Antibiotics in the Management of Serious Hospital-Acquired Infections

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1 Chapter 83 Antibiotics in the Management of Serious Hospital-Acquired Infections Mollie Gowan, Jennifer Bushwitz, and Marin H. Kollef Introduction As antimicrobial resistance spreads and new antimicrobial agents are developed, designing an empiric antibiotic regimen for patients in the intensive care unit (ICU) has become increasingly complex. In order to ensure that the initial antibiotic agents chosen are appropriate, clinicians must consider a variety of risk factors for infection with resistant pathogens that are specific to the patient, hospital, and community, as well as drug-specific properties that affect efficacy at the site of infection. Although recently developed rapid diagnostic techniques and biomarkers may aid in optimizing antimicrobial therapy, these technologies are not currently widely available. This chapter not only reviews factors predisposing patients to infection with resistant organisms and available diagnostic tests to streamline antibiotic therapy, but also discusses strategies to improve antimicrobial stewardship and limit the spread of resistance. Pathophysiology Clinical Factors That Affect Initial Antimicrobial Selection When developing an empirical antimicrobial regimen, choice of agents should be based on multiple factors, including likely causative pathogens, local pathogen distribution, resistance patterns, and patient-specific risk factors for resistance. Reports from the National Nosocomial Infections Surveillance (NNIS) System describe hospital and ICU infection rates in participating acute care general hospitals throughout the United States. A 2005 publication also reported pathogen distribution by site of infection and compared data from 1975 and 2003, as shown in Table Overall, the occurrence of hospitalacquired infections caused by potentially resistant bacteria, such as Staphylococcus aureus and Pseudomonas aeruginosa, is increasing. In hospital-acquired pneumonia, gram-negative aerobes remain the most frequently reported pathogens; however, S. aureus was the most frequently reported single species (1,2). A 2013 report published by the National Healthcare Safety Network (NHSN) demonstrated that S. aureus was, overall, the pathogen isolated most frequently in hospitalacquired infections from 2009 to S aureus was also the predominant pathogen in ventilator-associated pneumonia (VAP), followed by P. aeruginosa and Klebsiella species (3). One of the most concerning trends reported in the NNIS data is the increasing isolation of Acinetobacter species in urinary tract infections, pneumonia, and surgical site infections (1,2,5). Although overall numbers of isolates of Acinetobacter are still relatively small (approximately 2.0%), the p ercentage increase is significant. Similarly, the NHSN report showed that Acinetobacter was the fifth most common pathogen isolated in VAP (3). Even more concerning is the recent report of community-acquired pneumonia (CAP) now attributed to Acinetobacter species, suggesting that this pathogen is extending its area of influence outside of the health care setting (6). Also disconcerting is the observation made by the NNIS report that for each of the antibiotic pathogen combinations tested, there was a significant increase in resistance between study periods. Most impressive were trends in carbapenem- and cephalosporin-resistant P. aeruginosa and Acinetobacter species (1,2). The NHSN data demonstrate that over 60% of tested Acinetobacter isolates in VAP were resistant to imipenem and meropenem, and an even greater percentage met the definition of multidrug resistant (MDR) (3). Many isolates lack effective treatment options and represent a serious public health concern (2,7). Rates of carbapenem resistance, up to 30% in P. aeruginosa isolates and 12.8% in Klebsiella species, are concerning as these organisms are often MDR and have very limited treatment options in hospitals in the United States (3,4). The prevalence of MDR pathogens varies by patient population, hospital, and type of floor or unit in which the patient resides, underscoring the need for local surveillance data. MDR pathogens are more commonly isolated from patients with severe, chronic underlying disease for example, those with risk factors for health care associated infection (Table 83.2) and patients with late-onset hospital-acquired infections. Specifically, in patients with VAP, prolonged ventilation and recent antibiotic exposure have been identified as significant risk factors for infection with MDR organisms (8). Distribution of MDR pathogens has been shown to be highly variable not only between cities and countries but also among different ICUs within the same hospital (9 11). These data suggest that consensus guidelines for antimicrobial therapy will need to be modified at the local level (e.g., according to county, city, hospital, and ICU) to take into account local patterns of antimicrobial resistance. Additionally, it is helpful for clinicians to appreciate local specific resistance rates of certain gram-negative pathogens such as extended- spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae or Escherichia coli, fluoroquinolone-resistant P. aeruginosa, or carbapenem-resistant Acinetobacter baumannii. When risk of these pathogens is identified, empirical therapy must be tailored accordingly. In addition to local or regional variance, numerous patientspecific factors affect the risk of isolation of a resistant pathogen. Therefore, the choice of empiric antibiotic agents should be based on local patterns of antimicrobial susceptibility and must also take into account patient-specific characteristics that may influence the risk of infection with a resistant pathogen. Patients of particular concern are those at risk for 964 LWBK1580_C83_p indd 964

2 Table 83.1 Relative Percentage by Site of Infection of Pathogens Associated with Nosocomial Infection (2,4) Pathogen Pneumonia BSI SSI UTI Year a b c Number 4,018 65,056 4,365 6,632 1,054 50,091 2,351 27,766 7,848 22,043 2,984 16,019 16,434 47,502 4,109 19,058 Staphylococcus aureus Pseudomonas aeruginosa Enterococcus subspecies Enterobacter subspecies Escherichia coli Klebsiella subspecies Serratia subspecies Acinetobacter species a Ventilator-associated pneumonia b Catheter-associated bloodstream infection c Catheter-associated urinary tract infection BSI, bloodstream infection; SSI, surgical site infection; UTI, urinary tract infection;, not reported. 965 LWBK1580_C83_p indd 965

