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InternalMed_Harrison. LUNG TRANSPLANTATION Early Infections It is not surprising that lung transplant recipients are predisposed to the development of pneumonia. The combination of ischemia and the resulting mucosal damage, together with accompanying denervation and lack of lymphatic drainage, probably contributes to the high rate of pneumonia (66% in one series). The prophylactic use of high doses of broad-spectrum antibiotics for the first 3–4 days after surgery may decrease the incidence of pneumonia. Gram-negative pathogens (Enterobacteriaceae and Pseudomonas species) are troublesome in the first 2 weeks after surgery (the period of maximal vulnerability). Pneumonia can also be caused by Candida (possibly as a result of colonization of the donor lung), Aspergillus, and Cryptococcus. Many centers use antifungal prophylaxis (typically fluconazole or liposomal amphotericin B) for the first 1–2 weeks.


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InternalMed_Harrison. Mediastinitis may occur at an even higher rate among lung transplant recipients than among heart transplant recipients and most commonly develops within 2 weeks of surgery. In the absence of prophylaxis, pneumonitis due to CMV (which may be transmitted as a consequence of transplantation) usually presents between 2 weeks and 3 months after surgery, with primary disease occurring later than reactivation disease.


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InternalMed_Harrison. Middle-Period Infections The incidence of CMV infection, either reactivated or primary, is 75–100% if either the donor or the recipient is seropositive for CMV. CMV-induced disease after solid organ transplantation appears to be most severe in recipients of lung and heart-lung transplants. Whether this severity relates to the mismatch in lung antigen presentation and host immune cells or is attributable to nonimmunologic factors is not known. More than half of lung transplant recipients with symptomatic CMV disease have pneumonia. Difficulty in distinguishing the radiographic picture of CMV infection from that of other infections or from organ rejection further complicates therapy. CMV can also cause bronchiolitis obliterans in lung transplants. The development of pneumonitis related to HSV has led to the prophylactic use of acyclovir. Such prophylaxis may also decrease rates of CMV disease, but ganciclovir is more active against CMV and is also active against HSV. The prophylaxis of


InternalMed_Harrison

InternalMed_Harrison. has led to the prophylactic use of acyclovir. Such prophylaxis may also decrease rates of CMV disease, but ganciclovir is more active against CMV and is also active against HSV. The prophylaxis of CMV infection with IV ganciclovir—or increasingly with valganciclovir, the oral alternative—is recommended for lung transplant recipients. Antiviral alternatives are discussed in the earlier section on HSC transplantation. Although the overall incidence of serious disease is decreased during prophylaxis, late disease may occur when prophylaxis is stopped—a pattern observed increasingly in recent years. With recovery from peritransplantation complications and, in many cases, a decrease in immunosuppression, the recipient is often better equipped to combat late infection.


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InternalMed_Harrison. Late Infections The incidence of Pneumocystis infection (which may present with a paucity of findings) is high among lung and heart-lung transplant recipients. Some form of prophylaxis for Pneumocystis pneumonia is indicated in all organ transplant situations (Table 169-5). Prophylaxis with TMP-SMX for 12 months after transplantation may be sufficient to prevent Pneumocystis disease in patients whose immunosuppression is not increased.


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InternalMed_Harrison. As in other transplant recipients, EBV infection in lung and heart-lung recipients may cause either a mononucleosis-like syndrome or EBV-LPD. The tendency of the B cell blasts to present in the lung appears to be greater after lung transplantation than after the transplantation of other organs, possibly because of a rich source of B cells in bronchus-associated lymphoid tissue. Reduction of immunosuppression and switching of regimens, as discussed in earlier sections, cause remission in some cases, but mTor inhibitors such as rapamycin may contribute to lung toxicity. Airway compression can be fatal, and rapid intervention may therefore become necessary. The approach to EBV-LPD is similar to that described in other sections.


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InternalMed_Harrison. LIVER TRANSPLANTATION Early Infections As in other transplantation settings, early bacterial infections are a major problem after liver transplantation. Many centers administer systemic broad-spectrum antibiotics for the first 24 h or sometimes longer after surgery, even in the absence of documented infection. However, despite prophylaxis, infectious complications are common and correlate with the duration of the surgical procedure and the type of biliary drainage. An operation lasting >12 h is associated with an increased likelihood of infection. Patients who have a choledochojejunostomy with drainage of the biliary duct to a Roux-en-Y jejunal bowel loop have more fungal infections than those whose bile is drained 927 via anastomosis of the donor common bile duct to the recipient common bile duct. Overall, liver transplant patients have a high incidence of fungal infections, and the occurrence of fungal (often candidal) infection in the setting of choledochojejunostomy correlates


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InternalMed_Harrison. bile duct. Overall, liver transplant patients have a high incidence of fungal infections, and the occurrence of fungal (often candidal) infection in the setting of choledochojejunostomy correlates with retransplantation, elevated creatinine levels, long procedures, transfusion of >40 units of blood, reoperation, preoperative use of glucocorticoids, prolonged treatment with antibacterial agents, and fungal colonization 2 days before and 3 days after surgery. Many centers give antifungal agents prophylactically in this setting.


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InternalMed_Harrison. Peritonitis and intraabdominal abscesses are common complications of liver transplantation. Bacterial peritonitis or localized abscesses may result from biliary leaks. Early leaks are especially common with live-donor liver transplants. Peritonitis in liver transplant recipients is often polymicrobial, frequently involving enterococci, aerobic gram-negative bacteria, staphylococci, anaerobes, or Candida and sometimes involving other invasive fungi. Only one-third of patients with intraabdominal abscesses have bacteremia. Abscesses within the first month after surgery may occur not only in and around the liver but also in the spleen, pericolic area, and pelvis. Treatment includes antibiotic administration and drainage as necessary.


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InternalMed_Harrison. Middle-Period Infections The development of postsurgical biliary stricture predisposes patients to cholangitis. The incidence of strictures is increased in live-donor liver transplantation. Transplant recipients who develop cholangitis may have high spiking fevers and rigors but often lack the characteristic signs and symptoms of classic cholangitis, including abdominal pain and jaundice. Although these findings may suggest graft rejection, rejection is typically accompanied by marked elevation of liver function enzymes. In contrast, in cholangitis in transplant recipients, results of liver function tests (with the possible exception of alkaline phosphatase levels) are often within the normal range. Definitive diagnosis of cholangitis in liver transplant recipients requires demonstration of aggregated neutrophils in bile duct biopsy specimens. Unfortunately, invasive studies of the biliary tract (either T-tube cholangiography or endoscopic retrograde cholangiopancreatography) may


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InternalMed_Harrison. of aggregated neutrophils in bile duct biopsy specimens. Unfortunately, invasive studies of the biliary tract (either T-tube cholangiography or endoscopic retrograde cholangiopancreatography) may themselves lead to cholangitis. For this reason, many clinicians recommend an empirical trial of therapy with antibiotics covering gram-negative organisms and anaerobes before these procedures are undertaken as well as antibiotic coverage if procedures are eventually performed.


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InternalMed_Harrison. Reactivation of viral hepatitis is a common complication of liver transplantation (Chap. 360). Recurrent hepatitis B and C infections, for which transplantation may be performed, are problematic. To prevent hepatitis B virus reinfection, prophylaxis with an optimal antiviral agent or combination of agents (lamivudine, adefovir, entecavir) and hepatitis B immune globulin is currently recommended, although the optimal dose, route, and duration of therapy remain controversial. Success in preventing reinfection with hepatitis B virus has increased in recent years. Complications related to hepatitis C infection are the most common reason for liver transplantation in the United States. Reinfection of the graft with hepatitis C virus occurs in all patients, with a variable time frame. Studies of aggressive pretransplantation treatment of selected recipients with antiviral agents and prophylactic/ preemptive regimens are ongoing. However, early posttransplantation initiation of treatment for


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InternalMed_Harrison. aggressive pretransplantation treatment of selected recipients with antiviral agents and prophylactic/ preemptive regimens are ongoing. However, early posttransplantation initiation of treatment for histologically documented disease with the classic combination of ribavirin and pegylated interferon has produced sustained responses at rates in the range of 25–40%. Several protease and polymerase inhibitors that block production of hepatitis C virus as well as regimens that spare interferon and a monoclonal antibody to the virus are undergoing preclinical and clinical trials for prevention and or control of infection after transplantation (Chap. 360).


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InternalMed_Harrison. As in other transplantation settings, reactivation disease with herpesviruses is common (Table 169-3). Herpesviruses can be transmitted in donor organs. Although CMV hepatitis occurs in ∼4% of liver transplant recipients, it is usually not so severe as to require retransplantation. Without prophylaxis, CMV disease develops in the majority of seronegative recipients of organs from CMV-positive donors, but fatality rates are lower among liver transplant recipients than among lung or heart-lung transplant recipients. Disease due to CMV can also 928 be associated with the vanishing bile duct syndrome after liver transplantation. Patients respond to treatment with ganciclovir; prophylaxis with oral forms of ganciclovir or high-dose acyclovir may decrease the frequency of disease. A role for HHV-6 reactivation in early posttransplantation fever and leukopenia has been proposed, although the more severe sequelae described in HSC transplantation are unusual. HHV-6 and HHV-7 appear to


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InternalMed_Harrison. for HHV-6 reactivation in early posttransplantation fever and leukopenia has been proposed, although the more severe sequelae described in HSC transplantation are unusual. HHV-6 and HHV-7 appear to exacerbate CMV disease in this setting. EBVLPD after liver transplantation shows a propensity for involvement of the liver, and such disease may be of donor origin. See previous sections for discussion of EBV infections in solid organ transplantation.


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InternalMed_Harrison. Pancreas transplantation is most frequently performed together with or after kidney transplantation, although it may be performed alone. Transplantation of the pancreas can be complicated by early bacterial and yeast infections. Most pancreatic transplants are drained into the bowel, and the rest are drained into the bladder. A cuff of duodenum is used in the anastomosis between the pancreatic graft and either the gut or the bladder. Bowel drainage poses a risk of early intraabdominal and allograft infections with enteric bacteria and yeasts. These infections can result in loss of the graft. Bladder drainage causes a high rate of urinary tract infection and sterile cystitis; however, such infection can usually be cured with appropriate antimicrobial agents. In both procedures, prophylactic antimicrobial agents are commonly used at the time of surgery. Aggressive immunosuppression, especially when the patient receives a kidney and a pancreas from different donors, is associated with


InternalMed_Harrison

InternalMed_Harrison. antimicrobial agents are commonly used at the time of surgery. Aggressive immunosuppression, especially when the patient receives a kidney and a pancreas from different donors, is associated with late-onset systemic fungal and viral infections; thus many centers administer an antifungal drug and an antiviral agent (ganciclovir or a congener) for extended prophylaxis.


