Diego E. Gomez and J. Scott Weese Infectious diseases occur because the host is exposed to enough organisms with the capacity to cause disease (e.g., Salmonella), or because there is an assault on the host’s specific and nonspecific immune system (e.g., traumatic injury, surgical procedure, dramatic change in environment, or neutropenia). These assaults on physical barriers or defense mechanisms predispose the host to infection from opportunist pathogens in its normal microbiota or from organisms with which it might come in contact. It is not uncommon for a clinician, recognizing the assault on the host’s immune system, to initiate antimicrobial therapy to ward off the pending infection or to assist the host in combating the infection until the immune system recovers. When antimicrobial therapy is initiated in an animal that is about to undergo a surgical procedure or has experienced a traumatic injury and the clinician wants to protect against infection, such therapy is referred to as prophylaxis. When an antimicrobial agent is administered to a herd or flock of animals that are at risk of a disease outbreak due to transport, crowding, or some other exposure to infectious agents, and where infection is present, the therapy is referred to as metaphylaxis. When therapy is initiated in a neutropenic animal, with or without an ongoing infection, the use of antimicrobial agents may be considerably different from that in animals with intact defense mechanisms. This chapter discusses the prophylactic or metaphylactic use of antimicrobial agents in a herd situation, use prior to a surgical procedure, and use in neutropenic animals. The prophylactic and metaphylactic uses of antimicrobial agents have a tremendous impact on the prevention and control of infectious diseases in veterinary medicine, particularly in farm animals. In the United States, prevention is used synonymously with prophylaxis, and control with metaphylaxis (Table 24.1). However, these approaches have several drawbacks, the most obvious being the risk of selection for resistant organisms. For this reason, and because particularly prophylactic use may in the past have sometimes been automatic, it is an area of intense and ongoing discussion (European Medicines Agency, 2022) (Chapters 24, 25). In the European Union (EU), under EU regulation 2019/6, prophylaxis must be used in exceptional cases only, in an individual or a restricted number of animals, when the risk of infection is very high and the consequences are likely to be severe. In addition, it would be restricted to individual animal only use, not mass food or water medication. The intent of the EU regulation is to restrict the “routine” preventive use of antimicrobials in the feed of food animals. The practices of prophylaxis and of metaphylaxis in food animals are the subject of extensive ongoing research (Sargeant et al., 2019; Vriezen et al., 2019), aimed at continuing to reduce antimicrobial use in animals to where the benefits are clear and substantial. Table 24.1 Definitions of antimicrobial prophylaxis (prevention) and metaphylaxis (control) in the European Union and the United States as applied to groups of food animals. To minimize the risk of selecting for resistant organisms, several guidelines for using antimicrobial drugs prophylactically have been proposed. Antimicrobial drugs are often administered prophylactically to young animals (e.g., pigs, calves) when being moved from breeding to growing areas, because disturbances in the microbiota, alteration of the homeostatic stage, and the sudden exposure to pathogens can trigger outbreaks of infectious disease. However, the potential effects of antimicrobial drug use on the development of resistant microorganisms must be considered, and the practice should be avoided in the absence of evidence for its efficacy, or of documentation for its likely efficacy. Thus, wherever possible, prophylaxis should be replaced by adequate preventive husbandry practices (Chapter 23). Addressing disease prevention by improving immune status of the animals (i.e., ensuring adequate colostrum intake or vaccination) and environmental hygiene contributes to reducing the incidence of infection in production animals. For example, a large body of literature indicates that the most critical factor associated with morbidity and mortality in young animals during the preweaning period is an inadequate transfer of passive immunity (TPI) through colostrum. Of interest, prophylactic administration of antimicrobial drugs to calves with failure of transfer of passive immunity has proved to delay the onset of morbidity, decrease overall morbidity, and increase