3 966 Section 9 Infectious Disease Table 83.2 Definitions of Infection Categories (with Focus on Bacterial Pathogens) Infection Category Communityacquired infection Hospital-acquired infection Health care associated infection Definition Patients with a first-positive bacterial culture obtained within 48 hrs of hospital admission lacking risk factors for health care associated infection Patients with a first-positive bacterial culture >48 hrs after hospital admission Patients with a first-positive bacterial culture within 48 hrs of admission and any of the following: Admission source indicates a transfer from another health care facility (e.g., hospital, nursing home) Receiving hemodialysis, wound, or infusion therapy as an outpatient Prior hospitalization for 3 days within 90 days Immunocompromised state due to underlying disease or therapy (human immunodeficiency virus, chemotherapy) hospital-acquired infections caused by S. aureus, P. aeruginosa, and Acinetobacter species due to the high frequency with which they cause infection, their resistance to numerous antibiotics, and their associated high mortality rates. Infections with these potentially antibiotic-resistant bacteria have occurred primarily among hospitalized patients and/or among patients with an extensive hospitalization history and other predisposing risk factors like indwelling catheters, past antimicrobial use, decubitus ulcers, postoperative surgical wound infections, or treatment with enteral feedings or dialysis. Antimicrobial Resistance: Risk Factors and Influence on Outcome Although several factors contribute to the emergence of antimicrobial resistance, antibiotic use is the key driver for its development in both gram-positive and gram-negative bacteria (8,12,13). Prolonged hospitalization, invasive devices such as endotracheal tubes and intravascular catheters, residence in long-term treatment facilities, and inadequate infection control practices also promote resistance (12). Furthermore, the emergence of new bacterial strains in the community setting, such as community-associated methicillin-resistant S. aureus, has created additional stressors favoring the entry of resistant microorganisms into the hospital setting (14). However, the prolonged administration of antimicrobial therapy appears to be the most important factor associated with the emergence of resistance that is potentially amenable to intervention (8,15,16). It is critical to maintain awareness of risk factors associated with the development of antimicrobial resistance as clinical investigations have repeatedly demonstrated that inappropriate initial antimicrobial therapy is associated with greater in-hospital mortality (17 22). When initial therapy is inadequate, adjusting treatment regimens once antimicrobial sensitivity data is available has not been shown to improve patient outcomes (23). Antimicrobial resistance is also associated with excess costs. While most of this is associated with the acquisition of a nosocomial infection, the presence of antibiotic resistance may confer additional morbidity and further increase cost (8,24,25). For these reasons, local antibiograms, both within individual hospitals and ICUs, should be updated frequently to guide clinicians in choosing appropriate therapy. Diagnosis A thorough diagnostic assessment is essential to ensure initiation of appropriate antimicrobial therapy and allow for deescalation. Data from a patient history, physical examination, and imaging are combined to create an initial antimicrobial regimen. The development of rapid molecular diagnostics has added a new element to the clinician s arsenal that may improve the likelihood of covering all possible pathogens early in the course of therapy. Cultures from likely infectious sources enable the clinician to streamline initial antimicrobial regimens. The use of such targeted therapies minimizes the risk of medication adverse effects, decreases the risk of selecting for new, resistant pathogens, and reduces cost. Rapid Microbiologic Diagnostics Conventional microbiologic procedures are time consuming and often delay identification of resistant bacteria resulting in inadvertent administration of inappropriate initial antimicrobial therapy. Recently, several molecular diagnostic platforms for the rapid identification of infectious organisms and their accompanying resistance genes have been introduced and evaluated. Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) Mass spectrometry was first utilized for bacterial identification in the 1970s (26). This technique has evolved significantly in recent years and has the potential to revolutionize the way pathogens are identified in clinical practice. Following organism isolation from a clinical specimen, MALDI-TOF MS utilizes mass spectrometry to rapidly identify pathogens. The use of this technique has been reported to decrease time to bacterial identification by up to 48 hours compared to conventional techniques (27). Further, when combined with interventions from an antimicrobial stewardship team, MALDI-TOF has been shown to decrease not only time to bacterial identification but also time to effective antibiotic therapy, mortality, ICU length of stay, and recurrent bacteremia compared to conventional microbiologic methods (28). While most research has focused on the identification of bacterial isolates, MALDI-TOF has also been investigated for the identification of fungi and viruses. Practical hurdles to the wide spread adaptation of this evolving technology exist including a large upfront investment in the instrument and a current lack of clarity regarding how to best utilize MALDI-TOF when dealing with specimens other than blood (29). As this technology continues to evolve however it is likely to become a prominent feature of infectious disease management in the future. Peptide Nucleic Acid Fluorescent In Situ Hybridization (PNA-FISH) PNA-FISH allows for rapid identification of bacteria and yeast from positive blood cultures. Compared to conventional methods, PNA-FISH has been shown to decrease time to organism LWBK1580_C83_p indd 966

