Antibiotics in the Management of Serious Hospital-Acquired ... · niques and biomarkers may aid in optimizing antimicrobial therapy, these technologies are not currently widely available

964

Chapter

83Antibiotics in the Management of Serious Hospital-Acquired InfectionsMollie Gowan, Jennifer Bushwitz, and Marin h. Kollef

IntroductIon

As antimicrobial resistance spreads and new antimicrobial agents are developed, designing an empiric antibiotic regi-men for patients in the intensive care unit (ICU) has become increasingly complex. In order to ensure that the initial anti-biotic 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 tech-niques 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 strate-gies 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, resis-tance patterns, and patient-specific risk factors for resistance. Reports from the National Nosocomial Infections Surveillance (NNIS) System describe hospital and ICU infection rates in par-ticipating 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 83.1. Overall, the occurrence of hospital-acquired 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; how-ever, 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 hospital-acquired infections from 2009 to 2010. 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 uri-nary 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 percentage

increase is significant. Similarly, the NHSN report showed that Acinetobacter was the fifth most common pathogen iso-lated 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 extend-ing 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. aerugi-nosa 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 popu-lation, 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. Spe-cifically, in patients with VAP, prolonged ventilation and recent antibiotic exposure have been identified as significant risk fac-tors 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 ther-apy 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 help-ful 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 patient-specific factors affect the risk of isolation of a resistant patho-gen. Therefore, the choice of empiric antibiotic agents should be based on local patterns of antimicrobial susceptibility and must also take into account patient-specific characteris-tics that may influence the risk of infection with a resistant pathogen. Patients of particular concern are those at risk for

LWBK1580_C83_p964-981.indd 964 29/07/17 11:37 AM

Tabl

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LWBK1580_C83_p964-981.indd 965 29/07/17 11:37 AM

966 SeCtion 9 infeCtious Disease

hospital-acquired infections caused by S. aureus, P. aerugi-nosa, and Acinetobacter species due to the high frequency with which they cause infection, their resistance to numerous antibiotics, and their associated high mortality rates. Infec-tions 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 anti-microbial 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 anti-microbial resistance, antibiotic use is the key driver for its development in both gram-positive and gram-negative bacte-ria (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 emer-gence of new bacterial strains in the community setting, such as community-associated methicillin-resistant S. aureus, has cre-ated additional stressors favoring the entry of resistant microor-ganisms 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 inappro-priate initial antimicrobial therapy is associated with greater in-hospital mortality (17–22). When initial therapy is inad-equate, adjusting treatment regimens once antimicrobial sensi-tivity 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 acquisi-tion of a nosocomial infection, the presence of antibiotic resis-tance 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 fre-quently to guide clinicians in choosing appropriate therapy.

dIAgnoSIS

A thorough diagnostic assessment is essential to ensure initia-tion of appropriate antimicrobial therapy and allow for de-escalation. 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 inad-vertent administration of inappropriate initial antimicrobial therapy. Recently, several molecular diagnostic platforms for the rapid identification of infectious organisms and their accom-panying 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 organ-ism isolation from a clinical specimen, MALDI-TOF MS uti-lizes mass spectrometry to rapidly identify pathogens. The use of this technique has been reported to decrease time to bacte-rial 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 identifi-cation but also time to effective antibiotic therapy, mortal-ity, 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 adap-tation of this evolving technology exist including a large up-front 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 meth-ods, PNA-FISH has been shown to decrease time to organism

Table 83.2 Definitions of Infection Categories (with Focus on bacterial Pathogens)

Infection Category Definition

Community-acquired infection

Patients with a first-positive bacterial cul-ture obtained within 48 hrs of hospital admission lacking risk factors for health care–associated infection

hospital-acquired infection

Patients with a first-positive bacterial culture >48 hrs after hospital admission

health care–asso-ciated infection

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)