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InternalMed_Harrison. Issues related to the development of CMV infection, EBV-LPD, and infections with opportunistic pathogens in patients receiving a pancreatic transplant are similar to those in other SOT recipients.


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InternalMed_Harrison. Composite tissue allotransplantation (CTA) is a new field in which, rather than a single organ, multiple tissue types composing a major body part are transplanted. The sites involved have included an upper extremity, the face, the trachea, the knee, and the abdominal wall. The numbers of recipients are limited. The different procedures and the associated infectious complications vary. Nevertheless, some early trends related to infectious complications have become apparent, as very intense and prolonged immunosuppression is typically required to prevent rejection. For example, in the early postoperative period, bacterial infections are especially frequent in facial transplant recipients. Perioperative prophylaxis is tailored to the organisms likely to complicate the different procedures. As in SOT recipients, complicated CMV infections have been observed in several CTA settings, particularly when the recipient is seronegative and the donor is seropositive. In some patients, anti-CMV


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InternalMed_Harrison. As in SOT recipients, complicated CMV infections have been observed in several CTA settings, particularly when the recipient is seronegative and the donor is seropositive. In some patients, anti-CMV immune globulin in addition to ganciclovir (as used in HSC transplant recipients with CMV pneumonia) was needed to control disease, and ganciclovir resistance requiring alternative therapies developed in several patients. Infectious complications from reactivation of other members of the human herpesvirus family and other latent viruses also caused significant morbidity, as discussed for SOT recipients. Prophylaxis for CMV infection, P. jirovecii infection, toxoplasmosis, and fungal infection is administered for several months on the basis of the limited studies available.


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InternalMed_Harrison. MISCELLANEOUS INFECTIONS IN SOLID ORGAN TRANSPLANTATION Indwelling IV Catheter Infections The prolonged use of indwelling IV catheters for administration of medications, blood products, and nutrition is common in diverse transplantation settings and poses a risk of local and bloodstream infections. Exit-site infection is most commonly caused by staphylococcal species. Bloodstream infection most frequently develops within 1 week of catheter placement or in patients who become neutropenic. Coagulase-negative staphylococci are the most common isolates from blood. Although infective endocarditis in HSC transplant recipients is uncommon, the incidence of endocarditis in SOT recipients has been estimated to be as high as 1%, and this infection is associated with excessive high mortality in this population. Although staphylococci predominate, the involvement of fungal and gram-negative organisms may be more common than in the general population.


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InternalMed_Harrison. For further discussion of differential diagnosis and therapeutic options, see Chap. 104.


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InternalMed_Harrison. Tuberculosis The incidence of tuberculosis within the first 12 months after solid organ transplantation is greater than that observed after HSC transplantation (0.23–0.79%) and ranges broadly worldwide (1.2– 15%), reflecting the prevalence of tuberculosis in local populations. Lesions suggesting prior tuberculosis on chest radiography, older age, diabetes, chronic liver disease, GVHD, and intense immunosuppression are predictive of tuberculosis reactivation and development of disseminated disease in a host with latent disease. Tuberculosis has rarely been transmitted from the donor organ. In contrast to the low mortality rate among HSC transplant recipients, mortality rates among SOT recipients are reported to be as high as 30%. Vigilance is indicated, as the presentation of disease is often extrapulmonary (gastrointestinal, genitourinary, central nervous, endocrine, musculoskeletal, laryngeal) and atypical; tuberculosis in this setting sometimes manifests as fever of unknown origin.


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InternalMed_Harrison. extrapulmonary (gastrointestinal, genitourinary, central nervous, endocrine, musculoskeletal, laryngeal) and atypical; tuberculosis in this setting sometimes manifests as fever of unknown origin. Careful elicitation of a history and direct evaluation of both the recipient and the donor prior to transplantation are optimal. Skin testing of the recipient with purified protein derivative may be unreliable because of chronic disease and/or immunosuppression. Cell-based assays that measure interferon γ and/or cytokine production may prove more sensitive in the future. Isoniazid toxicity has not been a significant problem except in the setting of liver transplantation. Therefore, appropriate prophylaxis should be used (see recommendations from the Centers for Disease Control and Prevention [CDC] at www.cdc.gov/tb/topic/treatment/ltbi.htm). An assessment of the need to treat latent disease should include careful consideration of the possibility of a false-negative test result. Pending final


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InternalMed_Harrison. at www.cdc.gov/tb/topic/treatment/ltbi.htm). An assessment of the need to treat latent disease should include careful consideration of the possibility of a false-negative test result. Pending final confirmation of suspected tuberculosis, aggressive multidrug treatment in accordance with the guidelines of the CDC, the Infectious Diseases Society of America, and the American Thoracic Society is indicated because of the high mortality rates among these patients. Altered drug metabolism (e.g., upon coadministration of antituberculous medications and certain immunosuppressive agents) can be managed with careful monitoring of drug levels and appropriate dose adjustment. Close follow-up of hepatic enzymes is warranted. Drug-resistant tuberculosis is especially problematic in these individuals (Chap. 202).


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InternalMed_Harrison. Virus-Associated Malignancies In addition to malignancy associated with gammaherpesvirus infection (EBV, KSHV) and simple warts (HPV), other tumors that are virus-associated or suspected of being virus-associated are more likely to develop in transplant recipients, particularly those who require long-term immunosuppression, than in the general population. The interval to tumor development is usually >1 year. Transplant recipients develop nonmelanoma skin or lip cancers that, in contrast to de novo skin cancers, have a high ratio of squamous cells to basal cells. HPV may play a major role in these lesions. Cervical and vulvar carcinomas, which are quite clearly associated with HPV, develop with increased frequency in female transplant recipients. The frequency of Merkel cell carcinoma associated with Merkel cell polyomavirus is also increased in transplant recipients; however, it is unclear whether recipients infected with HTLV-1 are at increased risk of leukemia. Among renal


InternalMed_Harrison

InternalMed_Harrison. associated with Merkel cell polyomavirus is also increased in transplant recipients; however, it is unclear whether recipients infected with HTLV-1 are at increased risk of leukemia. Among renal transplant recipients, rates of melanoma are modestly increased and rates of cancers of the kidney and bladder are increased.


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InternalMed_Harrison. (See also Chap. 148) In addition to receiving antibiotic prophylaxis, transplant recipients should be vaccinated against likely pathogens (Table 169-6). In the case of HSC transplant recipients, optimal responses cannot be achieved until after immune reconstitution, despite previous immunization of both donor and recipient. Recipients of an allogeneic HSC transplant must be reimmunized if they are to be protected against pathogens. The situation is less clear-cut in the case of autologous transplantation. T and B cells in the peripheral blood may reconstitute the immune response if they are transferred Type of Transplantation aImmunizations should be given before solid organ transplantation whenever possible.


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InternalMed_Harrison. Type of Transplantation aImmunizations should be given before solid organ transplantation whenever possible. Abbreviations: CDC, Centers for Disease Control and Prevention; ACIP, Advisory Committee on Immunization Practices; DTaP, full-level diphtheria and tetanus toxoids and acellular pertussis, adsorbed; GVHD, graft-versus-host disease; Tdap, tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; IDSA, Infectious Diseases Society of America. Note: Recommendations from the CDC should be checked regularly as they frequently change upon receipt of new clinical information and new formulations of specific vaccines.


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InternalMed_Harrison. in adequate numbers. However, cancer patients (particularly those with Hodgkin’s disease, in whom vaccination has been extensively studied) who are undergoing chemotherapy do not respond normally to immunization, and titers of antibodies to infectious agents fall more rapidly than in healthy individuals. Therefore, even immunosuppressed patients who have not undergone HSC transplantation may need booster vaccine injections. If memory cells are specifically eliminated as part of a stem cell “cleanup” procedure, it will be necessary to reimmunize the recipient with a new primary series. Optimal times for immunizations of different transplant populations are being evaluated. Yearly immunization of household and other contacts (including health care personnel) against influenza benefits the patient by preventing local spread.


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InternalMed_Harrison. In the absence of compelling data as to optimal timing, it is reasonable to administer the pneumococcal and H. influenzae type b conjugate vaccines to both autologous and allogeneic HSC transplant recipients beginning 12 months after transplantation. A series that includes both the 13-valent pneumococcal conjugate vaccine (Prevnar) and the 23-valent pneumococcal polysaccharide vaccine (Pneumovax) is now recommended (according to CDC guidelines). The pneumococcal and


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InternalMed_Harrison. H. influenzae type b vaccines are particularly important for patients who have undergone splenectomy. The Neisseria meningitidis polysaccharide conjugate vaccine (Menactra or Menveo) also is recommended. In addition, diphtheria, tetanus, acellular pertussis, and inactivated polio vaccines can all be given at these same intervals (12 months and, as required, 24 months after transplantation). Some authorities recommend a new primary series for tetanus/diphtheria/pertussis and inactivated poliovirus vaccines beginning 12 months after transplantation. Vaccination to prevent hepatitis B and hepatitis A (both killed vaccines) also seems advisable. A formal recommendation regarding 929 immunization with the tetravalent HPV virus-like particle vaccine (Gardasil) after HSC transplantation has not been issued. However, HPV vaccination, which can prevent genital warts as well as specific cancers, is recommended through age 26 for healthy young adults who previously have not been vaccinated or


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InternalMed_Harrison. been issued. However, HPV vaccination, which can prevent genital warts as well as specific cancers, is recommended through age 26 for healthy young adults who previously have not been vaccinated or have not received the full series. Live-virus measles/mumps/rubella (MMR) vaccine can be given to autologous HSC transplant recipients 24 months after transplantation and to most allogeneic HSC transplant recipients at the same point if they are not receiving maintenance therapy with immunosuppressive drugs and do not have ongoing GVHD. The risk of spread from a household contact is low for MMR vaccine. In parts of the world where live poliovirus vaccine is used, patients as well as contacts should be advised to receive only the killed vaccine. In the rare setting where both donor and recipient are VZV naïve and the recipient is no longer receiving acyclovir or ganciclovir prophylaxis, the patient should be counseled to receive varicella-zoster immune globulin (VariZIG) up to 10 days after


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InternalMed_Harrison. are VZV naïve and the recipient is no longer receiving acyclovir or ganciclovir prophylaxis, the patient should be counseled to receive varicella-zoster immune globulin (VariZIG) up to 10 days after an exposure to a person with chickenpox or uncovered zoster; such patients should avoid close contact with persons recently vaccinated with Varivax. A formal recommendation regarding Varivax immunization of such patients is not currently available. Neither patients nor their household contacts should receive vaccinia vaccine unless they have been exposed to smallpox virus. Among patients who have active GVHD and/or are taking high maintenance doses of glucocorticoids, it may be prudent to avoid all live-virus vaccines.