4 chapter 83 Antibiotics in the Management of Serious Hospital-Acquired Infections 967 identification by nearly 72 hours and has been associated with decreased mortality and antibiotic use (30,31). Compared with other rapid diagnostics, PNA-FISH has the advantage of a relatively small investment in equipment up front and comparative ease of use. A major limitation of this technology currently is the lack of probes for some clinically relevant organisms. However, this technology has evolved rapidly in recent years and will likely continue to grow and expand its place in therapy. Microarrays Compared to the previously discussed rapid diagnostic techniques, DNA-probe based assays, or microarrays, have the comparative advantage of being able to simultaneously identify organisms and resistance markers from positive blood cultures. Probes for commonly encountered resistance mechanisms, such as meca, vana/vanb, and a number of genes responsible for production of extended-spectrum β-lactamases and carbapenemases exist (32 34). To date, microarrays have been predominantly studied clinically in gram-positive bloodstream infections. In this setting, time to organism and resistance identification has been shown to be decreased by up to 48 hours compared to conventional techniques (32). As the role of microarrays for the treatment of gram-positive infections becomes more established, it is likely that its role will continue to expand to gram-negative infections as well. Quantitative Cultures and Assessment of Infection Risk Pneumonia is the most common hospital-acquired infection among mechanically ventilated patients. A meta-analysis of four randomized trials demonstrated that the use of quantitative bacterial cultures obtained from the lower respiratory tract may, in theory, facilitate de-escalation of empiric broadspectrum antibiotics and reduce drug-specific antibiotic days of treatment (35). Another study found that patients with a clinical suspicion for VAP and culture-negative bronchoalveolar lavage (BAL) results for a major pathogen could have antimicrobial therapy safely discontinued within 72 hours (36). Interestingly, the mean modified clinical pulmonary infection scores (CPISs) of these patients was approximately six, suggesting that this quantitative clinical assessment of the risk for VAP could have been used to discontinue antibiotics as previously suggested (37). Regardless of whether quantitative culture methods are used, the results of microbiologic testing should be used to routinely modify or discontinue antibiotic treatment in the appropriate clinical setting. Treatment Antibiotics, Their Mode of Action, Clinical Indications for Use, and Associated Toxicities Most antimicrobial agents used for the treatment of infections may be categorized according to their principal mechanism of action. For antibacterial agents, the major modes of action are the following (38): Interference with cell wall synthesis Disruption of the bacterial cell membrane Inhibition of protein synthesis Interference with nucleic acid synthesis Inhibition of a metabolic pathway Tables 83.3 to 83.5 review the major pathogens, the antimicrobials of choice by pathogen, and the major toxicities of specific agents, respectively. Cell Wall Active Antibiotics Antibacterial drugs that work by inhibiting bacterial cell wall synthesis include the β-lactams such as the penicillins, cephalosporins, carbapenems, and monobactams and the glycopeptides, including vancomycin and teicoplanin. β-lactam agents inhibit the synthesis of the bacterial cell wall by interfering with the enzymes required for the synthesis of the peptidoglycan layer. Vancomycin and teicoplanin also interfere with cell wall synthesis by preventing the cross-linking steps required for stable cell wall synthesis. Disruption of Bacterial Cell Membrane Disruption of the bacterial membrane is a less well characterized mechanism of action. Polymyxin antibiotics appear to exert their inhibitory effects by increasing bacterial membrane permeability, causing leakage of bacterial contents. The cyclic lipopeptide, daptomycin, appears to insert its lipid tail into the bacterial cell membrane, causing membrane depolarization and eventual death of the bacterium. Inhibition of Bacterial Protein Synthesis Macrolides, aminoglycosides, tetracyclines, chloramphenicol, streptogramins, and oxazolidinones produce their antibacterial effects by inhibiting protein synthesis. Bacterial ribosomes differ in structure from their counterparts in eukaryotic cells. Antibacterial agents take advantage of these differences to selectively inhibit bacterial growth. Macrolides, aminoglycosides, and tetracyclines bind to the 30S subunit of the ribosome, whereas chloramphenicol binds to the 50S subunit. Linezolid is a gram-positive antibacterial oxazolidinone that binds to the 50S subunit of the ribosome on a site that has not been shown to interact with other classes of antibiotics. Inhibition of Nucleic Acid Synthesis Fluoroquinolones exert their antibacterial effects by disrupting DNA synthesis and causing lethal double-strand DNA breaks during DNA replication. Inhibition of a Metabolic Pathway Sulfonamides and trimethoprim block the pathway for folic acid synthesis, which ultimately inhibits DNA synthesis. The common antibacterial drug combination of trimethoprim, a folic acid analogue, plus sulfamethoxazole (a sulfonamide) inhibits two steps in the enzymatic pathway for bacterial folate synthesis. Mechanisms of Resistance to Antibacterial Agents Most antimicrobial agents exert their effect by influencing a single step in bacterial reproduction or bacterial cell function. Therefore, resistance can emerge with a single point mutation aimed at bypassing or eliminating the action of the antibiotic. Some species of bacteria are innately resistant to at least one class of antimicrobial agents, with resulting resistance to all LWBK1580_C83_p indd 967

5 968 Section 9 Infectious Disease Table 83.3 Most Common Pathogens Associated with Sites of Serious Infection Commonly Seen in the Adult Intensive Care Unit Setting Infection Site Pathogens Pneumonia 1. Community-acquired pneumonia (nonimmunocompromised host) Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Mycoplasma pneumoniae Legionella pneumophila Chlamydia pneumoniae Methicillin-resistant Staphylococcus aureus (MRSA) Influenza virus 2. Health care associated pneumonia MRSA Pseudomonas aeruginosa Klebsiella pneumoniae Acinetobacter species Stenotrophomonas species Legionella pneumophila 3. Pneumonia (immunocompromised host) a. Neutropenia Any pathogen listed above Aspergillus species Candida species b. HIV Any pathogen listed above Pneumocystis jirovecii Mycobacterium tuberculosis Histoplasma capsulatum Other fungi Cytomegalovirus c. Solid organ transplant or bone marrow transplant Any pathogen listed above (Can vary depending on timing of infection to transplant) d. Cystic fibrosis Haemophilus influenzae (early) Staphylococcus aureus Pseudomonas aeruginosa Burkholderia cepacia 4. Lung abscess Bacteroides species Peptostreptococcus species Fusobacterium species Nocardia (in immunocompromised patients) Amebic (when suggestive by exposure) 5. Empyema Staphylococcus aureus Streptococcus pneumoniae Usually acute Group A Streptococci Haemophilus influenzae Meningitis Brain abscess Anaerobic bacteria Enterobacteriaceae Mycobacterium tuberculosis Streptococcus pneumoniae Neisseria meningitidis Listeria monocytogenes Haemophilus influenzae Escherichia coli Group B streptococci Staphylococcus aureus Enterobacteriaceae Pseudomonas aeruginosa Streptococci Bacteroides species Usually subacute or chronic Neonates Postsurgical or posttrauma Enterobacteriaceae Staphylococcus aureus Nocardia Toxoplasma gondii Postsurgical or posttrauma Immunocompromised or HIV infected LWBK1580_C83_p indd 968