weight gain (Berge et al., 2005). However, rearing the calves with inadequate transfer of passive immunity is more difficult and labor‐intensive than raising calves with adequate immunoglobulin concentrations, despite the use of prophylactic antimicrobial agents. Similarly, a multidisciplinary approach to reduce and refine antimicrobial drug usage comprising training of farmers on disease detection, improving calf immunity and caloric intake, implementation of protocols for antimicrobial treatment of diarrheic calves, and monthly auditing significantly reduced antimicrobial drug usage for treatment of diarrhea (Gomez et al., 2021). This multidisciplinary approach also eliminated the use of prophylactic antimicrobial drugs for prevention of diarrhea and pneumonia without negative effects on calf health and welfare. Together, these results suggest that antimicrobial prophylaxis can be avoided, in specific farms, by implementing management practices focused on improving calf immunity, nutrition, and education of farmers and veterinarians on disease prevention and responsible antimicrobial drug use. Thus, antimicrobial prophylaxis should be used only when other prevention and control measures cannot be implemented or are ineffective. As an example of the move to reduce prophylactic use of antimicrobials in food animals, there is increasing adoption of the use of targeted, bacterial culture‐based, selective rather than “blanket” dry‐cow therapy combined with other preventive approaches such as teat sealant (Winder et al., 2019; McMullen et al., 2021) (Chapter 24). Unlike in human medicine, metaphylaxis is employed extensively in veterinary medicine where herd health is at risk. Metaphylaxis consists of administration of preemptive medication to sick animals and in‐contact healthy individuals to prevent both development and dissemination of the disease. This intervention is based on knowledge that disease is present in the population and will continue to affect susceptible individuals. The concept of herd medication is to treat the whole group at risk rather than individuals. Typical examples of metaphylaxis in food‐producing animals include administration of antimicrobial drugs for prevention of dysentery in pigs, “blitz” therapy with intramammary penicillin G to eradicate Streptococcus agalactiae infection from a cow herd, and mass medication on arrival at the feedlot to decrease the incidence of bovine respiratory disease (BRD). The selection of an antimicrobial drug for metaphylaxis should include analysis not only of efficacy but also of overall cost/benefit and of antimicrobial stewardship analyses. Antimicrobial medicinal products should be used for metaphylaxis only when, because of the presence of infected animals, the risk of spread of an infection or of an infectious disease in the group of animals is high and no other appropriate alternatives are available. For example, metaphylaxis in calves at high risk for BRD has been found consistently to reduce morbidity and mortality when parenteral drugs are administered (O’Connor et al., 2019). Thus, many antimicrobial drugs have been approved in different jurisdictions for the control of BRD in cattle at risk of developing respiratory disease. A recent network metaanalysis reported that macrolides are more effective in preventing natural outbreaks of BRD, but oxytetracycline is also effective for controlling this disease (O’Connor et al., 2019). This of interest, because comparison of the prophylactic efficacy of macrolides and oxytetracycline shows a net economic advantage of using oxytetracycline because of lower cost even though macrolides are more effective in preventing respiratory disease (Schunich et al., 2002). In addition, the importance of macrolides for treatment of human disease is higher than that for oxytetracycline. These data suggest that metaphylaxis is an effective approach for disease prevention and treatment of a herd or flock of animals at risk of a disease outbreak, but before implementation a through evaluation is required, including of efficacy, cost/benefit, antimicrobial stewardship issues, and regulations relating to the use of critically important antimicrobials (Chapters 23, 25). Antimicrobials are extensively used perioperatively to reduce the risk of surgical site infections. Unfortunately, there is a profound dearth of objective information about perioperative prophylaxis in animals, and antimicrobials are often overused or misused. This includes use of antimicrobials for procedures where they are not likely indicated, use of poor dosing regimens and extended postoperative administration. A general goal of perioperative