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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 technol-ogy 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 tech-niques, DNA-probe–based assays, or microarrays, have the comparative advantage of being able to simultaneously iden-tify organisms and resistance markers from positive blood cultures. Probes for commonly encountered resistance mech-anisms, 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 blood-stream infections. In this setting, time to organism and resis-tance 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 infec-tions 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 quanti-tative bacterial cultures obtained from the lower respiratory tract may, in theory, facilitate de-escalation of empiric broad-spectrum antibiotics and reduce drug-specific antibiotic days of treatment (35). Another study found that patients with a clinical suspicion for VAP and culture-negative bronchoalveo-lar lavage (BAL) results for a major pathogen could have anti-microbial therapy safely discontinued within 72 hours (36). Interestingly, the mean modified clinical pulmonary infection scores (CPISs) of these patients was approximately six, sug-gesting 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 anti-microbials 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, ceph-alosporins, carbapenems, and monobactams—and the gly-copeptides, including vancomycin and teicoplanin. β-Lactam agents inhibit the synthesis of the bacterial cell wall by inter-fering with the enzymes required for the synthesis of the pep-tidoglycan 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 charac-terized 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 antibacte-rial 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, aminoglyco-sides, and tetracyclines bind to the 30S subunit of the ribo-some, 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 disrupt-ing 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

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Table 83.3 Most Common Pathogens associated with Sites of Serious Infection Commonly Seen in the adult Intensive Care Unit Setting

Infection Site Pathogens

Pneumonia1. Community-acquired pneumonia (nonimmunocompromised

host)Streptococcus pneumoniaeHaemophilus influenzae

Moraxella catarrhalis

Mycoplasma pneumoniaeLegionella pneumophilaChlamydia pneumoniaeMethicillin-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


Burkholderia cepacia

4. lung abscess Bacteroides species

Peptostreptococcus species

Fusobacterium species

Nocardia (in immunocompromised patients)

Amebic (when suggestive by exposure)

5. empyema Staphylococcus aureusStreptococcus pneumoniaeGroup a StreptococciHaemophilus influenzae

usually acute

anaerobic bacteriaEnterobacteriaceaeMycobacterium tuberculosis

usually subacute or chronic

Meningitis Streptococcus pneumoniae

Neisseria meningitidis

Listeria monocytogenes

Haemophilus influenzae

Escherichia coliGroup B streptococci

neonates

Staphylococcus aureusEnterobacteriaceaePseudomonas aeruginosa

Postsurgical or posttrauma

brain abscess streptococci

Bacteroides species

EnterobacteriaceaeStaphylococcus aureus

Postsurgical or posttrauma

NocardiaToxoplasma gondii

immunocompromised or hiV infected

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encephalitis west nile virus

herpes simplex

arbovirus

rabies

Cat-scratch disease

endocarditis Streptococcus viridans

Enterococcus species


Streptococcus bovis

Mrsa intravenous drug user, prosthetic valve

Candida species Prosthetic valve

Catheter-associated bacteremia Candida species



Enterobacteriaceae


Pyelonephritis Enterobacteriaceae

Escherichia coli


Pseudomonas aeruginosaAcinetobacter species

Catheter-associated, postsurgical

Peritonitis1. Primary or spontaneous Enterobacteriaceae

Streptococcus pneumoniae


anaerobic bacteria (rare)

2. secondary (bowel perforation) Enterobacteriaceae

Bacteroides species


Pseudomonas aeruginosa (uncommon)

3. tertiary (bowel surgery, hospitalized on antibiotics) Pseudomonas aeruginosaMrsa


Candida species

Skin structure infections1. Cellulitis Group a streptococci


Enterobacteriaceae Diabetics

2. Decubitus ulcer Polymicrobial

Streptococcus pyogenes


Enterobacteriaceae

anaerobic streptococci



Bacteroides species

3. necrotizing fasciitis Streptococcus species

Clostridia species

Mixed aerobic/anaerobic bacteria

Muscle infection1. Myonecrosis (gas gangrene) Clostridium perfringens

Other Clostridium species

2. Pyomyositis Staphylococcus aureus

Group a streptococci

anaerobic bacteria

Gram-negative bacteria (rare)

Table 83.3 Most Common Pathogens associated with Sites of Serious Infection Commonly Seen in the adult Intensive Care Unit Setting (Continued )

(Continued )

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Septic shock1. Community-acquired Streptococcus pneumoniae

Neisseria meningitidis

Haemophilus influenzae

Escherichia coli

Capnocytophaga (Df-2 with splenectomy)

2. health care—associated Mrsa



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.