6 chapter 83 Antibiotics in the Management of Serious Hospital-Acquired Infections 969 Table 83.3 Most Common Pathogens Associated with Sites of Serious Infection Commonly Seen in the Adult Intensive Care Unit Setting (Continued ) Infection Site Pathogens Encephalitis Endocarditis Catheter-associated bacteremia Pyelonephritis West Nile virus Herpes simplex Arbovirus Rabies Cat-scratch disease Streptococcus viridans Enterococcus species Staphylococcus aureus Streptococcus bovis MRSA Candida species Candida species Staphylococcus aureus Enterococcus species Enterobacteriaceae Pseudomonas aeruginosa Enterobacteriaceae Escherichia coli Enterococcus species Pseudomonas aeruginosa Acinetobacter species Peritonitis 1. Primary or spontaneous Enterobacteriaceae Streptococcus pneumoniae Enterococcus species Anaerobic bacteria (rare) 2. Secondary (bowel perforation) Enterobacteriaceae Bacteroides species Enterococcus species Pseudomonas aeruginosa (uncommon) 3. Tertiary (bowel surgery, hospitalized on antibiotics) Pseudomonas aeruginosa MRSA Acinetobacter species Candida species Skin structure infections 1. Cellulitis Group A streptococci Staphylococcus aureus Enterobacteriaceae Diabetics 2. Decubitus ulcer Polymicrobial Streptococcus pyogenes Enterococcus species Enterobacteriaceae Anaerobic streptococci Pseudomonas aeruginosa Staphylococcus aureus Bacteroides species 3. Necrotizing fasciitis Streptococcus species Clostridia species Mixed aerobic/anaerobic bacteria Muscle infection 1. Myonecrosis (gas gangrene) Clostridium perfringens Other Clostridium species 2. Pyomyositis Staphylococcus aureus Group A streptococci Anaerobic bacteria Gram-negative bacteria (rare) Intravenous drug user, prosthetic valve Prosthetic valve Catheter-associated, postsurgical (Continued ) LWBK1580_C83_p indd 969

7 970 Section 9 Infectious Disease Table 83.3 Most Common Pathogens Associated with Sites of Serious Infection Commonly Seen in the Adult Intensive Care Unit Setting (Continued ) Infection Site Pathogens Septic shock 1. Community-acquired Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae Escherichia coli Capnocytophaga (DF-2 with splenectomy) 2. Health care associated MRSA Pseudomonas aeruginosa Acinetobacter species Candida species 3. Toxic shock syndrome Staphylococcus aureus Streptococci species 4. Regional illness or special circumstances Rickettsial species Ehrlichiosis Babesiosis Cat-scratch disease (immunocompromised hosts) Yersinia pestis Francisella tularensis Leptospira Salmonella enteritidis Salmonella typhi HIV, human immune deficiency virus. the members of those antibacterial classes. However, the emergence and spread of acquired resistance due to the selective pressure to use specific antimicrobial agents is of greater concern due to the spread of such resistance. Several mechanisms of antimicrobial resistance are readily transferred to various bacteria. First, the organism may acquire genes encoding enzymes, such as β-lactamases, that destroy the antibacterial agent before it can have an effect. Second, bacteria may acquire efflux pumps that extrude the antibacterial agent from the cell before it can reach its target site and exert its effect. Third, bacteria may acquire several genes for a metabolic pathway that ultimately produces altered bacterial cell walls that no longer contain the binding site of the antimicrobial agent, or bacteria may acquire mutations that limit access of antimicrobial agents to the intracellular target site via downregulation of porin genes. Susceptible bacteria can also acquire resistance to an antimicrobial agent via new mutations such as are noted above. New Antimicrobial Agents Most new antibiotics have been developed for the treatment of gram-positive bacteria. Until recently, the glycopeptides, vancomycin and teicoplanin, were the only antibacterial compounds available to which MRSA strains remained uniformly susceptible. In 1996, the first clinical isolate of S. aureus with reduced susceptibility to vancomycin (vancomycin-intermediate S. aureus, or VISA) was reported in Japan and, since then, similar cases have been reported around the world. Only a few years later, clinical isolates of S. aureus that were fully resistant to vancomycin were reported in South Africa and Michigan. The emergence of MRSA strains with reduced vancomycin susceptibility has limited the treatment options and increased the incidence of treatment failure (39); infection with one of these strains may be an independent predictor of mortality (40). More concerning are the observations that upward drift in the minimum inhibitory concentrations (MICs) for vancomycin in MRSA are associated with an increased risk of clinical treatment failures (41). As a result of this upsurge in MRSA resistance, most of the recent advances in the development of new antibiotic agents have predominantly occurred for grampositive bacteria. Unfortunately, gram-negative antibiotic development has lagged behind. In an effort to encourage development and marketing of new antimicrobials against resistant bacteria, the FDA began offering a Qualified Infections Disease Product (QIDP) designation as a part of the Generating Antibiotic Incentives Now (GAIN) act in This designation allows priority review and an extended period of market exclusivity for qualifying products (42). All of the following antimicrobials marketed after 2012 were granted QIDP status. Dalbavancin (Dalvance) Approved by the FDA in 2014, dalbavancin is a lipoglycopeptide antimicrobial that has been studied in the treatment of complicated skin and skin structure infections and catheter-related bloodstream infection. Dalbavancin is a bactericidal agent whose long-terminal plasma half-life (8.5 days) allows for the unique dosing of 1,000 mg given on day 1 and 500 mg given on day 8. The long half-life may turn out to be the strength of the drug, allowing for more convenient treatment options in patients requiring prolonged antibiotic therapy (e.g., right-sided infective endocarditis or osteomyelitis). However, the impact of this prolonged half-life on adverse reactions also needs further evaluation. Oritavancin (Orbactiv) Oritavancin is a lipoglycopeptide antibacterial that gained FDA approval in It has demonstrated in vitro bactericidal LWBK1580_C83_p indd 970