antimicrobial use is to have therapeutic drug levels present throughout the “period of risk.” This starts at the time of first incision and ends at some point after surgery. The risk drops dramatically once the surgical wound has been closed but likely extends for a short duration postoperatively. This concept drives prophylaxis regimens and highlights the importance of focusing on proper treatment during the surgical period, with little to no benefit of antimicrobials after the period of risk has ended. Prospective study of perioperative antimicrobial use is challenging because of typically low infection rates and the corresponding need for large sample sizes. As a result, data are limited, studies are often underpowered and there is a reliance on retrospective studies that have many inherent limitations. Data from human medicine and experimental studies are also used to guide recommendations, with a need to acknowledge potential differences between humans and animals, and between different animal species and clinical environments. Surgical wound classification (Mangram et al., 1999) is a useful tool to determine whether antimicrobials are indicated (Table 24.2). Other factors can be considered, including the animal’s health status, presence of surgical implants, anticipated duration of surgery and the potential implications of infection. Generally, antimicrobials are not indicated for clean procedures that do not involve surgical implants, may be indicated for some (but not all) clean‐contaminated procedures, and are indicated for contaminated or dirty procedures. Table 24.2 Surgical wound classification. Source: Modified from Mangram et al. (1999). A variety of factors must be considered when choosing a perioperative antimicrobial. Drugs should be effective against the most common pathogens, safe, able to be administered intravenously, with known pharmacokinetics and ideally be lower tier drugs. Perioperative antimicrobials must typically be effective against staphylococci, as these are leading pathogens for most surgical procedures. Additional coverage against Gram‐negative bacteria or anaerobes may be indicated for some procedures. Accordingly, beta‐lactams are widely used. Cefazolin is the most common recommendation in humans (Bratzler et al., 2013; Berrios‐Torres et al., 2017) and is widely used in dogs and cats. Penicillins or cephalosporins are commonly used in cattle, while penicillin (often with an aminoglycoside) or ceftiofur are commonly used horses. Based on the concept of the period of risk, antimicrobials are typically administered intravenously, 30–60 minutes prior to surgery. Most of the antimicrobials used perioperatively have short half‐lives, which can result in subtherapeutic levels during the procedure. As a result, intraoperative redosing is common, with the general approach being to redose every two drug half‐lives until the procedure has finished. For example, cefazolin has a half‐life of approximately one hour in dogs, therefore it should be redosed every two hours during surgery. Once the period of risk is over, there is rarely a need for continued prophylaxis. In human surgery, it is very rare for prophylaxis to be extended more than 24 hours after surgery, even for complex procedures in highly compromised patients (Blatzler et al., 2013; Berrios‐Torres et al., 2017). Treatment for up to 24 hours postoperatively can be considered based on lack of clarity about when the period of risk truly ends. However, after that time, it is unlikely that continued treatment would be effective for control of bacterial contamination that occurred during surgery, since organisms would be expected to be either dead or resistant. In both of those scenarios, there would be no expected benefit of continued treatment. A potential exception is tibial plateau leveling osteotomy (TPLO) in dogs, a common procedure that often has a relatively high surgical site infection rate. While data are still mixed and the level of evidence low, some studies have indicated a protective effect of postoperative antimicrobials (Nazarali et al., 2014; Hagen et al., 2020). However, this finding has not been universal, and a systematic review concluded there was limited evidence supporting postoperative prophylaxis (Budsberg et al., 2021). Furthermore, “postoperative” has been broadly defined, with continuation of treatment of any duration after surgery included. Therefore, studies that reported a protective effect of postoperative antimicrobials may have simply identified a positive effect of continuing perioperative antimicrobials during the initial 24‐hour perioperative period. Study evaluating different