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InternalMed_Harrison. In the case of SOT recipients, administration of all the usual vaccines and of the indicated booster doses should be completed before immunosuppression, if possible, to maximize responses. For patients taking immunosuppressive agents, the administration of pneumococcal vaccine should be repeated every 5 years. No data are available for the meningococcal vaccine, but it is probably reasonable to administer it along with the pneumococcal vaccine. H. influenzae conjugate vaccine is safe and should be efficacious in this population; therefore, its administration before transplantation is recommended. Booster doses of this vaccine are not recommended for adults. SOT recipients who continue to receive immunosuppressive drugs should not receive live-virus vaccines. A person in this group who is exposed to measles should be given measles immune globulin. Similarly, an immunocompromised patient who is seronegative for varicella and who comes into contact with a person who has chickenpox should


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InternalMed_Harrison. to measles should be given measles immune globulin. Similarly, an immunocompromised patient who is seronegative for varicella and who comes into contact with a person who has chickenpox should be given varicellazoster immune globulin as soon as possible (optimally within 96 h; up to 10 days after contact); if this is not possible, a 10to 14-day course of acyclovir therapy should be started immediately. Upon the discontinuation of treatment, clinical disease may still occur in a small number of patients; thus vigilance is indicated. Rapid re-treatment with acyclovir should limit the symptoms of disease. Household contacts of transplant recipients can receive live attenuated VZV vaccine, but vaccinees should avoid direct contact with the patient if a rash develops. Virus-like particle vaccines have been licensed for the prevention of infection with several HPV serotypes most commonly implicated in cervical and anal carcinomas and in anogenital and laryngeal warts. These vaccines are not


InternalMed_Harrison

InternalMed_Harrison. have been licensed for the prevention of infection with several HPV serotypes most commonly implicated in cervical and anal carcinomas and in anogenital and laryngeal warts. These vaccines are not live; however, no information is yet available about their immunogenicity or efficacy in transplant recipients.


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InternalMed_Harrison. Immunocompromised patients who travel may benefit from some but not all vaccines (Chaps. 148 and 149). In general, these patients should receive any killed or inactivated vaccine preparation appropriate to the area they are visiting; this recommendation includes the vaccines for Japanese encephalitis, hepatitis A and B, poliomyelitis, meningococcal infection, and typhoid. The live typhoid vaccines are not recommended for use in most immunocompromised patients, but an inactivated or purified polysaccharide typhoid vaccine can be used. Live yellow fever vaccine should not be administered. On the other hand, primary immunization or boosting with the purified-protein hepatitis B vaccine is indicated. Inactivated hepatitis A vaccine should also be used in the appropriate setting (Chap. 148). A vaccine is now available that provides dual protection against hepatitis A and hepatitis


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InternalMed_Harrison. B. If hepatitis A vaccine is not administered, travelers should consider receiving passive protection with immune globulin (the dose depending on the duration of travel in the high-risk area).


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InternalMed_Harrison. 930 Treatment and Prophylaxis of Bacterial Infections David C. Hooper, Erica S. Shenoy, Christy A. Varughese Antimicrobial agents have had a major impact on human health. Together with vaccines, they have contributed to reduced mortality, extended lifespan, and enhanced quality of life. Among drugs used in human medicine, however, they are distinctive in that their use promotes the occurrence of drug resistance in the pathogens they are designed to treat as well as in other “bystander” organisms. Indeed, the history of antimicrobial development has been driven in large part by the medical need engendered by the emergence of resistance to each generation of agents. Thus, the careful and appropriate use of antimi-crobial drugs is particularly important not only for optimizing efficacy and minimizing adverse effects but also for minimizing the risk of resis-tance and preserving the value of existing agents. Although this chapter focuses on antibacterial agents, the optimal use of all


InternalMed_Harrison

InternalMed_Harrison. minimizing adverse effects but also for minimizing the risk of resis-tance and preserving the value of existing agents. Although this chapter focuses on antibacterial agents, the optimal use of all antimicrobials depends on an understanding of each drug’s mechanism of action, spectrum of activity, mechanisms of resistance, pharmacology, and adverse effect profile. This information is then applied in the context of the patient’s clinical presentation, underlying conditions, and epi-demiology to define the site and likely nature of the infection or other condition and thus to choose the best therapy. Gathering of microbio-logic information is important for refining therapeutic choices on the basis of documented pathogen and susceptibility data whenever pos-sible; this information also makes it possible to choose more targeted therapy, thereby reducing the risk of selection of resistant bacteria. Durations of therapy are chosen according to the nature of the infec-tion and the patient’s


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InternalMed_Harrison. it possible to choose more targeted therapy, thereby reducing the risk of selection of resistant bacteria. Durations of therapy are chosen according to the nature of the infec-tion and the patient’s response to treatment and are informed by clini-cal studies when they are available, with the understanding that shorter courses are less likely than longer ones to promote the emergence of resistance. This chapter provides specific information that is necessary for making informed choices among antibacterial agents. MECHANISMS OF ACTION AND RESISTANCE 170 SEC TIon 4 APPRoACH To THERAPy foR BACTERIAL DISEASES


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InternalMed_Harrison. The mechanisms of action of and resistance to antibacterial agents are discussed in detail in the text and are summarized for the most commonly used groups of agents in Table 170-1. A schematic of antibacterial targets is provided in Fig. 170-1.


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InternalMed_Harrison. Multiple essential components of bacterial cell structures and metabolism have been the targets of antibacterial agents used in clinical medicine, and the interaction of an agent with its target results in either inhibition of bacterial growth and replication (bacteriostatic effect) or bacterial killing (bactericidal effect). In general, targets have been chosen because they either do not exist in mammalian cells and physiology or are sufficiently different from their bacterial counterparts to allow selective bacterial targeting. Treatment with bacteriostatic agents is effective when the patient’s host defenses are sufficient to contribute to eradication of the infecting pathogen. In patients with impaired host defenses (e.g., neutropenia) or infections at body sites with impaired or limited host defenses (e.g., meningitis and endocarditis), bactericidal agents are generally preferred.


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InternalMed_Harrison. Inhibition of Cell Wall Synthesis The bacterial cell wall, which is external to the cytoplasmic membrane and has no counterpart in mammalian cells, protects bacterial cells from lysis under low osmotic conditions. The cell wall is a cross-linked peptidoglycan composed of a polymer of alternating units of N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM), four-amino-acid stem peptides linked to each NAM, and a peptide cross-bridge that links adjacent stem peptides to form a net-like structure. Several steps in peptidoglycan synthesis are targets of antibacterial agents. Inhibition of cell wall synthesis generally results in a bactericidal effect that is linked to cell lysis. This effect results not only from the blocking of new cell-wall formation but from the uninhibited action of cell wall–remodeling enzymes called autolysins, which cleave peptidoglycan as part of normal cell-wall growth.


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InternalMed_Harrison. In gram-positive bacteria the peptidoglycan is the most external cell structure, but in gram-negative bacteria an asymmetric lipid outer membrane is external to the peptidoglycan and contains diffusion channels called porins. The space between the cytoplasmic membrane peptidoglycan and the outer membrane is referred to as the periplasmic space. Most antibacterial drugs enter the gram-negative bacterial cell through a porin channel, since the outer membrane is a major diffusion barrier. Although the peptidoglycan layer is thicker in gram-positive (20–80 nm) than in gram-negative (1 nm) bacteria, peptidoglycan itself constitutes only a limited diffusion barrier for antibacterial agents. β-lactams The β-lactam drugs, including penicillins, cephalosporins, monobactams, and carbapenems, target transpeptidase enzymes (also called penicillin-binding proteins, or PBPs) involved in the stem-peptide cross-linking step.


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InternalMed_Harrison. glycopeptides The glycopeptides, including vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin, bind the two terminal d-alanine residues of the stem peptide, hindering the glycosyltransferase involved in polymerizing NAG–NAM units. Telavancin also binds to the lipid II intermediate that delivers cell-wall precursor subunits. Likewise, dalbavancin and oritavancin interact with the cell membrane, and oritavancin may also inhibit transpeptidases. Both β-lactams and glycopeptides interact with their targets external to the cytoplasmic membrane. bacitracin (topical) and fosfomycin These agents interrupt enzymatic steps in the production of peptidoglycan precursors in the cytoplasm.


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InternalMed_Harrison. bacitracin (topical) and fosfomycin These agents interrupt enzymatic steps in the production of peptidoglycan precursors in the cytoplasm. Inhibition of Protein Synthesis Most inhibitors of bacterial protein synthesis target bacterial ribosomes, whose difference from eukaryotic ribosomes allows selective antibacterial action. Some inhibitors bind to the 30S ribosomal subunit and others to the 50S subunit. Most protein synthesis–inhibiting agents are bacteriostatic; aminoglycosides are an exception and are bactericidal.


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InternalMed_Harrison. aminoglycosides Aminoglycosides (amikacin, gentamicin, kanamycin, netilmicin, streptomycin, tobramycin) bind irreversibly to 16S ribosomal RNA (rRNA) of the 30S ribosomal subunit, blocking the trans-location of peptidyl transfer RNA (tRNA) from the A (aminoacyl) to the P (peptidyl) site and, at low concentrations, causing misreading of messenger RNA (mRNA) codons and thus causing the introduction of incorrect amino acids into the peptide chain; at higher concentrations, translocation of the peptide chain is blocked. Cellular uptake of aminoglycosides is dependent on the electrochemical gradient across the bacterial membrane. Under anaerobic conditions, this gradient is reduced, with a consequent reduction in the uptake and activity of the aminoglycosides. Spectinomycin is a related aminocyclitol antibiotic that also binds to 16S rRNA of the 30S ribosomal subunit but at a different site. This drug inhibits translocation of the growing peptide chain but does not trigger codon misreading


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InternalMed_Harrison. antibiotic that also binds to 16S rRNA of the 30S ribosomal subunit but at a different site. This drug inhibits translocation of the growing peptide chain but does not trigger codon misreading and produces only a bacteriostatic effect.