8 chapter 83 Antibiotics in the Management of Serious Hospital-Acquired Infections 971 Table 83.4 Drugs of Choice in Serious Infections a Organism Drug of Choice Alternative Drugs GRAM-POSITIVE COCCI Staphylococcus aureus b or Staphylococcus epidermidis Penicillin-sensitive Penicillin G Cephalosporin, vancomycin, or clindamycin c Penicillinase-producing d Oxacillin or nafcillin Cephalosporin, vancomycin, or clindamycin Methicillin-resistant e Vancomycin (linezolid for pneumonia) Quinolone, TMP/SMX, minocycline, clindamycin, linezolid, ceftaroline, daptomycin (unless pneumonia) Nonenterococcal streptococci Penicillin G Cephalosporin, vancomycin, or clindamycin Enterococcus Penicillin or ampicillin + gentamicin Vancomycin + gentamicin Streptococcus pneumoniae f Penicillin G Cephalosporin, vancomycin, macrolide, or clindamycin GRAM-POSITIVE BACILLI Actinomyces israelii Penicillin G Tetracycline Bacillus anthracis Penicillin G Tetracycline, macrolide Clostridium difficile Metronidazole Oral vancomycin Clostridium perfringens Penicillin g Clindamycin, metronidazole, tetracycline, imipenem Clostridium tetani Penicillin h Tetracycline Corynebacterium diphtheriae Macrolide g Penicillin Corynebacterium JK Vancomycin Penicillin G + gentamicin, erythromycin Listeria monocytogenes Ampicillin gentamicin TMP/SMX Nocardia asteroides TMP/SMX carbapenem + amikacin Propionibacterium sp. Penicillin Clindamycin, erythromycin GRAM-NEGATIVE COCCI Moraxella catarrhalis TMP/SMX Amoxicillin/clavulanic acid, ceftriaxone, macrolide, tetracycline Neisseria gonorrhoeae Ceftriaxone Penicillin G, quinolone Neisseria meningitidis Penicillin G Ceftriaxone ENTERIC GRAM-NEGATIVE BACILLI Bacteroides Oral source Penicillin Clindamycin, cefoxitin, metronidazole, cefotetan Bowel source Metronidazole Cefoxitin, cefotetan, imipenem, ampicillin/sulbactam ticarcillin/clavulanate, piperacillin/tazobactam, clindamycin Citrobacter Cefepime or imipenem/meropenem Aminoglycoside, quinolone, piperacillin, aztreonam Enterobacter sp. i Cefepime or imipenem/meropenem Ciprofloxacin, aminoglycoside, aztreonam Escherichia coli j 3rd-generation cephalosporin Aminoglycoside, carbapenem, cefepime, ß-lactam/ß-lactamase inhibitor, ciprofloxacin, TMP/SMX Klebsiella j 3rd-generation cephalosporin As for E. coli Proteus mirabilis Ampicillin Aminoglycoside, quinolone, cephalosporin, piperacillin, ticarcillin, TMP/SMX Proteus, nonmirabilis 3rd-generation cephalosporin Aminoglycoside, quinolone, piperacillin, aztreonam, imipenem Providencia 2nd- or 3rd-generation cephalosporin Gentamicin, amikacin, piperacillin, aztreonam, imipenem, ticarcillin, mezlocillin, TMP/SMX Salmonella typhi Ceftriaxone or quinolone Ampicillin, TMP/SMX Salmonella, nontyphi k Cefotaxime, ceftriaxone, or quinolone Ampicillin, TMP/SMX Serratia Cefepime or imipenem/meropenem Aminoglycoside, aztreonam piperacillin, TMP/SMX, quinolone Shigella Quinolone Ampicillin, TMP/SMX, ceftriaxone, cefixime Yersinia enterocolitica TMP/SMX Aminoglycoside, tetracycline, 3rd-generation cephalosporin, quinolone OTHER GRAM-NEGATIVE BACILLI Acinetobacter Imipenem Cefepime, aminoglycoside, TMP/SMX, colistin, sulbactam Eikenella corrodens Ampicillin Penicillin G, erythromycin, tetracycline, ceftriaxone Francisella tularensis Streptomycin, gentamicin Tetracycline Fusobacterium Penicillin Clindamycin, metronidazole, cefoxitin Haemophilus influenzae 3rd-generation cephalosporin Ampicillin, imipenem, quinolone, cefuroxime l, quinolone, macrolide, TMP/SMX (Continued ) LWBK1580_C83_p indd 971

9 972 Section 9 Infectious Disease Table 83.4 Drugs of Choice in Serious Infections a (Continued ) Organism Drug of Choice Alternative Drugs Legionella Erythromycin (1 g q6h) + rifampin Pasteurella multocida Penicillin G Tetracycline, cephalosporin, ampicillin/sulbactam Pseudomonas aeruginosa Antipseudomonal penicillin m + aminoglycoside Pseudomonas cepacia TMP/SMX Ceftazidime Aztreonam, cefepime, imipenem, quinolone Spirillum minus Penicillin G Tetracycline, streptomycin Streptobacillus moniliformis Penicillin G Tetracycline, streptomycin Vibrio cholerae n Tetracycline TMP/SMX, quinolone Vibrio vulnificus Tetracycline Cefotaxime Xanthomonas maltophilia TMP/SMX Quinolone, minocycline, ceftazidime Yersinia pestis Streptomycin Tetracycline, gentamicin CHLAMYDIAE Chlamydia pneumoniae (TWAR) Macrolide Tetracycline Chlamydia psittaci Tetracycline Chloramphenicol Chlamydia trachomatis Macrolide Sulfonamide, tetracycline MYCOPLASMA sp. Macrolide Tetracycline Tetracycline Quinolone SPIROCHETES Borrelia burgdorferi Doxycycline, amoxicillin Penicillin G, macrolide, cefuroxime, ceftriaxone, cefotaxime Borrelia sp. Tetracycline Penicillin G Treponema pallidum Penicillin Tetracycline, ceftriaxone VIRUSES Cytomegalovirus Ganciclovir o Foscarnet, cidofovir Herpes simplex Acyclovir Foscarnet, ganciclovir HIV See Centers for Disease Control Web site Influenza Amantadine Rimantadine, oseltamivir, zanamivir Respiratory syncytial Ribavirin Varicella zoster Acyclovir Famciclovir p FUNGI Aspergillus Voriconazole Amphotericin B, echinocandin, Itraconazole r Blastomyces Amphotericin B or itraconazole Ketoconazole Candida q Mucosal Fluconazole, echinocandin s Ketoconazole, itraconazole Systemic Fluconazole, echinocandin Amphotericin B Coccidioides Amphotericin B or fluconazole Itraconazole, ketoconazole Cryptococcus Amphotericin Fluconazole, itraconazole Histoplasma Itraconazole or Amphotericin B Pseudallescheria Ketoconazole or itraconazole Zygomycosis ( mucor ) Amphotericin B Posaconazole a This table does not consider minor infections that may be treated with oral agents, single-agent therapy, or less toxic drugs. Sensitivity testing must be done on bacterial isolates to confirm the sensitivity pattern. b Some authorities recommend clindamycin as the first choice for susceptible toxin-producing staphylococci, streptococci, or clostridia. c First-generation cephalosporins are most active. If endocarditis is suspected, do not use clindamycin. Some authorities recommend the addition of gentamicin for endocarditis caused by nonenterococcal streptococci or tolerant staphylococci. d Penicillinase-producing staphylococci are also resistant to ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, and piperacillin. e Methicillin-resistant staphylococci should be assumed to be resistant to all cephalosporins and penicillins, even if disk testing suggests sensitivity. Dalbavancin and oritavancin may be alternatives for specific types of methicillin-resistant infection pending