Table 83.3 Most Common Pathogens associated with Sites of Serious Infection Commonly Seen in the adult Intensive Care Unit Setting (Continued )

the members of those antibacterial classes. However, the emer-gence and spread of acquired resistance due to the selective pressure to use specific antimicrobial agents is of greater con-cern 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 antimicro-bial 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 com-pounds available to which MRSA strains remained uniformly susceptible. In 1996, the first clinical isolate of S. aureus with reduced susceptibility to vancomycin (vancomycin-intermedi-ate 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 vanco-mycin in MRSA are associated with an increased risk of clini-cal 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 gram-positive bacteria.

Unfortunately, gram-negative antibiotic development has lagged behind. In an effort to encourage development and mar-keting 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 2012. This designation allows priority review and an extended period of market exclusivity for quali-fying products (42). All of the following antimicrobials mar-keted after 2012 were granted QIDP status.

Dalbavancin (Dalvance)

Approved by the FDA in 2014, dalbavancin is a lipoglycopep-tide antimicrobial that has been studied in the treatment of com-plicated 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 2014. It has demonstrated in vitro bactericidal

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Table 83.4 Drugs of Choice in Serious Infectionsa

Organism Drug of Choice alternative Drugs

GRaM-POSITIVe COCCIStaphylococcus aureusb or

Staphylococcus epidermidis

Penicillin-sensitive Penicillin G Cephalosporin, vancomycin, or clindamycinc

Penicillinase-producingd oxacillin or nafcillin Cephalosporin, vancomycin, or clindamycin

Methicillin-resistante Vancomycin (linezolid for pneumonia) Quinolone, tMP/sMX, minocycline, clindamycin, line-zolid, ceftaroline, daptomycin (unless pneumonia)

nonenterococcal streptococci Penicillin G Cephalosporin, vancomycin, or clindamycin

Enterococcus Penicillin or ampicillin + gentamicin Vancomycin + gentamicin

Streptococcus pneumoniaef Penicillin G Cephalosporin, vancomycin, macrolide, or clindamycin

GRaM-POSITIVe baCIllIActinomyces israelii Penicillin G tetracycline

Bacillus anthracis Penicillin G tetracycline, macrolide

Clostridium difficile Metronidazole oral vancomycin

Clostridium perfringens Penicilling Clindamycin, metronidazole, tetracycline, imipenem

Clostridium tetani Penicillinh tetracycline

Corynebacterium diphtheriae Macrolideg 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 COCCIMoraxella catarrhalis tMP/sMX amoxicillin/clavulanic acid, ceftriaxone, macrolide,

tetracycline

Neisseria gonorrhoeae Ceftriaxone Penicillin G, quinolone

Neisseria meningitidis Penicillin G Ceftriaxone

eNTeRIC GRaM-NeGaTIVe baCIllIBacteroides

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, nontyphik 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, cefuroximel, quinolone, macrolide, tMP/sMX

(Continued )

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Organism Drug of Choice alternative Drugs

Legionella erythromycin (1 g q6h) + rifampin

Pasteurella multocida Penicillin G tetracycline, cephalosporin, ampicillin/sulbactam

Pseudomonas aeruginosa antipseudomonal penicillinm + aminoglycoside

aztreonam, cefepime, imipenem, quinolone

Pseudomonas cepacia tMP/sMX Ceftazidime

Spirillum minus Penicillin G tetracycline, streptomycin

Streptobacillus moniliformis Penicillin G tetracycline, streptomycin

Vibrio choleraen tetracycline tMP/sMX, quinolone

Vibrio vulnificus tetracycline Cefotaxime

Xanthomonas maltophilia tMP/sMX Quinolone, minocycline, ceftazidime

Yersinia pestis streptomycin tetracycline, gentamicin

CHlaMYDIaeChlamydia pneumoniae (twar) Macrolide tetracycline

Chlamydia psittaci tetracycline Chloramphenicol

Chlamydia trachomatis Macrolide sulfonamide, tetracycline

MYCOPLASMA sp. Macrolide tetracycline

tetracycline Quinolone

SPIROCHeTeSBorrelia burgdorferi Doxycycline, amoxicillin Penicillin G, macrolide, cefuroxime, ceftriaxone,

cefotaxime

Borrelia sp. tetracycline Penicillin G

Treponema pallidum Penicillin tetracycline, ceftriaxone

VIRUSeSCytomegalovirus Gancicloviro 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 famciclovirp