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InternalMed_Harrison. tetracyclines and glycylcyclines Tetracyclines (doxycycline, minocycline, tetracycline) bind reversibly to the 16S rRNA of the 30S ribosomal subunit and block the binding of aminoacyl tRNA to the ribosomal A site, thereby inhibiting peptide elongation. Active transport of tetracyclines into bacterial but not mammalian cells contributes to the selectivity of these agents. Tigecycline, a derivative of minocycline and Antibacterial Agent(s) Major Target Mechanism(s) of Action Mechanism(s) of Resistance cytoplasmic membranes Daptomycin Cell membrane Produces membrane channel and membrane leakage Abbreviations: LPS, lipopolysaccharide; NAG, N-acetylglucosamine; PBP, penicillin-binding protein. 1. 2. 3. 1. 2. 1. 2. 1. 2. 3. Decreased permeation to target due to active efflux 1. 2. 1. 2. 1. Same as macrolides 2. 1. 2. Methylation of ribosome binding site 1. 2. 1. 2. 3. Protection of target from drug 4. 1. 2. 3.


InternalMed_Harrison

InternalMed_Harrison. 2. 1. 2. 1. Same as macrolides 2. 1. 2. Methylation of ribosome binding site 1. 2. 1. 2. 3. Protection of target from drug 4. 1. 2. 3. Altered cell membrane charge with reduced drug binding Altered cell membrane with reduced drug binding Treatment and Prophylaxis of Bacterial Infections the only available glycylcycline, acts similarly to the tetracyclines but is distinctive for its ability to circumvent the most common mechanisms of resistance to the tetracyclines. macrolides and Ketolides In contrast to the aminoglycosides and tetracyclines, the macrolides (azithromycin, clarithromycin, erythromycin) and ketolides (telithromycin) bind to the 23S rRNA of the 50S ribosomal subunit. These agents block translocation of the growing peptide chain by binding to the tunnel from which the chain exits the ribosome.


InternalMed_Harrison

InternalMed_Harrison. lincosamides Clindamycin is the only lincosamide in clinical use. It binds to the 23S rRNA of the 50S ribosomal subunit, interacting with both the ribosomal A and P sites and blocking peptide bond formation. streptogramins The only streptogramin in clinical use is a combination of quinupristin, a group B streptogramin, and dalfopristin, a group A streptogramin. Both components bind to 23S rRNA of the 50S ribosome: dalfopristin binds to both the A and P sites of the peptidyl transferase center, and quinupristin binds to a site that overlaps the macrolide-binding site, blocking the emergence of nascent peptide FIGURE 170-1 Antibacterial targets. A, aminoacyl site; DHFR, dihydrofolate reductase; DHPS, dihydropteroate synthetase; P, peptidyl site; PBP, penicillin-binding protein; tRNA-aa, aminoacyl tRNA.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 170-1 Antibacterial targets. A, aminoacyl site; DHFR, dihydrofolate reductase; DHPS, dihydropteroate synthetase; P, peptidyl site; PBP, penicillin-binding protein; tRNA-aa, aminoacyl tRNA. from the ribosome. The combination is bactericidal, but macrolideresistant bacteria exhibit cross-resistance to quinupristin, and the remaining activity of dalfopristin alone is bacteriostatic. cHlorampHenicol Chloramphenicol binds reversibly to the 23S rRNA of the 50S subunit in a manner that interferes with the proper positioning of the aminoacyl component of tRNA in the A site. This site of binding is near those of the macrolides and lincosamides. oxazolidinones Linezolid and tedizolid are the only oxazolidinones in clinical use. They bind directly to the A site in the 23S rRNA of the 50S ribosomal subunit and block binding of aminoacyl tRNA, inhibiting the initiation of protein synthesis.


InternalMed_Harrison

InternalMed_Harrison. mupirocin Mupirocin (pseudomonic acid) is used topically. It competes with isoleucine for binding to isoleucyl tRNA synthetase, depleting stores of isoleucyl tRNA and thereby inhibiting protein synthesis.


InternalMed_Harrison

InternalMed_Harrison. Inhibition of Bacterial Metabolism Available inhibitors (antimetabolites) target the pathway for synthesis of folate, which is a cofactor in a number of one-carbon transfer reactions involved in the synthesis of some nucleic acids, including pyrimidine, thymidine, and all purines (adenine and guanine), as well as some amino acids (methionine and serine) and acetyl coenzyme A (CoA). Two sequential steps in folate synthesis are targeted. The selective antibacterial effect stems from the inability of mammalian cells to synthesize folate; they depend instead on exogenous sources. Antibacterial activity, however, may be reduced in the presence of high exogenous concentrations of the end products of the folate pathway (e.g., thymidine and purines) that may occur in some infections, resulting from local breakdown of leukocytes and host tissues.


InternalMed_Harrison

InternalMed_Harrison. sulfonamides Sulfonamides, including sulfadiazine, sulfisoxazole, and sulfamethoxazole, inhibit dihydropteroate synthetase, which adds p-aminobenzoic acid (PABA) to pteridine, producing dihydropteroate. Sulfonamides are structural analogues of PABA and act as competing enzyme substrates. trimetHoprim Subsequent steps in folate synthesis are catalyzed by dihydrofolate synthase, which adds glutamate to dihydropteroate, and dihydrofolate reductase, which then generates the final product, tetrahydrofolate. Trimethoprim is a structural analogue of pteridine and inhibits dihydrofolate reductase. Trimethoprim is available alone but is most often used in combination products that also contain sulfamethoxazole and thus block two sequential steps in folate synthesis. Inhibition of DNA and RNA Synthesis or Activity A variety of antibacterial agents act on these processes.


InternalMed_Harrison

InternalMed_Harrison. Quinolones The quinolones include nalidixic acid, the first agent in the class, and newer, more widely used fluorinated derivatives (fluoroquinolones), including norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin. The quinolones are synthetic compounds that inhibit bacterial DNA synthesis by interacting with the DNA complexes of two essential enzymes, DNA gyrase and DNA topoisomerase IV, which alter DNA topology. Quinolones trap enzyme–DNA complexes in such a way that they block movement of the DNA replication apparatus and can generate lethal double-strand breaks in DNA, resulting in bactericidal activity. Although mammalian cells also have type II DNA topoisomerases like gyrase and topoisomerase IV, the structures of the mammalian enzymes are sufficiently different from those of the bacterial enzymes that quinolones have substantially selective antibacterial activity.


InternalMed_Harrison

InternalMed_Harrison. rifamycins Rifampin, rifabutin, and rifapentine are semisynthetic derivatives of rifamycin B and bind the β subunit of bacterial RNA polymerase, thereby blocking elongation of mRNA. Their action is highly selective for the bacterial enzyme over mammalian RNA polymerases. nitrofurantoin The reduction of nitrofurantoin, a nitrofuran compound, by bacterial enzymes produces highly reactive derivatives that are thought to cause DNA strand breakage. Nitrofurantoin is used only for the treatment of lower urinary tract infections.


InternalMed_Harrison

InternalMed_Harrison. metronidazole Metronidazole is a synthetic nitroimidazole with activity limited to anaerobic bacteria and certain anaerobic protozoa. Reduction of its nitro group by the electron-transport system in anaerobic bacteria produces reactive intermediates that damage DNA and result in bactericidal activity. Both nitrofurantoin and metronidazole have selective antibacterial activity because the reducing activity needed to generate active derivatives is generated only by bacterial and not mammalian enzymes. Disruption of Membrane Integrity The integrity of the bacterial cytoplasmic membrane—and, in gram-negative bacteria, the outer membrane—is important for bacterial viability. Two bactericidal drugs have membrane targets. polymyxins The polymyxins, including polymyxin B and polymyxin E (colistin), are cationic cyclic polypeptides that disrupt the cytoplasmic membrane and the outer membrane (the latter by binding lipopolysaccharide).


InternalMed_Harrison

InternalMed_Harrison. daptomycin Daptomycin is a lipopeptide that binds the cytoplasmic membrane of gram-positive bacteria in the presence of calcium, generating a channel that leads to leakage of cytoplasmic potassium ions and membrane depolarization.


InternalMed_Harrison

InternalMed_Harrison. Bacteria use a wide variety of mechanisms to block or circumvent the activity of antibacterial agents. Although myriad, these mechanisms can generally be grouped into three categories: (1) altered or bypass targets that exhibit reduced binding of the drug, (2) altered access of the drug to its target by reductions in uptake or increases in active efflux, and (3) a modification of the drug that reduces its activity. These mechanisms result from either mutations in bacterial chromosomal genes occurring spontaneously during bacterial DNA replication or the acquisition of new genes by DNA transfer from other bacteria or uptake of exogenous DNA. New genes are most often acquired on self-replicating plasmids or other DNA elements transferred from other bacteria. However, some bacteria, such as Streptococcus pneumoniae and Neisseria gonorrhoeae, can also take up fragments of environmental DNA from related species and recombine that DNA directly into their own chromosomes, a process called


InternalMed_Harrison

InternalMed_Harrison. Streptococcus pneumoniae and Neisseria gonorrhoeae, can also take up fragments of environmental DNA from related species and recombine that DNA directly into their own chromosomes, a process called transformation. Not uncommonly, resistant bacteria have combinations of resistance mechanisms either within one category or among categories, and many plasmids contain more than one resistance gene. Thus, plasmid acquisition itself can in many cases confer resistance to multiple antibacterial agents.


InternalMed_Harrison

InternalMed_Harrison. Many antibacterial drugs are derived from natural products of microbial species. Some genes encoding resistance to these drugs may have evolved and been mobilized onto plasmids from a protection mechanism in the producer organism or in other surviving bacteria in the exposed environment. Exposure to antibacterial agents either in nature or from human or animal use results in the selection of resistant strains within an otherwise susceptible bacterial population. Because the patterns and extent of resistance may differ among settings, initial choices of antibacterial drugs should be based, whenever possible, on local susceptibility data and should be modified as needed as soon as specific microbiology susceptibility data become available.


InternalMed_Harrison

InternalMed_Harrison. β-Lactams The most common mechanism of resistance to β-lactams 933 is their degradation by β-lactamases, enzymes that break down the core β-lactam ring and destroy drug activity. Different β-lactamases degrade different β-lactams. Some β-lactamases are encoded on the bacterial chromosome, and their activity contributes to the susceptibility profile of a particular species. Because other β-lactamases are encoded by acquired plasmids, their resistance profiles may be present in some strains of a species but not others. In gram-positive bacteria β-lactamases are secreted into the extracellular environment, whereas in gram-negative bacteria these enzymes are secreted into the periplasmic space between the cytoplasmic and outer membranes. Thus, in gram-negative bacteria, access of β-lactams both to their target PBPs and to β-lactamases requires diffusion across the outer membrane, generally through the porin channels.