future studies and indications. f Some strains show intermediate- or high-level penicillin resistance. Highly resistant strains are treated with vancomycin, or rifampin, or both. In regions with high prevalence of resistant pneumococcus, ceftriaxone or vancomycin should be considered until sensitivity is known. g Use as an adjunct to debridement of infected tissues. h Use as an adjunct to active and passive immunization. i Because of rapid development of resistance, cephalosporins not recommended even if initial tests indicate susceptibility. j Klebsiella sp. and E. coli producing extended-spectrum β-lactamase (ESBL) should be preferentially managed with a carbapenem. k Uncomplicated Salmonella enteritis should not be treated with antibiotics. l Should not be used in meningitis because of poor CNS penetration. m Antipseudomonal penicillins include ticarcillin, mezlocillin, and piperacillin. n Primary therapy is fluid and electrolyte repletion. o Oral form should be used only in maintenance therapy of retinal cytomegalovirus. p Approved only for mild herpes zoster in immunocompetent hosts. q Candida krusei and Torulopsis glabrata may be resistant to azole therapy, Candida parapsilosis may be resistant to echinocandins. r In multidrug combinations. s Echinocandins include caspofungin, micafungin, and anidulafungin. LWBK1580_C83_p indd 972

10 chapter 83 Antibiotics in the Management of Serious Hospital-Acquired Infections 973 Table 83.5 Toxicities Associated with Antimicrobials Antimicrobial Serious Toxicities, Uncommon Common Toxicities a Penicillins Ampicillin Penicillin Antistaphylococcal penicillins Nafcillin Oxacillin a-lactam/a-lactamase inhibitors Amoxicillin/clavulanate Ampicillin/sulbactam Piperacillin/tazobactam Ticarcillin/clavulanate Cephalosporins Carbapenems Imipenem Meropenem Ertapenem Doripenem Glycopeptides Vancomycin Oxazolidinones Linezolid Anaphylaxis, seizures, hemolytic anemia, neutropenia, thrombocytopenia, drug fever Anaphylaxis, neutropenia, thrombocytopenia, acute interstitial nephritis, hepatotoxicity Anaphylaxis, seizures, hemolytic anemia, neutropenia, thrombocytopenia Clostridium difficile colitis, cholestatic jaundice, drug fever Anaphylaxis, seizures, neutropenia, thrombocytopenia, drug fever Anaphylaxis, seizures (imipenem > meropenem, ertapenem, doripenem) C. difficile colitis, drug fever Ototoxicity, nephrotoxicity (unlikely without concomitant nephrotoxins), thrombocytopenia More common with long-term use: Peripheral and optic neuropathy, myelosuppression Possible with short-term use: Lactic acidosis, myopathy anemia Diarrhea, nausea, vomiting Diarrhea, nausea, vomiting Diarrhea, nausea, vomiting Diarrhea, nausea, vomiting Diarrhea, nausea, vomiting Red-man syndrome Diarrhea Lipopeptides Daptomycin Diarrhea, constipation, vomiting Streptogramin Arthralgia, myalgia, inflammation, pain, Quinupristin/dalfopristin edema at infusion site, hyperbilirubinemia Aminoglycosides Nephrotoxicity, ototoxicity Amikacin Gentamicin Tobramycin Fluoroquinolones 2nd generation Anaphylaxis, dysglycemia QTc prolongation, joint toxicity in children Nausea, vomiting, diarrhea, photosensitivity, rash Ciprofloxacin CNS stimulation, dizziness, somnolence 3rd generation Levofloxacin 4th generation Gatifloxacin Moxifloxacin Gemifloxacin Macrolides QTc prolongation (erythromycin > clarithromycin > Nausea, vomiting, diarrhea, abnormal taste Erythromycin Azithromycin Clarithromycin azithromycin), cholestasis Ketolides Acute hepatic failure Nausea, vomiting, diarrhea Telithromycin QTc prolongation Clindamycin C. difficile colitis Nausea, vomiting, diarrhea, abdominal pain, rash Tetracyclines Tooth discoloration and retardation of bone growth Photosensitivity, diarrhea Tetracycline Doxycycline Minocycline pseudotumor cerebri (in children), renal tubular necrosis, dizziness, vertigo Glycylcyclines Nausea, vomiting, diarrhea Tigecycline Trimethoprim/sulfamethoxazole Myelosuppression Rash, nausea, vomiting, diarrhea Stevens Johnson syndrome, hyperkalemia, aseptic meningitis, hepatic necrosis Metronidazole Seizures, peripheral neuropathy Nausea, vomiting, metallic taste, disulfiramlike reaction (Continued ) LWBK1580_C83_p indd 973

11 974 Section 9 Infectious Disease Table 83.5 Toxicities Associated with Antimicrobials (Continued ) Antimicrobial Serious Toxicities, Uncommon Common Toxicities a Nitrofurantoin Pulmonary toxicity, peripheral neuropathy Urine discoloration, photosensitivity ANTIFUNGAL AGENTS Azoles Fluconazole Itraconazole Voriconazole Posaconazole Amphotericin B products Amphotericin B deoxycholate ABLC ABCD Liposomal amphotericin B Echinocandins Caspofungin Micafungin Anidulafungin Flucytosine Hepatic failure, increased AST/ALT, cardiovascular toxicity, hypertension, edema Acute liver failure, myelosuppression Hepatotoxicity, infusion-related rash, flushing, itching Myelosuppression, hepatotoxicity, confusion, hallucinations, sedation Nausea, vomiting, diarrhea, rash, visual disturbances, phototoxicity Nephrotoxicity (less common with lipid formulations), acute infusionrelated reactions, hypokalemia, hypomagnesemia Nausea, vomiting, diarrhea, rash ANTIVIRAL AGENTS Nucleoside analogues Acyclovir Nephrotoxicity, rash, encephalopathy, inflammation at injection site, phlebitis Bone marrow suppression, headache, nausea, vomiting, diarrhea (with oral forms) Valaciclovir Ganciclovir Valganciclovir Amantadine CNS disturbances (amantadine > rimantadine) Nausea, vomiting, anorexia, xerostomia Rimantadine Neuraminidase inhibitors Oseltamivir Anaphylaxis, bronchospasm Nausea, vomiting, cough, local discomfort Zanamivir Cidofovir Anemia, neutropenia, fever, rash Nephrotoxicity, uveitis/iritis, nausea, vomiting Foscarnet Seizures, anemia, fever Nephrotoxicity, electrolyte abnormalities (hypocalcemia, hypomagnesemia, hypokalemia, hypophosphatemia), nausea, vomiting, diarrhea, headache a Toxicities were classified as common relative to the other toxicities that agent is known to cause. Because toxicities are classified as common does not imply they are not serious. activity against a variety of gram-positive organisms including methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant, S. aureus and vancomycin-resistant VanA and VanE strains of Enterococcus faecalis and Enterococcus faecium (43,44). Oritavancin has been investigated chiefly for the treatment of skin and skin structure infections. It has been observed to have a terminal half-life of approximately 10 days allowing for single-dose administration to treat most infections (45). Tedizolid (Sivextro) Tedizolid is an oxazolidinone antibacterial that gained FDA approval in Tedizolid has a similar spectrum of activity