FUNGIAspergillus Voriconazole amphotericin B, echinocandin, itraconazoler

Blastomyces amphotericin B or itraconazole Ketoconazole

Candidaq

Mucosal fluconazole, echinocandins 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

athis 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.

bsome authorities recommend clindamycin as the first choice for susceptible toxin-producing staphylococci, streptococci, or clostridia.cfirst-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.dPenicillinase-producing staphylococci are also resistant to ampicillin, amoxicillin, carbenicillin, ticarcillin, mezlocillin, and piperacillin.eMethicillin-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.fsome 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.guse as an adjunct to debridement of infected tissues.huse as an adjunct to active and passive immunization.iBecause of rapid development of resistance, cephalosporins not recommended even if initial tests indicate susceptibility.jKlebsiella sp. and E. coli producing extended-spectrum β-lactamase (esBl) should be preferentially managed with a carbapenem.kuncomplicated Salmonella enteritis should not be treated with antibiotics.lshould not be used in meningitis because of poor Cns penetration.mantipseudomonal penicillins include ticarcillin, mezlocillin, and piperacillin.nPrimary therapy is fluid and electrolyte repletion.ooral form should be used only in maintenance therapy of retinal cytomegalovirus.papproved only for mild herpes zoster in immunocompetent hosts.qCandida krusei and Torulopsis glabrata may be resistant to azole therapy, Candida parapsilosis may be resistant to echinocandins.rin multidrug combinations.sechinocandins include caspofungin, micafungin, and anidulafungin.

Table 83.4 Drugs of Choice in Serious Infectionsa (Continued )

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Table 83.5 Toxicities associated with antimicrobials

antimicrobial Serious Toxicities, Uncommon Common Toxicitiesa

PenicillinsampicillinPenicillin

anaphylaxis, seizures, hemolytic anemia, neutrope-nia, thrombocytopenia, drug fever

Diarrhea, nausea, vomiting

antistaphylococcal penicillinsnafcillinoxacillin

anaphylaxis, neutropenia, thrombocytopenia, acute interstitial nephritis, hepatotoxicity


a-lactam/a-lactamase inhibitors anaphylaxis, seizures, hemolytic anemia, neutrope-nia, thrombocytopenia

Clostridium difficile colitis, cholestatic jaundice, drug fever


amoxicillin/clavulanate

ampicillin/sulbactam

Piperacillin/tazobactam

ticarcillin/clavulanate

Cephalosporins anaphylaxis, seizures, neutropenia, thrombocytopenia, drug fever


Carbapenemsimipenem

anaphylaxis, seizures (imipenem > meropenem, ertapenem, doripenem)


Meropenem C. difficile colitis, drug fever

ertapenem

Doripenem

GlycopeptidesVancomycin

ototoxicity, nephrotoxicity (unlikely without concomitant nephrotoxins), thrombocytopenia

red-man syndrome

Oxazolidinoneslinezolid

More common with long-term use: Peripheral and optic neuropathy, myelosuppression

Diarrhea

Possible with short-term use:

lactic acidosis, myopathy anemia

lipopeptidesDaptomycin Diarrhea, constipation, vomiting

Streptogramin arthralgia, myalgia, inflammation, pain, edema at infusion site, hyperbilirubinemiaQuinupristin/dalfopristin

aminoglycosides nephrotoxicity, ototoxicity

amikacin

Gentamicin

tobramycin

Fluoroquinolones2nd generation

anaphylaxis, dysglycemia Qtc prolongation, joint toxicity in children

nausea, vomiting, diarrhea, photosensitiv-ity, rash

Ciprofloxacin Cns stimulation, dizziness, somnolence

3rd generation

levofloxacin

4th generation

Gatifloxacin

Moxifloxacin

Gemifloxacin

MacrolideserythromycinazithromycinClarithromycin

Qtc prolongation (erythromycin > clarithromycin > azithromycin), cholestasis

nausea, vomiting, diarrhea, abnormal taste

Ketolides acute hepatic failure nausea, vomiting, diarrhea

telithromycin Qtc prolongation

Clindamycin C. difficile colitis nausea, vomiting, diarrhea, abdominal pain, rash