InternalMed_Harrison

InternalMed_Harrison. Most strains of Staphylococcus aureus produce a plasmid-encoded β-lactamase that degrades penicillin but not semisynthetic penicillins, such as oxacillin and nafcillin. The most common plasmid-encoded β-lactamases of gram-negative bacteria are able to inactivate all penicillins and most earlier-generation cephalosporins. Extended-spectrum β-lactamase (ESBL) variants of these early enzymes that can degrade later-generation cephalosporins (ceftriaxone, cefotaxime, ceftazidime) as well as the monobactam aztreonam have now emerged and are widely disseminated. Some ESBLs also degrade the fourth-generation cephalosporin cefepime. Carbapenems (imipenem, meropenem, ertapenem, doripenem) are not degraded by ESBLs, but additional β-lactamases, called carbapenemases, that degrade carbapenems and most if not all other β-lactams have begun to emerge.


InternalMed_Harrison

InternalMed_Harrison. The chromosomal β-lactamase of Klebsiella pneumoniae preferentially degrades penicillins but not cephalosporins. In contrast, the chromosomal β-lactamase of Enterobacter and related genera, AmpC, can degrade almost all cephalosporins but is normally expressed in small amounts. Mutations that cause increased amounts of AmpC to be produced confer full resistance to penicillins and cephalosporins; the exceptions are cefoxitin and cefepime, which are relatively stable to AmpC. Resistance to cefepime can develop, however, through the combined effects of increased AmpC production and decreased porin diffusion channels. Genes encoding AmpC have also been found on plasmids but are less common than plasmid-encoded ESBLs.


InternalMed_Harrison

InternalMed_Harrison. Inhibitors of β-lactamases such as clavulanate, sulbactam, and tazobactam have been developed and paired with amoxicillin and ticarcillin, ampicillin, and piperacillin, respectively. These inhibitors have little or no antibacterial activity of their own but inhibit plasmid-mediated β-lactamases, including ESBLs but not AmpC enzymes. Resistance to β-lactams also occurs through alterations in their target PBPs. In S. pneumoniae, N. gonorrhoeae, and Neisseria meningitidis, resistance to penicillin occurs by recombination of transformed DNA from related species. In staphylococci, resistance to methicillin and other β-lactams occurs by the acquisition of the mec gene, which encodes PBP2a with reduced drug affinity. Ceftaroline is the only β-lactam that has affinity for PBP2a and is thus active against methicillin-resistant staphylococcal strains.


InternalMed_Harrison

InternalMed_Harrison. Glycopeptides Resistance to vancomycin in enterococci is due to the acquisition of a set of van genes that result in (1) the production of d-alanine-d-lactate—instead of the normal d-alanine-d-alanine—at the end of the peptidoglycan stem peptide and (2) the reduction of existing d-alanine-d-alanine terminated peptides. Vancomycin binds d-alanine-d-lactate with a thousandfold lower affinity than d-alanined-alanine. In a small number of cases, the van gene cassettes have been transferred from enterococci to S. aureus, with the consequent generation of full vancomycin resistance. Particularly in patients receiving prolonged courses of vancomycin, intermediate resistance to this drug has developed in S. aureus by a different mechanism: multiple chromosomal mutations that result in a thickened and poorly cross-linked cell wall in which multiple distant d-alanine-d-alanine stem peptide termini exist and bind vancomycin, impeding its access to the binding sites proximal to the cell membrane


InternalMed_Harrison

InternalMed_Harrison. and poorly cross-linked cell wall in which multiple distant d-alanine-d-alanine stem peptide termini exist and bind vancomycin, impeding its access to the binding sites proximal to the cell membrane where new cell-wall synthesis occurs and where binding would block transpeptidase and transglycosylase enzymes. Susceptibility to telavancin, dalbavancin, and oritavancin is


InternalMed_Harrison

InternalMed_Harrison. Treatment and Prophylaxis of Bacterial Infections 934 also reduced in strains that exhibit resistance or intermediate susceptibility to vancomycin, although in some cases strains may still be classified as susceptible on the basis of clinical interpretive criteria.


InternalMed_Harrison

InternalMed_Harrison. Aminoglycosides The most common mechanism of resistance is due to acquisition of plasmid genes encoding transferase enzymes that modify aminoglycosides by the addition of acetyl, adenyl, or phosphate groups; these added groups decrease the drugs’ binding affinity to their ribosomal target site. Transferases differ in which aminoglycosides they modify, and amikacin resistance occurs less often than resistance to gentamicin or tobramycin. More recently, plasmids encoding methyltransferases that modify the ribosomal site of aminoglycoside binding and confer resistance to all aminoglycosides have been found in enteric gram-negative bacteria. For streptomycin, a ribosomal protein mutation may cause resistance. In Pseudomonas aeruginosa, resistance may also occur through mutations causing increased expression of a chromosomally encoded efflux pump, MexXY.


InternalMed_Harrison

InternalMed_Harrison. Tetracyclines and Glycylcyclines For tetracyclines, resistance is most often plasmid mediated and attributable either to active efflux pumps, which are generally specific for tetracyclines, or to proteins that protect the ribosome from tetracycline action. Resistance to the glycylcycline tigecycline, which is not affected by the usual tetracycline resistance mechanisms, can occur through mutations that cause overexpression of certain broad-spectrum efflux pumps in Proteus species.


InternalMed_Harrison

InternalMed_Harrison. Macrolides, Ketolides, Lincosamides, and Streptogramins Resistance to macrolides, clindamycin, and quinupristin is most often due to plasmid-acquired methylases that modify the drug binding site on the ribosome. Resistance to quinupristin by this mechanism renders the quinupristin-dalfopristin combination bacteriostatic rather than bactericidal. Telithromycin, a ketolide, has an additional binding site on the ribosome and remains active in the presence of these methylases. Acquired genes encoding active efflux pumps can also contribute to resistance to macrolides in streptococci and resistance to macrolides, clindamycin, and dalfopristin in staphylococci. Plasmid-acquired drug-modifying enzymes in staphylococci can also cause resistance to quinupristin and dalfopristin. Macrolide resistance due to 23S rRNA mutations is uncommon in staphylococci and streptococci because of the multiple copies of the rRNA genes on the chromosomes of these species; such resistance may occur more


InternalMed_Harrison

InternalMed_Harrison. resistance due to 23S rRNA mutations is uncommon in staphylococci and streptococci because of the multiple copies of the rRNA genes on the chromosomes of these species; such resistance may occur more frequently, however, in mycobacteria and Helicobacter pylori, which have only single chromosomal copies of these rRNA genes.


InternalMed_Harrison

InternalMed_Harrison. Chloramphenicol Resistance to chloramphenicol is most often due to a plasmid-encoded drug-modifying acetyltransferase. Oxazolidinones Linezolid resistance has been seen in enterococci more often than in staphylococci and, in both organisms, is due to mutations in multiple copies of the 23S rRNA genes that reduce drug binding to the ribosome. A plasmid-acquired ribosomal methylase gene that confers resistance to both chloramphenicol and linezolid has also been found in some strains of staphylococci but is not yet widespread. Tedizolid may still be active against some but not all linezolidresistant strains. Mupirocin Resistance to mupirocin occurs by either mutation in the target leucyl-tRNA synthetase (low-level resistance) or the acquisition of a plasmid-encoded resistant tRNA synthetase (high-level resistance).


InternalMed_Harrison

InternalMed_Harrison. Sulfonamides and Trimethoprim Resistance to both of these antimetabolites is due to plasmid-acquired genes encoding resistant enzymes that bypass the inhibition of the native sensitive enzymes—a resistant dihydropteroate synthetase in the case of sulfonamides and a resistant dihydrofolate reductase in the case of trimethoprim.


InternalMed_Harrison

InternalMed_Harrison. Quinolones Resistance to quinolones is most often due either to chromosomal mutations altering the target enzymes DNA gyrase and DNA topoisomerase IV, with consequent reduction in drug binding, or to mutations that increase the expression of native broad-spectrum efflux pumps for which quinolones (among other compounds) are substrates. In addition, three types of genes can confer reduced susceptibility or low-level resistance by protecting target enzymes, modifying some quinolones, or pumping quinolones out of the cell (efflux). These genes are located on multidrug resistance plasmids that have spread worldwide. Their presence can promote the selection of higher levels of quinolone resistance linked to resistance to other antibacterial drugs that is encoded on the same plasmid.


InternalMed_Harrison

InternalMed_Harrison. Rifampin and Rifabutin Single mutations in the β subunit of RNA polymerase can cause high-level resistance to rifampin. Thus rifampin and other rifamycins are used for treatment of infections only in combination with other antibacterial drugs in order to prevent resistance. Metronidazole Acquired resistance to metronidazole in Bacteroides species is rare. Such resistance has been reported in strains that lack endogenous nitroreductase activity or that have acquired nim genes responsible for further reduction of DNA-damaging nitroso intermediates to an inactive derivative. Active efflux and enhanced DNA repair mechanisms also have been associated with resistance. Nitrofurantoin Resistance to nitrofurantoin in Escherichia coli can emerge through a series of mutations that progressively decrease the nitroreductase activity necessary for generating active nitrofuran metabolites.


InternalMed_Harrison

InternalMed_Harrison. Polymyxins Because of emerging multidrug resistance in gram-negative bacteria, colistin and polymyxin B are being used increasingly for infections due to resistant Enterobacteriaceae, P. aeruginosa, and Acinetobacter species. Rates of resistance vary. Resistance can emerge during therapy through mutations that cause reductions in the negative charge of the gram-negative bacterial cell surface, thereby reducing binding of the positively charged colistin. Daptomycin The mechanisms of resistance to daptomycin are complex and involve mutations in several genes that can alter cell membrane charge and reduce daptomycin binding. Resistance to daptomycin is relatively infrequent but has emerged in some S. aureus strains with intermediate vancomycin susceptibility from patients treated with vancomycin but not with daptomycin. In some methicillin-resistant


InternalMed_Harrison

InternalMed_Harrison. S. aureus (MRSA) strains, daptomycin resistance has been linked to acquired susceptibility to β-lactams; combinations of daptomycin and nafcillin have been successful for treatment of patients infected with resistant strains when daptomycin alone or in combination with other agents has failed. The mechanism of this effect is not yet clear. The term pharmacokinetics describes the disposition of a drug in the body, whereas pharmacodynamics describes the determinants of drug action on the pathogen in relation to pharmacokinetic factors. An understanding of the principles governing these two areas is required for effective drug selection, dosing, and prevention of toxicities. The process of drug disposition has four principal phases: absorption, distribution, metabolism, and excretion. These components determine the time course of drug concentrations in serum and subsequently the concentrations in other tissues and body fluids.