postoperative durations is lacking and is needed to determine whether administration beyond 24 hours after surgery is protective. Various studies have evaluated surgical prophylaxis practices in small animals, horses, and cattle, and most have found poor compliance with basic recommendations (Dallap Schaer et al., 2012; Nazarali et al., 2014; Hardefeldt et al., 2017a, 2017b, 2018, 2019, 2020; Hagen et al., 2020; Ceriotti et al., 2021). Commonly identified errors include inappropriate timing of the first dose, inadequate dosing, failing to redose intraoperatively, long postoperative courses, inappropriate drug selection, and use in procedures where there is no evidence of need (e.g., arthroscopy). Immunosuppression in animals can result from acquired immune deficiency (e.g., neoplasia, immune‐mediated disease, endocrine disease, immunosuppressive drug therapy) or uncommonly from a congenital immune defect. The risk of infectious diseases in immunosuppressed animals depends on the severity and duration of the immunosuppressive disease or therapy. In recent years, the increasing use of newer and potent immunosuppressive drugs to treat immune‐mediated or neoplastic diseases or to prevent renal transplant rejection has allowed emergence of infections involving unusual organisms (Sykes, 2008). Immunosuppressed individuals can be at increased risk of disease caused by common pathogens, increased risk of disease caused by organisms that typically do not cause disease or increased risk for severe disease, when compared to their immunocompetent counterparts. The development of infectious diseases in immunosuppressed animals is a major challenge because it increases the risk of morbidity and mortality, the cost of treatment, and hospital stay (High and Olivry, 2020). Immunosuppression is not a specific or single state. Rather, individuals can be anywhere on a continuum from immunocompetent to profoundly immunosuppressed. It is also not a static event since the degree of immunosuppression can vary within an individual over time. These factors, along with difficulties in assessing immunocompetence, create challenges in determining and classifying potential infectious disease risks. The innate and acquired immune system comprises the host defense against pathogenic organisms. The innate immune system includes cellular (e.g., monocytes, neutrophils, natural killer cells) and humoral (e.g., complement, antimicrobial peptides) mechanisms (Blijlevens et al., 2020). The innate immune system rapidly recognizes pathogens and initiates their destruction and elimination via pattern recognition receptors that identify pathogen‐associated molecular patterns and elicits the consequent adaptive immune response (Lewis et al., 2012). Diseases, nutritional and reproductive (e.g., pregnancy) stage, toxins, trauma, and therapeutic interventions can alter the mechanism of defense, causing immunosuppression and predisposing animals to opportunistic infections (Datz, 2010). In patients with cancer, immunosuppression can be caused by both the disease and the treatment (Blijlevens et al., 2020). Immunosuppression can occur secondary to specific infectious diseases. In dogs, canine parvovirus‐2 and Ehrlichia canis are the principal infectious causes of neutropenia and immunosuppression. Neutropenia is also seen with Babesia spp. and Leishmania chagasi infections because of direct damage to the immune cells. In cats, feline panleukopenia virus, feline leukemia virus, and feline immunodeficiency virus infections are the principal infectious causes of neutropenia. Histoplasma capsulatum can also cause neutropenia in both dogs and cats secondary to bone marrow invasion and cell damage. Overwhelming gastrointestinal bacterial infection (e.g., salmonellosis, and Neorickettsia risticii and equine coronavirus infections) causes neutropenia in horses with normal granulopoiesis, by exhausting marrow granulocyte reserve. Patients with a preexistent immune deficiency such as a congenital immunodeficiency syndrome suffering from infectious diseases are doubly jeopardized. Endocrinopathies have detrimental effects on the immune system. Posterior pars intermedia dysfunction (PPID) and diabetes mellitus are associated with immunosuppression in adult horses and dogs, respectively. Hyperadrenocorticism is also associated with immunosuppressive effects in dogs (Datz, 2010). Deficiencies in a variety of essential and nonessential nutrients including fatty acids and vitamins A, B, C, D, and E, carotenoids, minerals (e.g., zinc, iron, selenium) can lead to decreased leukocyte function and immunosuppression (Datz, 2010). In dogs and cats, short‐term feeding