to linezolid with the added advantage of having activity against linezolid-resistant strains of MRSA (46). Tedizolid has a similar side effect profile to linezolid and is available in both oral and IV dosage forms (47). Ceftaroline (Teflaro) Ceftaroline is an intravenous, broad-spectrum, cephalosporin antibiotic that gained FDA approval in Ceftaroline has activity against gram-positive organisms, oral anaerobes, and a variety of Enterobacteriaceae. It is the only antibiotic in the cephalosporin class with activity against methicillin-resistant, vancomycin-intermediate, and vancomycin-resistant S. aureus. Its activity against Enterobacteriaceae, though, is limited to organisms that do not produce Amp-C β-lactamase. Additionally, most nonfermenting gram-negative bacilli, such as P. aeruginosa, are inherently resistant to ceftaroline (48). The adverse effects of ceftaroline are similar to those observed with other cephalosporins (49). Originally approved for the treatment of skin and skin structure infections and community-acquired pneumonia, clinical experience with ceftaroline has expanded to a variety of infectious processes and is likely to continue to expand based on its spectrum of activity and favorable side effect profile. Ceftolozane/Tazobactam (Zerbaxa) This intravenous combination product was approved by the FDA in 2014 and contains ceftolozane, a new cephalosporin antibiotic, and tazobactam, a β-lactamase inhibitor. Ceftolozane alone is a broad-spectrum, bactericidal antibiotic that closely resembles ceftazidime. Ceftolozane has activity against a variety of resistant gram-negative bacilli including some ESBL producing strains. The addition of tazobactam extends this spectrum of activity to include many ESBL organisms, MDR strains of P. aeruginosa, and some anaerobes (50,51). LWBK1580_C83_p indd 974

12 chapter 83 Antibiotics in the Management of Serious Hospital-Acquired Infections 975 Ceftazidime/Avibactam (Avycaz) This intravenous combination product was approved by the FDA in 2015 and contains the cephalosporin ceftazidime with a new synthetic β-lactamase inhibitor, avibactam. The addition of avibactam expands the gram-negative spectrum of ceftazidime to include activity against a variety of otherwise resistant organisms. Notably ceftazidime/avibactam has demonstrated activity against a variety of carbapenemase producing Enterobacteriaceae and MDR P. aeruginosa. The addition of avibactam does not appear however to enhance the activity of ceftazidime against Acinetobacter spp or enhance its grampositive spectrum (52,53). Initial Antimicrobial Therapy An initial appropriate antibiotic regimen should be prescribed with adequate activity against all pathogens likely to be responsible for the infection. Inappropriate initial antibiotic therapy has been associated with a very high risk of mortality in patients with septic shock attributable to a variety of bacterial and fungal pathogens from numerous sources (17,19,21,54 58). Patient history, including drug intolerances, recent receipt of antibiotics, underlying disease, the clinical syndrome, and susceptibility patterns of pathogens in the community and hospital should be utilized when making decisions regarding initial antimicrobial regimen selection. However, given the severity of illness for patients with severe sepsis and septic shock, erring on the side of initial overtreatment may be preferable to the administration of an inappropriately narrow initial antibiotic regimen. Balancing these competing interests is at the core of antimicrobial stewardship in the ICU; methods for refining this balance are described below. Strategies that Optimize the Efficacy of Antibiotics While Minimizing Antibiotic Resistance Hospital and System Level Interventions Formal Protocols and Guidelines Antibiotic practice guidelines or protocols have emerged as a means of both avoiding unnecessary antibiotic administration and increasing the effectiveness of prescribed antibiotics. Automated antimicrobial utilization guidelines have been successfully used to identify and minimize the occurrence of adverse drug effects and improve antibiotic selection (12). Their use has also been associated with stable antibiotic susceptibility patterns for both gram-positive and gram-negative bacteria, possibly as a result of promoting antimicrobial heterogeneity and specific end points for antibiotic discontinuation. Automated and nonautomated guidelines have also been employed to reduce overall antibiotic use and limit inappropriate antimicrobial exposure, both of which could affect the development of antibiotic resistance (59). One way these guidelines limit the unnecessary use of antimicrobial agents is by recommending that therapy be modified when initial empiric broad-spectrum antibiotics are prescribed and the culture results reveal that narrow-spectrum antibiotics can be used. Hospital Formulary Restrictions Restricted use of specific antibiotics or antibiotic classes from the hospital formulary has been used to reduce resistance, minimize adverse drug reactions, and reduce cost. However, not all experiences have been uniformly successful, and the homogeneous use of a single or limited number of drug classes may actually promote the emergence of resistance (12). Restricted use of specific antibiotics has generally been applied to those drugs with a broad spectrum of action (e.g., carbapenems), rapid emergence of antibiotic resistance (e.g., cephalosporins), and readily identified toxicity (e.g., aminoglycosides). To date, it has been difficult to demonstrate that restricted hospital formularies are effective in curbing the overall emergence of antibiotic resistance. While this may be due in large part to methodologic problems, their use has been successful in specific outbreaks of infection with antibiotic-resistant bacteria, particularly in conjunction with infection control practices and antibiotic educational activities. Formalized Antimicrobial Stewardship Programs Formally implemented antimicrobial stewardship programs (ASPs) have been associated not only with reduced infection rates but also significant cost savings associated with reductions in the defined daily doses of the antimicrobials targeted by the ASP (60,61). ASPs have been shown to increase the appropriateness of therapy and increase the number of infectious diseases consultations, which may improve patient outcomes including mortality, hospital lengths of stay, and readmission rates by providing more precise antibiotic prescription (60,62 65). These attributes of ASPs account for why they are now recognized as mandatory components of hospital quality improvement efforts. Formalized