InternalMed_Harrison

InternalMed_Harrison. Absorption When a drug is given by a particular route, absorption is defined as the percentage of the dose that reaches the systemic circulation. For example, since IV administration provides direct access to the systemic circulation, 100% of a drug dose given IV is usually absorbed. The level of absorption becomes more relevant when non-IV routes are used—e.g., the oral, IM, SC, and topical routes. The percentage of a drug that is absorbed is termed its bioavailability. Examples of antibacterial agents with a high oral bioavailability include metronidazole, levofloxacin, and linezolid. IV administration and oral dosing for highly bioavailable agents usually give equivalent results. Many factors can affect a drug’s oral bioavailability, including the timing of food consumption relative to drug administration, drug-metabolizing enzymes, efflux transporters, concentration-dependent solubility, and acid degradation. Underlying conditions such as diarrhea or ileus can also affect the site


InternalMed_Harrison

InternalMed_Harrison. drug administration, drug-metabolizing enzymes, efflux transporters, concentration-dependent solubility, and acid degradation. Underlying conditions such as diarrhea or ileus can also affect the site of drug absorption and thereby alter bioavailability. Certain orally administered drugs have lower bioavailability because of the first-pass effect—the process by which drugs are absorbed in the small intestine through the portal circulation and then directly transported to the liver for metabolism.


InternalMed_Harrison

InternalMed_Harrison. Distribution Distribution describes the process by which a drug transfers reversibly between the general circulation and the tissues. After absorption into the general circulation and the central compartment (the extensively perfused organs), the drug will also distribute into the peripheral compartment (less well-perfused tissues). The volume of distribution (Vd) is a pharmacokinetic parameter that describes the amount of drug in the body at a given time relative to the measured serum concentration. Properties such as the drug’s lipophilicity, partition coefficient within different body tissues, and protein binding; blood flow; and pH can affect the volume of distribution. Drugs with a small volume of distribution are limited to certain areas within the body (typically extracellular fluid), whereas those with a higher volume of distribution penetrate extensively into tissues throughout the body. Antibacterial drugs can bind to serum proteins, and a given drug is usually described as


InternalMed_Harrison

InternalMed_Harrison. whereas those with a higher volume of distribution penetrate extensively into tissues throughout the body. Antibacterial drugs can bind to serum proteins, and a given drug is usually described as either poorly or highly protein bound. Only the unbound (free) drug is active and available to exert antibacterial effects. For example, because tigecycline is highly protein bound and also has a large volume of distribution, concentrations of free drug in the serum are low.


InternalMed_Harrison

InternalMed_Harrison. Metabolism Metabolism is the chemical transformation of a drug by the body. This modification can occur within several areas; the liver is the organ most commonly involved. Drugs are metabolized by enzymes, but enzyme systems have a finite capacity to metabolize a substrate drug. If a drug is given in a dose at which the concentration does not exceed the rate of metabolism, then the metabolic process is generally linear. If the dose exceeds the amount that can be metabolized, drug accumulation and potential toxicity may occur. Drugs are metabolized through phase I or phase II reactions. In phase I reactions, the drug is made more polar through dealkylation, hydroxylation, oxidation, and deamination. Polarity facilitates drug removal from the body. Phase II reactions, which include glucuronidation, sulfation, and acetylation, result in compounds larger and more polar than the parent drug. Both phases usually inactivate the parent drug, but some drugs are rendered more active. The


InternalMed_Harrison

InternalMed_Harrison. sulfation, and acetylation, result in compounds larger and more polar than the parent drug. Both phases usually inactivate the parent drug, but some drugs are rendered more active. The cytochrome P450 (CYP) enzyme system is responsible for phase I reactions and is generally found in the liver. CYP3A4 is a common subfamily within this system that is responsible for the majority of drug metabolism. Antibacterial drugs can be substrates, inhibitors, or inducers of a particular CYP enzyme. Inducers, such as rifampin, can increase the production of CYP enzymes and consequently increase the metabolism of other drugs. Inhibitors, such as quinupristin-dalfopristin, cause a decrease in enzyme activity (or competition for CYP substrate) and therefore an increase in the concentration of the interacting drug.


InternalMed_Harrison

InternalMed_Harrison. Excretion Excretion describes the body’s mechanisms of drug elimination. Drugs can be eliminated through more than one mechanism. Renal clearance is the most common route and includes elimination through glomerular filtration, tubular secretion, and/or passive diffusion. Some agents have nonrenal clearance and rely on the biliary tree or the intestine for excretion. Excretion affects the half-life of a drug—i.e., the time it takes for the blood concentration of a drug to decrease by one-half. This value can range from minutes to days. Approximately five to seven half-lives are required for a drug to reach steady state when multiple doses are given in a time frame shorter than the half-life itself. Drug half-life and overall clearance can be extended if the organ responsible for clearance is impaired. Patients with renal or hepatic impairment may require dose adjustments that take delayed clearance into account and prevent toxicities from drug accumulation. For example, imipenem is


InternalMed_Harrison

InternalMed_Harrison. is impaired. Patients with renal or hepatic impairment may require dose adjustments that take delayed clearance into account and prevent toxicities from drug accumulation. For example, imipenem is cleared predominantly through glomerular filtration, and in the presence of renal impairment the dosing interval is typically increased to account for the increased half-life.


InternalMed_Harrison

InternalMed_Harrison. The term pharmacodynamics describes the relationship between the serum concentrations that determine the efficacy of the drug and the serum concentrations that produce the toxic effects of the drug. For an antibacterial agent, the pharmacodynamic focus is the type of drug FIGURE 170-2 Pharmacokinetic and pharmacodynamic model predicting efficacy of antibacterial drugs. AUC, area under the time–concentration curve; Cmax, peak serum concentration of drug; MIC, minimal inhibitory concentration; T>MIC, duration of drug concentrations above the MIC.


InternalMed_Harrison

InternalMed_Harrison. exposure needed for optimal antibacterial effect in relation to the minimal inhibitory concentration (MIC)—the lowest drug concentration that inhibits the visible growth of a microorganism under standardized laboratory conditions. Antibacterial effect usually correlates with one of the following parameters: (1) ratio of peak serum concentration to the MIC (Cmax/MIC), (2) ratio of the area under the concentration– time curve to the MIC (AUC/MIC), or (3) duration of concentrations above the MIC (T>MIC) (Fig. 170-2).


InternalMed_Harrison

InternalMed_Harrison. For concentration-dependent killing agents, as the designation implies, the higher the drug concentration, the higher the rate and extent of bacterial killing. Aminoglycosides fit into the Cmax/MIC model of pharmacodynamics activity, and a particular peak serum concentration is often targeted to achieve optimal killing. Fluoroquinolones exemplify antibacterial agents for which the AUC/MIC is a predictor of efficacy. For example, studies have found that an AUC/MIC ratio of >30 will maximize killing of S. pneumoniae by fluoroquinolones. In contrast, time-dependent killing agents reach a ceiling at which higher concentrations do not result in increased effect. Instead, these agents are active against bacteria only when the drug concentration is above the MIC. The T>MIC predicts clinical efficacy for all β-lactams. The longer the concentration of the β-lactam remains above the MIC for an infecting pathogen during the dosing interval, the greater the killing effect. For some drug classes,


InternalMed_Harrison

InternalMed_Harrison. for all β-lactams. The longer the concentration of the β-lactam remains above the MIC for an infecting pathogen during the dosing interval, the greater the killing effect. For some drug classes, such as aminoglycosides, a postantibiotic effect—the delayed regrowth of surviving bacteria after exposure to an antibiotic—supports less frequent dosing.


InternalMed_Harrison

InternalMed_Harrison. The approach to antibiotic therapy is driven by host factors, site of infection, and local resistance profiles of suspected or known pathogens. Further, national and local drug shortages and formulary restrictions can affect available therapies. Regular monitoring of the patient and collection of laboratory data should be undertaken to streamline antibacterial therapy as appropriate and to investigate the possibility of treatment failure if the patient fails to respond appropriately.


InternalMed_Harrison

InternalMed_Harrison. Therapy is considered empirical when the causative agent has yet to be determined and therapeutic decisions are based on the severity of illness and the clinician’s assessment of likely pathogens in light of the clinical syndrome, the patient’s medical conditions and prior therapy, and relevant epidemiologic factors. For patients with severe illness, empirical therapy often takes the form of an antibacterial combination that provides broad coverage of diverse agents and thus ensures adequate treatment of possible pathogens while additional data are being collected. Directed therapy is predicated on identification of the


InternalMed_Harrison

InternalMed_Harrison. Treatment and Prophylaxis of Bacterial Infections 936 pathogen, determination of its susceptibility profile, and establishment of the extent of the infection. Directed therapy generally allows the use of more targeted and narrower-spectrum antibacterial agents than does empirical therapy. Information on epidemiology, exposures, and local antibacterial susceptibility patterns can help guide empirical therapy. When empirical treatment is clinically appropriate, care should be taken to obtain clinical specimens for microbiologic analysis before the initiation of therapy and to de-escalate therapy as new information is obtained about the patient’s clinical condition and the causal pathogens. De-escalation to the point of directed therapy can limit unnecessary risks to the patient as well as the risk of emergence of antibacterial resistance.


InternalMed_Harrison

InternalMed_Harrison. The site of infection is a consideration in antibacterial therapy, largely because of the differing abilities of drugs to penetrate and achieve adequate concentrations at particular body sites. For example, to be effective in the treatment of meningitis, an agent must (1) be able to cross the blood–brain barrier and reach adequate concentrations in the cerebrospinal fluid (CSF) and (2) be active against the relevant pathogen(s). Dexamethasone, administered with or 15–20 min before the first dose of an antibacterial drug, has been shown to improve outcomes in patients with acute bacterial meningitis, but its use may reduce penetration of some antibacterial agents, such as vancomycin, into the CSF. In this case, rifampin is added because its penetration is not reduced by dexamethasone. Infections at other sites where either pathogens are protected from normal host defenses or penetration of an antibacterial drug is suboptimal include osteomyelitis, prostatitis, intraocular infections,


InternalMed_Harrison

InternalMed_Harrison. at other sites where either pathogens are protected from normal host defenses or penetration of an antibacterial drug is suboptimal include osteomyelitis, prostatitis, intraocular infections, and abscesses. In such cases, consideration must be given to the mechanism of drug delivery (e.g., intravitreal injections) as well as to the role of interventions to drain, debride, or otherwise reduce the barriers to effective antibacterial therapy.