TetracyclinestetracyclineDoxycyclineMinocycline pseudotumor

cerebri

tooth discoloration and retardation of bone growth (in children), renal tubular necrosis, dizziness, vertigo

Photosensitivity, diarrhea

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, disulfiram-like reaction

(Continued )

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antimicrobial Serious Toxicities, Uncommon Common Toxicitiesa

Nitrofurantoin Pulmonary toxicity, peripheral neuropathy urine discoloration, photosensitivity

aNTIFUNGal aGeNTSazoles

fluconazoleitraconazoleVoriconazolePosaconazole

hepatic failure, increased ast/alt, cardiovascular toxicity, hypertension, edema

nausea, vomiting, diarrhea, rash, visual disturbances, phototoxicity

amphotericin b productsamphotericin B deoxycholateaBlCaBCDliposomal amphotericin B

acute liver failure, myelosuppression nephrotoxicity (less common with lipid formulations), acute infusion-related reactions, hypokalemia, hypomagnesemia

echinocandinsCaspofunginMicafunginanidulafungin

hepatotoxicity, infusion-related rash, flushing, itching

Flucytosine Myelosuppression, hepatotoxicity, confusion, hallucinations, sedation

nausea, vomiting, diarrhea, rash

aNTIVIRal aGeNTSNucleoside analogues

acyclovirValaciclovirGanciclovirValganciclovir

nephrotoxicity, rash, encephalopathy, inflammation at injection site, phlebitis

Bone marrow suppression, headache, nau-sea, vomiting, diarrhea (with oral forms)

amantadine Cns disturbances (amantadine > rimantadine) nausea, vomiting, anorexia, xerostomia

RimantadineNeuraminidase 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, hypo-kalemia, hypophosphatemia), nausea, vomiting, diarrhea, headache

atoxicities 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.

Table 83.5 Toxicities associated with antimicrobials (Continued )

activity against a variety of gram-positive organisms includ-ing methicillin-resistant, vancomycin-intermediate, and vanco-mycin-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 treat-ment 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 2014. Tedizolid has a similar spectrum of activ-ity 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 2010. 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. Addition-ally, most nonfermenting gram-negative bacilli, such as P. aeru-ginosa, 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. Ceftolo-zane 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).

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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 addi-tion of avibactam expands the gram-negative spectrum of ceftazidime to include activity against a variety of otherwise resistant organisms. Notably ceftazidime/avibactam has dem-onstrated activity against a variety of carbapenemase produc-ing 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 gram-positive spectrum (52,53).

Initial Antimicrobial Therapy

An initial appropriate antibiotic regimen should be pre-scribed with adequate activity against all pathogens likely to be responsible for the infection. Inappropriate initial anti-biotic therapy has been associated with a very high risk of mortality in patients with septic shock attributable to a vari-ety 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 com-munity 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. Auto-mated antimicrobial utilization guidelines have been success-fully 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. Auto-mated and nonautomated guidelines have also been employed to reduce overall antibiotic use and limit inappropriate antimi-crobial 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, min-imize adverse drug reactions, and reduce cost. However, not all experiences have been uniformly successful, and the homo-geneous 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 spe-cific 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 reduc-tions 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 infec-tious diseases consultations, which may improve patient outcomes including mortality, hospital lengths of stay, and readmission rates by providing more precise antibiotic pre-scription (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 anti-microbial 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 narrow-spectrum 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 reintro-duction 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 antibiotic-resistant 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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Combination antibiotic Therapy

Several meta-analyses recommend the use of monotherapy with a β-lactam antibiotic, as opposed to combination ther-apy 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 com-bination antimicrobial therapy. However, empiric combination therapy directed against high-risk pathogens such as P. aeru-ginosa 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 emer-gence 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 infec-tions. Several clinical trials have found that 7 to 8 days of anti-biotic treatment is acceptable for most nonbacteremic patients with VAP (15,37). Similarly, shorter courses of antibiotic treat-ment 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 antibi-otic 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 regi-men is prescribed, modification of the regimen using a de-esca-lation 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 anti-biotic regimen should include decreasing the number and/or spectrum of antibiotics, if possible based on culture and sen-sitivity 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 concen-tration 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 infu-sions can increase the T greater than MIC and improve clini-cal and microbiologic cure rates. To maximize the bactericidal

