteristic red man syndrome. Some of these toxicities may be dose related and toxicity often occurs when doses are not adjusted properly for renal dysfunction and thus accumulate to a toxic level. Proper dosage adjustment can reduce the risk of dose-related toxicities. Superinfection The human body is colonized by a variety of bacteria and fungi. These organisms are generally considered commensals, in that they benefit from living on or in the body but do not cause harm (within their ecologic niches). Colonization with commensal organisms can be beneficial, given that they compete with and crowd out more pathogenic organisms. They may even have a role in the prevention of other human diseases. When administration of antibiotics kills off the commensal flora, pathogenic drug-resistant organisms can flourish because of the absence of competition. This is considered a superinfection (i.e., an infection on top of another infection). For example, administration of antibiotics can lead to the overgrowth of the gastrointestinal (GI) pathogen Clostridium difficile, which is clinically resistant to most antibiotics. C. difficile can cause diarrhea and life- threatening bowel inflammation. Similarly, administration of broad-spectrum antibacterial drugs can select for the overgrowth of fungi, most commonly yeasts of the genus Candida. Disseminated Candida infections carry a high risk of death. To reduce the risk of the impact of antibiotics on the commensal flora, and thus the likelihood of superinfection, antibiotics should be administered only to patients with proven or probable infections, using the most narrow-spectrum agents appropriate to the infection for the shortest effective duration. Antibiotic Resistance www.allmedicalbooks.com Antibiotic Resistance Thousands of studies have documented the relationship between antibiotic use and resistance, both at a patient level (if you receive an antibiotic, you are more likely to become infected with a drug-resistant organism) and a society level (the more antibiotics a hospital, region, or country uses, the greater the antibiotic resistance). The development of antibiotic resistance leads to a vicious spiral where resistance necessitates the development of broader-spectrum antibiotics, leading to evolution of bacteria resistant to those new antibiotics, requiring ever broader-spectrum drugs, and so on. This is particularly problematic because antibiotic development has slowed down greatly. Although we can see clearly the broad relationship between antibiotic use and resistance, many of the details of this relationship are not clear. Why do some bacteria develop resistance rapidly and others never develop resistance? What is the proper duration of treatment to maximize the chance of cure and minimize the risk of resistance? www.allmedicalbooks.com 6: Antibiotic Resistance Though it may seem that the antibiotic era was introduced in the 1930s with the sulfonamides and penicillin, it had actually started millions of years earlier. Alexander Fleming only discovered one of the weapons of a war going on underfoot\u2014literally, under our feet. In the soil and elsewhere, microbes are locked in life-and-death battles for dominance over each other for the limited resources they have access to. Among their weapons are antibiotics. Causes of Antibiotic Resistance The basic cause of antibiotic resistance is simple: antibiotic use. Some organisms are notorious for an intrinsic ability to express multiple types of resistance, such as Acinetobacter baumannii or Pseudomonas aeruginosa. Others have been generally treatable for many years and are only recently becoming highly drug-resistant through acquiring new resistance elements, such as Klebsiella pneumoniae. And some have remained highly susceptible to \u201cold\u201d antibiotics ever since their introduction, such as Streptococcus pyogenes and penicillin. Where Does Antibiotic Resistance Come From? www.allmedicalbooks.com Where Does Antibiotic Resistance Come From? In any species of bacteria, antibiotic resistance needs to have a point of origin. Resistance can emerge in the organism of interest through random mutations to the antibiotic\u2019s target or other key elements. However, it is more common that a given species of bacteria acquired the genes, which enable a mechanism of resistance, from another species of bacteria that already had it through the transfer of mobile genetic elements. Bacteria are promiscuous little organisms and they are not picky\u2014they often swap genes not only between their own species, but different species and even genera. There are several ways that genes are transmitted between bacteria, but the most important is by the transmission of plasmids via conjugation. Plasmids are loops of DNA that may contain multiple genes in them that encode for various processes (including antibiotic resistance), and they are highly portable. Since plasmids can contain multiple genes, they can encode for multiple types of resistance that are not related, such as resistance to cephalosporins via the production of a beta-lactamase and resistance to fluoroquinolone due to an efflux pump. With one act of gene swapping, a multiply-resistant bacterial strain is born. Mechanisms of Antibiotic Resistance The multiple mechanisms by which resistance occurs can be confusing, but here we are going to\u2014wait for it\u2014simplify it into four basic mechanisms, which are outlined in Figure 6\u20131. www.allmedicalbooks.com Figure 6\u20131 Mechanisms of Antibiotic Resistance Decreased permeability prevents the antibiotic from penetrating the bacterial cell, decreasing the intracellular concentration of the antibiotic.