restriction reduces the concentration of immunoglobulin concentrations, complement factors, antibody titers, and counts of total leukocytes and neutrophils. However, these functions return to normal after refeeding which suggests a significant association between a balanced nutrition and the immune system function in animals. Immunosuppressants and immunomodulators are medications commonly used in small and large animals to treat immune‐mediated, inflammatory, and neoplastic conditions. Glucocorticoids are the most common drugs used to modify immune response in animals with immune‐mediated diseases via inhibition of cytokine and adhesion protein production, reduction of expression and function of Fc receptors on macrophages and neutrophils, and reduced phagocytic or cytotoxic ability of the immune system. Cyclosporine is an immunosuppressant used mainly in small animals to manage immune‐mediated and allergic diseases and to prevent allograft transplant rejection (Datz, 2010). Cyclosporine suppresses the expression of activated T‐lymphocytes and other immune cells (Datz, 2010). Increased susceptibility to opportunistic infections has been documented in both small and large animals with the use of glucocorticoids and cyclosporine. Azathioprine is an immunosuppressant that interferes with lymphocyte proliferation, causing lymphopenia and reducing T‐cell‐dependent antibody production. Myelosuppression and gastrointestinal inflammation are common adverse effects reported in small animals treated with azathioprine, with myelosuppression being observed after 7–14 days of therapy. Chlorambucil, an immunosuppressive drug used for treatment of lymphoma and inflammatory bowel disease in cats, can cause myelosuppression 7–14 days after treatment is initiated. Opportunistic infections are reported in immunosuppressed small animals treated with azathioprine and chlorambucil (Worthing et al., 2019). Other drugs with a known but unpredictable risk for causing immunosuppression include estrogen and phenylbutazone in dogs, and chloramphenicol, griseofulvin, propylthiouracil, methimazole, carbimazole, and lithium in cats. Theoretically, any drug can cause an idiosyncratic reaction resulting in neutropenia and immunosuppression (e.g., albendazole, captopril, cephalosporins, fenbendazole, phenobarbital, primidone, quinidine, trimeprazine, and sulfonamides). Chemotherapy and radiation therapy are therapeutic interventions used in veterinary cancer patients that frequently cause bone marrow suppression as a side‐effect (Bergman, 2019). Most of the chemotherapeutic agents target tissues with a high growth fraction, so that rapidly dividing hematopoietic cells of the bone marrow are damaged, resulting in myelosuppression (Blijlevens et al., 2020). The consequences of bone marrow dysfunction are neutropenia (moderate to severe), followed by thrombocytopenia and anemia although the latter is usually rare and generally mild to moderate (Blijlevens et al., 2020). Profound neutropenia is also caused by total body irradiation. Limited information is available regarding the effects of chemotherapy on immune responses in small and large animals with cancer. In dogs with lymphoma and osteosarcoma, doxorubicin treatment has no effect on T‐ or B‐cell absolute count, but treatment with combination chemotherapy caused a significant and persistent decrease in B‐cell numbers (Walter et al., 2006). Further, antibody titers after vaccination are not significantly different between control and chemotherapy‐treated dogs (Walter et al., 2006). Neutropenic animals are at increased risk of developing bacterial, viral, and fungal infections, and established infections in neutropenic patients are more difficult to eradicate even with appropriate antimicrobial therapy. These infections can be caused by common opportunistic pathogens or those that rarely cause disease in animals with normal defense mechanisms (Sykes, 2008). Factors determining the probability of acquiring an opportunistic infection, and the severity and outcome of an established infection during neutropenia include the magnitude and duration of neutropenia, disruption of natural barriers (e.g., skin, mucosa), defects in specific immune factors, the organisms involved, the site of infection, the type of tumor and its biological stage, and the age, species, breed, and weight of the patient. In a case–control study to evaluate risk factors for the development of neutropenia (<2.5 × 109/l) and fever (>39.2 °C or 102.5 °F) in dogs receiving chemotherapy, dogs with lymphoma were at greater risk than dogs with solid tumors, although age, stage of the disease, and remission versus relapse did