Step 1: Initial suspicion of serious infection in critically ill patient:

Step 2: Subsequent evaluation of clinical and microbiologic date:

ClinicalImprovement

Lack ofClinical

Improvement

Evaluate patient’s clinicalresponse at 48–72 hours

(temperature, white blood cellcount, organ function)

• Narrow antimicrobial spectrum based on microbiologic data (Figure 2)

• Reassess antimicrobial need beyond 7 days (unless bactermia is present)

Reassess patient for the following:

Obtain appropriatespecimens for culture and

special stains

Begin initial antimicrobial based onrisk factors for antibiotic-resistant pathogens

(resistant hospitalization or antibiotictherapy, admission from nursing home,

late-onset infection)

• 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 suscepti-bility are known.

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effects of aminoglycosides, clinicians must optimize the maxi-mum drug concentration (Cmax)-to-MIC ratio. A Cmax:MIC ratio of at least 10:1 using once-daily aminoglycoside dosing (5–7 mg/kg) has been associated with preventing the emer-gence of resistant organisms, improving clinical response to treatment, and avoiding toxicity. The 24-hour area under the antibiotic concentration curve-to-MIC ratio (AUIC) is corre-lated with fluoroquinolone efficacy and prevention of resis-tance development. An AUIC value higher than 100 has been associated with a significant reduction in the risk of resistance development while on therapy. As a general rule, clinicians should use the maximum approved dose of an antibiotic for a potentially life-threatening infection to optimize tissue concen-trations of the drug and killing of pathogens.

Augmented Renal Clearance

Augmented renal clearance (ARC) is defined as an 8-hour creati-nine clearance more than or equal to 130 mL/min/1.73 m2 (39). It has been suggested that a large proportion of ICU patients experience at least one occasion of ARC during the first 7 days of their critical illness (75). ARC has been linked with subtherapeu-tic β-lactam (76) and glycopeptide concentrations (77), as well

as increased therapeutic failures in patients receiving antimicro-bial therapy resulting in adverse patient outcomes (78,79). Addi-tionally, data suggest that shorter durations of therapy among patients with ARC, and thus lower circulating antibiotic levels, may contribute to excess mortality (80).

A scoring system to identify patients at high risk for ARC has been developed (81) and validated with a 100% sensitiv-ity and 71.4% specificity (82). The following factors were included: age of 50 years or younger (6 points), trauma (3 points), and SOFA score of 4 or less (1 point). Monte Carlo pharmacokinetic simulations demonstrated increased time at therapeutic antibiotic levels with the use of extended infusion dosing in the setting of ARC at a drug cost savings of up to 66.7% over multiple intermittent dosing regimens. In addi-tion to ARC, the use of renal replacement therapies can also result in under exposure of antibiotics at the site of infection requiring careful dosing adjustments (83).

Therapeutic Drug Monitoring

The use of therapeutic drug monitoring (TDM) for antibiot-ics other than vancomycin, aminoglycosides, and voriconazole has not become a routine or standard practice in most ICUs. TDM for β-lactams and carbapenems can be accomplished by several methodologies (84,85). Unfortunately, at the present time, large variations exist in the type of β-lactams tested, the patients selected for TDM, drug assay methodologies, Pk/Pd targets, and dose-adjustment strategies employed in the criti-cally ill (86). Further studies are needed to determine which patients should receive TDM and how best to perform it, to include robustly defining Pk/Pd targets and dosing adjustments for optimizing β-lactam and carbapenem delivery.

controverSIeS

Antibiotic Cycling and Scheduled Antibiotic Changes

The concept of antibiotic class cycling, in which a class of anti-biotics or a specific drug is withdrawn from use for a defined period of time and later reintroduced, has been suggested as

Escalation/De-escalation

Increasing

Decreasing

Narrow BroadN

umbe

r of

Ant

imic

robi

als

De-escalation

De-escalation De-escalation

Antibiotic Spectrum of Activity

Initial AntimicrobialRegimen

Escalation Escalation

Escalation

Escalation

fIgure 83.2 antimicrobial de-escalation promotes initial administration of broad-spectrum antibiotics to patients at risk for infection with multidrug-resistant patho-gens, followed by the reduction of the number of antimicrobials used and/or their spectrum of activity based on subsequent pathogen identification and antimicrobial susceptibility testing.