ASPs not only restrict the use of unnecessary antibiotics but also insure that antimicrobials are employed in an effective manner to optimize patient outcomes. Antimicrobial Exposure Use of Narrow-Spectrum Antibiotics Another proposed strategy to curtail the development of antimicrobial resistance, in addition to the judicious overall use of antibiotics, is to use drugs with a narrow antimicrobial spectrum. Several investigations have suggested that infections such as CAP can usually be successfully treated with narrowspectrum antibiotic agents, especially if the infections are not life threatening. Similarly, the avoidance of broad-spectrum antibiotics, especially those associated with rapid emergence of resistance (cephalosporins, quinolones), and the reintroduction of narrow-spectrum agents (penicillin, trimethoprim, gentamicin), along with infection control practices have been successful in reducing the occurrence of specific infections in the hospital setting (12). Unfortunately, ICU patients often have already received prior antimicrobial treatment, making it more likely that they will be infected with an antibioticresistant pathogen (8). Therefore, initial empiric treatment with broad-spectrum agents is often initially necessary for hospitalized patients to avoid inappropriate treatment until culture results become available and de-escalation can occur (Fig. 83.1) (18). 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13 976 Section 9 Infectious Disease Step 1: Initial suspicion of serious infection in critically ill patient: Obtain appropriate specimens for culture and special stains Begin initial antimicrobial based on risk factors for antibiotic-resistant pathogens (resistant hospitalization or antibiotic therapy, admission from nursing home, late-onset infection) Step 2: Subsequent evaluation of clinical and microbiologic date: Clinical Improvement Narrow antimicrobial spectrum based on microbiologic data (Figure 2) Reassess antimicrobial need beyond 7 days (unless bactermia is present) Evaluate patient s clinical response at hours (temperature, white blood cell count, organ function) Lack of Clinical Improvement Reassess patient for the following: Pathogen(s) resistant to inital therapy Unidentifield source of infection Complication of infection (abscess) Noninfectious cause (drug fever) Consider a change in antimicrobial therapy (Tables 3 and 4) Figure 83.1 Clinical algorithm for the de-escalation approach to antibiotic treatment of serious infections in patients with risk factors for multidrug-resistant pathogens. Optimally, de-escalation of antimicrobial treatment would always occur once the pathogen causing infection and its antimicrobial susceptibility are known. Combination Antibiotic Therapy Several meta-analyses recommend the use of monotherapy with a β-lactam antibiotic, as opposed to combination therapy including an aminoglycoside, for the definitive treatment of severe sepsis once antimicrobial susceptibilities are known (66,67). Additionally, there is no definitive evidence that the emergence of antibiotic resistance is reduced by the use of combination antimicrobial therapy. However, empiric combination therapy directed against high-risk pathogens such as P. aeruginosa should be encouraged until the results of antimicrobial susceptibility become available. Such an approach to empiric treatment can increase the likelihood of providing appropriate initial antimicrobial therapy with improved outcomes (19). Shorter Courses of Antibiotic Treatment Prolonged administration of antibiotics to hospitalized patients has been shown to be an important risk factor for the emergence of colonization and infection with antibiotic-resistant bacteria (8,16). Therefore, attempts have been made to reduce the duration of antibiotic treatment for specific bacterial infections. Several clinical trials have found that 7 to 8 days of antibiotic treatment is acceptable for most nonbacteremic patients with VAP (15,37). Similarly, shorter courses of antibiotic treatment have been successfully used in patients at low risk for VAP (36,37,59), with pyelonephritis (68), and for CAP (69). In general, the shorter-course treatment regimens have been associated with a significantly lower risk for the emergence of antimicrobial resistance and several guidelines for the antibiotic management of nosocomial pneumonia and severe sepsis currently recommend the discontinuation of empiric antibiotic therapy after 48 to 72 hours if cultures are negative or the signs of infection have resolved (70,71). There are clinical scenarios in which shorter durations of therapy may not be appropriate, including fungemia, endocarditis, osteomyelitis, meningitis, and VAP caused by P. aeruginosa or other nonfermenters. In ICU patients, all antimicrobials should be reviewed on a daily basis to ensure they are needed (59). De-escalation Approach for the Antibiotic Treatment of Serious Infection in the Hospitalized Patient After an initial, appropriately broad-spectrum, antibiotic regimen is prescribed, modification of the regimen using a de-escalation strategy should occur based on the results of the patient s clinical response and microbiologic testing (Fig. 83.2). Based on the de-escalation strategy, modification of the initial antibiotic regimen should include decreasing the number and/or spectrum of antibiotics, if possible based on culture and sensitivity results, shortening the duration of therapy in patients with uncomplicated infections who are demonstrating signs of clinical improvement, or discontinuing antibiotics altogether in patients who have a noninfectious cause identified accounting for the patient s signs and symptoms. A number of strategies have been used to promote de-escalation including the use of computer decision support systems, protocol-guided therapies, and clinical pharmacist supported guidelines (60,72 74). Pharmacokinetic Considerations Optimizing Pharmacokinetic/ Pharmacodynamic (Pk/Pd) Principles Antibiotic concentrations that are sublethal can promote the emergence of resistant pathogens. Optimization of antibiotic regimens on the basis of pharmacokinetic/pharmacodynamic principles could play a role in the reduction of antibiotic resistance (13). The duration of time the serum drug concentration remains above the MIC of the antibiotic (T > MIC) enhances bacterial eradication with β-lactams, carbapenems, monobactams, glycopeptides, and oxazolidinones (Fig. 83.3). Frequent dosing, prolonged infusion times, or continuous infusions can increase the T greater than MIC and improve clinical and microbiologic cure rates. To maximize the bactericidal LWBK1580_C83_p indd 976