InternalMed_Harrison

InternalMed_Harrison. Host factors, including immune function, pregnancy, allergies, age, renal and hepatic function, drug–drug interactions, comorbid conditions, and occupational or social exposures, should be considered. Immune Dysfunction Patients with deficits in immune function that blunt the response to bacterial infection, including neutropenia, deficient humoral immunity, and asplenia (either surgical or functional), are all at increased risk of severe bacterial infection. Such patients should be treated aggressively and often broadly in the early stages of suspected infection pending results of microbiologic tests. For asplenic patients, treatment should include coverage of encapsulated organisms, particularly S. pneumoniae, that may cause rapidly life-threatening infection.


InternalMed_Harrison

InternalMed_Harrison. Pregnancy Pregnancy affects decisions regarding antibacterial therapy in two respects. First, pregnancy is associated with an increased risk of particular infections (e.g., those caused by Listeria). Second, the potential risks to the fetus that are posed by specific drugs must be considered. As for other drugs, the safety of the vast majority of antibacterial agents in pregnancy has not been established, and such agents are grouped in categories B and C by the U.S. Food and Drug Administration. Drugs in categories D and X are contraindicated in pregnancy or lactation due to established risks. The risks associated with antibacterial use in pregnancy and during lactation are summarized in Table 170-2.


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InternalMed_Harrison. Allergies Allergies to antibiotics are among the most common allergies reported, and an allergy history should be obtained whenever possible before therapy is chosen. A detailed allergy history can shed light on the type of reaction experienced previously and on whether rechallenge with the same or a related medication is advisable (and, if so, under what circumstances). Allergies to the penicillins are most common. Although as many as 10% of patients may report an allergy to penicillin, studies suggest that up to 90% of these patients could tolerate a penicillin or cephalosporin. Adverse effects (Table 170-3) should be distinguished from true allergies to ensure appropriate selection of antibacterial therapy. Drug–Drug Interactions Patients commonly receive other drugs that may interact with antibacterial agents. A summary of the most common drug–drug interactions, by antibacterial class, is provided in Table 170-4.


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InternalMed_Harrison. Exposures Exposures, both occupational and social, may provide clues to likely pathogens. When relevant, inquiries about exposure to ill contacts, animals, insects, and water should be included in the history, along with sites of residence and travel. Other Host Factors Age, renal and hepatic function, and comorbid conditions are all considerations in the choice of and schedule for therapy. Dose adjustments should be made accordingly. In patients with decreased or unreliable oral absorption, IV therapy may be preferred to ensure adequate blood levels of drug and delivery of the antibacterial agent to the site of infection.


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InternalMed_Harrison. Whether empirical or directed, the duration of therapy should be planned in most clinical situations. Guidelines that synthesize available literature and expert opinion provide recommendations on therapy duration that are based on infecting organism, organ system, and patient factors. For example, the American Heart Association has published guidelines endorsed by the Infectious Diseases Society of America (IDSA) on diagnosis, antibacterial therapy, and management of complications of infective endocarditis. Similar guidelines from the IDSA exist for bacterial meningitis, catheter-associated urinary tract infections, intraabdominal infections, communityand hospital-acquired pneumonia, and other infections.


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InternalMed_Harrison. If a patient does not respond to therapy, investigations often should include the collection of additional specimens for microbiologic testing and imaging as indicated. Failure to respond can be the result of an antibacterial regimen that does not address the underlying causative organism, the development of resistance during therapy, or the existence of a focus of infection at a site poorly penetrated by systemic therapy. Some infections may also require surgical interventions for cure (e.g., large abscesses, myonecrosis). Fever due to allergic drug reactions can sometimes complicate assessment of the patient’s response to antibacterial treatment. Selected websites with the most up-to-date information and guidance for the clinician include the following: Johns Hopkins ABX Guide (www.hopkins-abxguide.org) IDSA Practice Guidelines (www.idsociety.org/IDSA_Practice_Gui delines/) Center for Disease Dynamics, Economics and Policy Resistance Map (www.cddep.org/map)


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InternalMed_Harrison. IDSA Practice Guidelines (www.idsociety.org/IDSA_Practice_Gui delines/) Center for Disease Dynamics, Economics and Policy Resistance Map (www.cddep.org/map) CDC Antibiotic/Antimicrobial Resistance (www.cdc.gov/drug resistance/) The clinical application of antibacterial therapy is guided by the spectrum of the agent and the suspected or known target pathogen. Infections for which specific antibacterial agents are among the drugs of choice are listed, along with associated pathogens and susceptibility data, in Table 170-5. Resistance rates of specific organisms are dynamic and should be taken into account in the approach to antibacterial therapy. While national resistance rates can serve as a reference, the most useful reference for the clinician is the most recent local laboratory antibiogram, which provides details on local resistance patterns, often on an annual or semiannual basis.


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InternalMed_Harrison. The β-lactam class of antibiotics consists of penicillins, cephalosporins, carbapenems, and monobactams. The term β-lactam reflects the drugs’ four-membered lactam ring, which is their core structure. The differing aCategory B: Either animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women; or animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester. Category C: Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of


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InternalMed_Harrison. Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. bFetal risk recommendation and breast-feeding risk recommendation adapted from GG Briggs et al, eds: Drugs in Pregnancy and Lactation, 9th ed. Philadelphia, Lippincott Williams and Wilkins, 2011; and the U.S. Food and Drug Administration (Drugs@FDA). cA registry has been established to monitor pregnancy outcomes of pregnant women exposed to telavancin. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves by calling 1-855-633-8479.


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InternalMed_Harrison. Abbreviation: G6PD, glucose-6-phosphate dehydrogenase.


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InternalMed_Harrison. side chains among the agents of this family determine the spectrum of as penicillin G, are active against non-β-lactamase-producing gram-activity. All β-lactams exert a bactericidal effect by inhibiting bacterial positive and gram-negative bacteria, anaerobes, and some gram-negative cell-wall synthesis. The β-lactams are classified as time-dependent kill-cocci. Penicillin G is used for penicillin-susceptible streptococcal infecing agents; therefore, their clinical efficacy is best correlated with the tions, pneumococcal and meningococcal meningitis, enterococcal endoproportion of the dosing interval during which the drug levels remain carditis, and syphilis. The antistaphyloccocal penicillins, which have above the MIC for the pathogenic organism. potent activity against methicillin-susceptible S. aureus (MSSA), include nafcillin, oxacillin, dicloxacillin, and flucloxacillin. Aminopenicillins, Penicillins and β-Lactamase Inhibitors Penicillin, the first β-lactam, was such as ampicillin


InternalMed_Harrison

InternalMed_Harrison. S. aureus (MSSA), include nafcillin, oxacillin, dicloxacillin, and flucloxacillin. Aminopenicillins, Penicillins and β-Lactamase Inhibitors Penicillin, the first β-lactam, was such as ampicillin and amoxicillin, provide added coverage beyond discovered in 1928 by Alexander Fleming. Natural penicillins, such penicillin against gram-negative cocci, such as Haemophilus influenzae,


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InternalMed_Harrison. Treatment and Prophylaxis of Bacterial Infections Note: All systemic antibiotics have the potential to alter abdominal flora and induce Clostridium difficile infection. Abbreviations: aPTT, activated partial thromboplastin time; CPK, creatine phosphokinase; INR, international normalized ratio; LFT, liver function test; PT, prothrombin time; TMP-SMX, trimethoprim-sulfamethoxazole.


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InternalMed_Harrison. and some Enterobacteriaceae, including E. coli, Proteus mirabilis, species (such as Bacteroides fragilis), which produce β-lactamases and Salmonella, and Shigella. The aminopenicillins are hydrolyzed by many are generally resistant. The rising prevalence of β-lactamase-producing common β-lactamases. These drugs are commonly used for otitis media, bacteria has led to the increased use of β-lactam/β-lactamase inhibitor respiratory tract infections, intraabdominal infections, endocarditis, combinations, such as ampicillin-sulbactam, amoxicillin-clavulanate, meningitis, and urinary tract infections. The antipseudomonal penicil-ticarcillin-clavulanate, and piperacillin-tazobactam. The β-lactamase lins include ticarcillin and piperacillin. These penicillin groups gener-inhibitors themselves do not have antibacterial activity (with the excepally offer adequate anaerobic coverage; the exceptions are Bacteroides tion of sulbactam, which has activity against Acinetobacter baumannii)


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InternalMed_Harrison. Nafcillin Warfarin, cyclosporine, tacrolimus Linezolid, tedizolid Serotonergic and adrenergic agents (e.g., SSRIs, vasopressors) Quinupristin dalfopristin Substrates of cytochrome CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil) Sucralfate; antacids containing aluminum, calcium, or magnesium; ferrous sulfate and zinc-containing multivitamins Rifampin Substrates of cytochrome CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil, protease inhibitors, voriconazole) Substrates of cytochrome CYP2C19 (e.g., omeprazole, lansoprazole) Substrates of cytochrome CYP2C9 (e.g., warfarin, tolbutamide) Substrates of cytochrome CYP2C8 (e.g., repaglinide, rosiglitazone) Substrates of cytochrome CYP2B6 (e.g., efavirenz) Hormone therapy (e.g., norethindrone) Tetracyclines Antacids or drugs containing calcium, magnesium, iron, or aluminum Macrolidesb Substrates of cytochrome CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil)


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InternalMed_Harrison. Tetracyclines Antacids or drugs containing calcium, magnesium, iron, or aluminum Macrolidesb Substrates of cytochrome CYP3A4 (e.g., warfarin, ritonavir, cyclosporine, diazepam, verapamil) QTc-prolonging agents (e.g., fluoroquinolones, sotalol) Protease inhibitors (e.g., ritonavir) Oritavancin Substrates of cytochrome CYP3A4 (e.g., cyclosporine, warfarin) and CYP2D6 (e.g., aripiprazole) Substrates of cytochrome CYP2C19 (e.g., omeprazole) and CYP2C9 (e.g., warfarin) Decreased levels of warfarin, cyclosporine via CYP3A4 induction. Monitor levels of affected drug closely if drugs are given concomitantly. Concomitant use is contraindicated in neonates (<28 days); the combination can lead to precipitation of ceftriaxone-calcium particulate. Ceftriaxone and calcium-containing solutions can be given to infants >28 days of age provided they are given sequentially and the lines are thoroughly flushed between infusions.


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InternalMed_Harrison. Ceftriaxone and calcium-containing solutions can be given to infants >28 days of age provided they are given sequentially and the lines are thoroughly flushed between infusions. Decreased levels of valproic acid. Monitor valproic acid levels closely if drugs are given concomitantly. Increased levels of serotonergic and adrenergic agents. Monitor for serotonin syndrome. Tedizolid may have less potential than linezolid to cause this drug interaction. Can result in increased levels of interacting drug. Erythromycin and clarithromycin are more potent CYP3A4 inhibitors than azithromycin. Avoid concomitant administration if possible. Can result in subtherapeutic fluoroquinolone levels. Administer fluoroquinolone 2 h before or 6 h after interacting drug. Can result in increased levels of tizanidine and hypotensive, sedative effects. Monitor for side effects if drugs are given concomitantly.