not affect risk (Sorenmo et al., 2010). The risk of infection is related to the degree of neutropenia, and neutropenia is graded to assist in predicting such risk (Veterinary Cooperative Oncology Group, 2016). Neutropenia is defined when a neutrophil count (segments and bands) is <0.5 × 109/l or <1 × 109/l with a predicted decline to 0.5 × 109/l within the next two days (Heinz et al., 2017). For a given degree of neutropenia, a higher risk of infection is associated with a falling rather than stable neutrophil count. These correlations between neutrophil count and risk of infection during an immunosuppressive stage are based on a classic study of humans with leukemia (Bodey et al., 1966). Studies investigating similar associations have not been conducted with small or large animals but based upon experimental studies with total body irradiation and clinical experience with veterinary cancer patients, this classification appears to be applicable to small animals (Abrams‐Ogg et al., 1993; Kruse et al., 2010; Veterinary Cooperative Oncology Group, 2016). The outcome of an opportunistic infection is also related to the duration of neutropenia. In humans, neutropenia of short duration (<7 days) is unlikely to predispose to severe infections that cannot be controlled with appropriate antimicrobial therapy. Infections accompanying neutropenia of moderate duration (7–14 days) are more difficult to treat. Infections in patients with prolonged neutropenia (>14 days) are even more difficult to manage, especially if the neutrophil count is <0.2 × 109/l. This difficulty is because antimicrobial agents act in concert with host defenses in eradicating infections. The risk of infection during neutropenia is increased by disruption of natural physical barriers, also known as mucositis (Castagnola et al., 2020
24
Antimicrobial Prophylaxis, Metaphylaxis, and the Treatment of Immunocompromised Patients
Introduction
Prophylactic and Metaphylactic Use of Antibiotics in Livestock
Term
European Union
American Veterinary Medical Association
Prophylaxis
(in the United States, prevention is synonymous with prophylaxis)
Administration before clinical signs of a disease to prevent the occurrence of disease or infection
As proposed in the EU, prophylactic use is only in exceptional cases, in an individual or a restricted number of animals treated individually, when the risk of infection is very high and the consequences likely to be severe
Administration to animals, none of which have evidence of disease or infection, when transmission of existing undiagnosed infections, or the introduction of pathogens, is anticipated based on history, clinical judgment, or epidemiological knowledge
Metaphylaxis
(in the United States, control is synonymous with metaphylaxis)
Administration after a diagnosis of clinical disease in part of the group has been established, with the aim of treating the clinically sick animals and controlling the spread of the disease to animals in close contact and at risk and which may already be subclinically infected
The use of antimicrobial drugs to reduce the incidence of infectious disease in a group of animals that already has some individuals with evidence of infectious disease or evidence of infection
Prophylaxis in Livestock
Metaphylaxis in Livestock
Antimicrobial Prophylaxis for Surgery
When Antimicrobials are Indicated
Classification
Description
Clean
Site with no prior trauma or inflammation, no breaks in sterile technique during surgery, and no contact with mucosal surfaces such as the respiratory, genitourinary, or alimentary tracts
Clean‐contaminated
Minor breaks in surgical technique (e.g., torn glove), contact with normal mucosae of the gastrointestinal (GI) tract without spillage of contents, or contact with uninfected genitourinary, biliary, or respiratory tracts. This also includes otherwise clean procedures involving drain placement
Contaminated
Accidental GI tract spillage from an infected viscus or tissue, foreign bodies, devitalized tissue, or pus, or a significant break in sterile technique
Dirty
Surgical wounds that are already infected or have breaks in the skin associated with blunt trauma. Devitalized tissues, foreign bodies, or purulent discharges are often observed
Drug Selection
Dosing Regimens
Postoperative Administration
Compliance with Surgical Prophylaxis Recommendations
Antimicrobial Prophylaxis and Treatment of Immunocompromised Patients
Introduction
Causes of Immunosuppression in Small and Large Animals
Nutrition
Drugs
Cancer therapy
Risk Factors for Opportunistic Infection in Immunosuppressed Patients
Neutropenia
Mucositis
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