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InternalMed_Harrison. Can result in increased levels of tizanidine and hypotensive, sedative effects. Monitor for side effects if drugs are given concomitantly. Can result in decreased levels of interacting drug. Avoid concomitant use if possible. If giving drugs concomitantly, monitor drug levels if possible. Can result in decreased levels of hormone. If oral contraceptive and rifampin are given concomitantly, use alternative form of birth control. Can result in decreased absorption of tetracyclines. Administer tetracycline 2 h before or 6 h after interacting drug. Avoid concomitant administration if possible. Increased risk of cardiotoxicity and arrhythmias. Monitor QTc. Can result in increased levels of both macrolides and protease inhibitors. Avoid concomitant use if possible. Cimetidine can increase levels of macrolides. Can result in disulfiram-like reaction. Ethanol may be present in some for mulations of oral drug suspensions (e.g., ritonavir).


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InternalMed_Harrison. Can increase warfarin levels. Monitor INR closely if drugs are given concomitantly. Increased effect of warfarin. Monitor levels closely if drugs are given concomitantly. Increased levels of phenytoin. Monitor levels closely if drugs are given concomitantly. Increased levels of methotrexate. Monitor levels closely if drugs are given concomitantly. Can result in decreased levels of interacting drug. Avoid concomitant use if possible. If giving drugs concomitantly, monitor drug levels if possible. Can result in increased levels of interacting drug. Avoid concomitant use if possible. If giving drugs concomitantly, monitor drug levels if possible.


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InternalMed_Harrison. Treatment and Prophylaxis of Bacterial Infections aDrug reaction described with ciprofloxacin only. bClarithromycin and erythromycin are potent CYP3A4 inhibitors; the probability of a drug interaction with azithromycin is lower. Abbreviations: INR, international normalized ratio; SSRI, selective serotonin-reuptake inhibitor; TMP-SMX, trimethoprim-sulfamethoxazole. but typically inhibit the S. aureus class A β-lactamase, β-lactamases of H. influenzae and Bacteroides species, and a number of plasmid-encoded β-lactamases. These combination agents are typically used when broader-spectrum coverage is needed—e.g., in pneumonia and intraabdominal infections. Piperacillin-tazobactam is a useful agent for broad coverage in febrile neutropenic patients. The combination agents, however, are not effective against organisms that produce AmpC β-lactamases or carbapenemases.


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InternalMed_Harrison. Cephalosporins The cephalosporin drug class encompasses five generations determined by spectrum of antibacterial activity. The first generation (cefazolin, cefadroxil, cephalexin) largely has activity 940 TABLE 170-5 DRug InDICATIonS foR SPECIfIC InfECTIonS, ASSoCIATED PATHogEnS, AnD SAMPLE SuSCEPTIBILITy RATES Antimicrobial(s) Infections Common Pathogens (% Susceptible); Resistance as Noteda Ampicillin, amoxicillin Nafcillin, oxacillin Piperacillin-tazobactam Cefazolin Cefoxitin, cefotetan Ceftriaxone Ceftazidime, cefepime Ceftaroline Imipenem, meropenem Ertapenem Aztreonam Vancomycin Telavancin Dalbavancin, oritavancin Daptomycin Gentamicin, tobramycin, amikacin Azithromycin, clarithromycin, erythromycin Clindamycin Doxycycline, minocycline Intraabdominal infections (facultative enteric gram-negative bacilli and obligate anaerobes); infections caused by mixed flora (aspiration pneumonia, diabetic foot ulcers); infections caused by


InternalMed_Harrison

InternalMed_Harrison. Intraabdominal infections (facultative enteric gram-negative bacilli and obligate anaerobes); infections caused by mixed flora (aspiration pneumonia, diabetic foot ulcers); infections caused by E. coli UTI; surgical prophylaxis; MSSA bacteremia and endocarditis Hospital-acquired infections caused by facultative gram-negative bacilli and Pseudomonas spp. CAP caused by S. pneumoniae, MSSA, H. influenzae, K. pneumoniae, Klebsiella oxytoca, and E. coli; acute bacterial skin and skin-structure infections caused by MSSA, MRSA, Streptococcus pyogenes, Streptococcus agalactiae, E. coli, K. pneumoniae, and K. oxytoca Intraabdominal infections, infections caused by Enterobacter spp. and ESBL-producing gram-negative bacilli CAP; complicated UTIs, including pyelonephritis; acute pelvic infections; complicated intraabdominal infections; complicated skin and skin-structure infections, excluding diabetic foot infections accompanied by osteomyelitis or caused by P. aeruginosa


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InternalMed_Harrison. Bacteremia, endocarditis, and other invasive disease caused by MRSA; pneumococcal meningitis; oral formulation for CDAD Combined with penicillin for staphylococcal, enterococcal, or streptococcal endocarditis; combined with β-lactam for gram-negative bacteremia; pyelonephritis Legionella, Campylobacter, and Mycoplasma infections; CAP; GAS pharyngitis in penicillin-allergic patients; bacillary angiomatosis; gastric infections due to Helicobacter pylori; MAI infections Severe, invasive GAS infections (with β-lactam); infections caused by obligate anaerobes; infections caused by susceptible staphylococci


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InternalMed_Harrison. Severe, invasive GAS infections (with β-lactam); infections caused by obligate anaerobes; infections caused by susceptible staphylococci Acute bacterial exacerbations of chronic bronchitis; granuloma inguinale; brucellosis (with streptomycin); tularemia; glanders; melioidosis; spirochetal infections caused by Borrelia (Lyme disease and relapsing fever; doxycycline); infections caused by Vibrio vulnificus; some Aeromonas infections; infections due to Stenotrophomonas (minocycline); plague; ehrlichiosis; chlamydial infections (doxycycline); granulomatous infections due to Mycobacterium marinum (minocycline); rickettsial infections; mild CAP; skin and soft tissue infections caused by gram-positive cocci (e.g., CA-MRSA infections); leptospirosis; syphilis; and actinomycosis in the penicillin-allergic patient CAP caused by S. pneumoniae, H. influenzae, or Legionella pneumophila; complicated skin infections caused by E. coli, MRSA, MSSA,


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InternalMed_Harrison. CAP caused by S. pneumoniae, H. influenzae, or Legionella pneumophila; complicated skin infections caused by E. coli, MRSA, MSSA, S. pyogenes, Streptococcus anginosus, S. agalactiae, B. fragilis; complicated intraabdominal infections caused by E. coli, vancomycinsusceptible E. faecalis, Citrobacter freundii, Enterobacter cloacae, K. pneumoniae, K. oxytoca, Bacteroides spp., Clostridium perfringens, and Peptostreptococcus spp. Escherichia coli (52%); H. influenzae (70%); Salmonella spp. (91%) P. aeruginosa (88%)b E. coli (85%) Bacteroides fragilis (60%)c S. pneumoniae (93%);d E. coli (93%); Klebsiella pneumoniae (89%) P. aeruginosa (89%) Mostly susceptible; four strains of MRSA with ceftaroline MICs >4 μg/mL reported in isolates from a single Greek hospitale P. aeruginosa (76% and 83%); Acinetobacter calcoaceticusbaumannii complex (81% and 82%) Enterobacter cloacae (87%); K. pneumoniae (97%) P. aeruginosa (76%) S. aureus (100%); E. faecalis (89%); E. faecium (24%)


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InternalMed_Harrison. Enterobacter cloacae (87%); K. pneumoniae (97%) P. aeruginosa (76%) S. aureus (100%); E. faecalis (89%); E. faecium (24%) S. aureus (100%) S. aureus (100%) E. faecalis (99.9%);f E. faecium (99.7%);f S. aureus (99.9%)f E. coli (gentamicin, 91%); P. aeruginosa (amikacin, 87%; gentamicin, 81%); A. calcoaceticus-baumannii complex (amikacin, 68%; gentamicin, 83%) S. pneumoniae (59%); group A streptococci (78%); H. pylori (75%)g S. aureus (67%) S. pneumoniae (75%); S. aureus (94%) Mostly susceptible, though case reports of resistance in A. baumannii and K. pneumoniae 941TABLE 170-5 DRug InDICATIonS foR SPECIfIC InfECTIonS, ASSoCIATED PATHogEnS, AnD SAMPLE SuSCEPTIBILITy RATES (CONTINUED)


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InternalMed_Harrison. Antimicrobial(s) Infections Common Pathogens (% Susceptible); Resistance as Noteda aUnless otherwise noted, susceptibility rates are based on isolates from the Massachusetts General Hospital Clinical Microbiology Laboratory collected between January and December 2012. Local rates will vary. bThe Center for Disease Dynamics, Economics and Policy Resistance Map, Washington, DC. cS Sepehri et al: Prevalence of antimicrobial resistance among clinical isolates of Bacteroides fragilis group in Canada in 2010–2011: CANWARD Surveillance Study. Abstract C2-1814, presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, 2011. Available at www.can-r.com/posters/ICAAC2011/Sepehri%20Prevalence%20Bfragilis%20ICAAC2011.pdf. dGV Doern et al: Clin Infect Dis 41:139, 2005. eRE Mendes et al: J Antimicrob Chemother 67:1321, 2012. fHS Sader et al: J Chemother 23:200, 2011. gJ Torres et al: J Clin Microbiol 39:2677, 2001. hWS Oh et al: Antimicrob Agents Chemother 49:5176,


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InternalMed_Harrison. eRE Mendes et al: J Antimicrob Chemother 67:1321, 2012. fHS Sader et al: J Chemother 23:200, 2011. gJ Torres et al: J Clin Microbiol 39:2677, 2001. hWS Oh et al: Antimicrob Agents Chemother 49:5176, 2005. iAE Simor et al: Antimicrob Agents Chemother 51:3880, 2007.


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InternalMed_Harrison. Abbreviations: CA-MRSA, community-acquired MRSA; CAP, community-acquired pneumonia; CA-UTI, community-acquired UTI; CDAD, Clostridium difficile–associated diarrhea; ESBL, extended-spectrum β-lactamase; GAS, group A streptococcal; HAI, hospital-acquired infection; MAI, Mycobacterium avium-intracellulare; MIC, minimal inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; TMP-SMX, trimethoprim-sulfamethoxazole; UTI, urinary tract infection; VRE, vancomycin-resistant Enterococcus. against gram-positive bacteria, with some additional activity against