Pharmacodynamic Parameters

Cmax (Peak Concentration)

AUC

Dru

g C

once

ntra

tion

Time

fIgure 83.3 Pharmacodynamic parameters found to be important for the efficacy of antimicrobial agents. auC, area under the concentra-tion–time curve; Cmax, maximum concentration; MiC, minimum inhibitory concentration; t, time.

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a potential strategy for reducing the emergence of antimicro-bial resistance (12). Early mathematical modeling suggested that the use of antibiotic cycling would be inferior to mixing empiric antibiotics as a strategy to reduce the emergence of antimicrobial resistance (87). Subsequent studies of antimicro-bial cycling have found beneficial effects on antibiotic resis-tance, including a 2014 meta-analysis of 11 clinical studies demonstrating that antibiotic cycling reduced the number of resistant infections (88,89). Although antimicrobial heteroge-neity or mixing seems to be a logical policy, simple cycling of antibiotics combined with prolonged treatment exposures seems to be a strategy that will only promote further antibiotic resistance.

Antimicrobial Decolonization Strategies

The prophylactic administration of parenteral antibiotics has been shown to reduce the occurrence of nosocomial infections in specific high-risk patient populations requiring intensive care (90). Similarly, selective digestive decontamination with topical antibiotics, with or without concomitant parenteral antibiotics, has also been shown to be effective at reducing nosocomial infections caused by the targeted organism(s) (91,92). However, the routine use of selective digestive decon-tamination has also been linked to the emergence of antimi-crobial resistance (93). Similarly, selective oropharyngeal decontamination has also produced mixed results (93–96). Based on these studies, antimicrobial and non-antimicrobial agents should be considered for oral decontamination only in appropriate high-risk ICU patients or to assist in the contain-ment of outbreaks of MDR bacterial infections in conjunction with established infection control practices.

Use of Antibiotic Resistance Prediction Tools

Knowledge of patient risk factors for the presence of infection with antibiotic-resistant pathogens should be a routine part of antibiotic decision making and can be used in a de-escalation algorithm. For example, antibiotic-resistant pathogens are more commonly found in patients with CAP who have health care–associated risk factors (recent hospitalization, admission from a nursing home, recent antibiotic treatment). Shorr et al. examined patients admitted with pneumonia and found four variables predictive of antibiotic-resistant pneumonia: recent hospitalization, nursing home residence, hemodialysis, and ICU admission (97). A scoring system assigning 4, 3, 2, and 1 points, respectively, for each variable had moderate predic-tive power for segregating those with and without resistant bacteria. Among patients with fewer than 3 points, the preva-lence of resistant pathogens was less than 20% compared with 55% and more than 75% in persons with scores ranging from 3 to 5 and more than 5 points, respectively (p < 0.001). In an independent population, this score better identified patients infected with resistant bacteria than the definition of HCAP (98). Similarly, a 2014 meta-analysis also found that the cur-rent definition of HCAP did not accurately identify infections caused by antibiotic-resistant pathogens, further underscoring the need for more objective criteria to determine patients’ risk for resistant infections (99).

Independent risk factors for antibiotic-resistant bacteria have been demonstrated in both patients diagnosed with CAP and HCAP including prior hospitalization, immunosuppression,

previous antibiotic use, use of gastric acid–suppressive therapy, tube feeding, and nonambulatory status (100). In another pro-spective study of CAP and HCAP patients, MDR pathogens were more common in patients with HCAP (101). Basing empiric antibiotic therapy on disease severity and the presence of multiple risk factors for MDR pathogens may be a poten-tially useful approach that achieves good outcomes without excessive use of broad-spectrum antibiotic therapy. However, it is not clear that clinicians can effectively apply such prediction tools prospectively in order to target broad-spectrum antibiotics to patients at greatest risk for infection with antibiotic-resistant infections.

Clinical decision support systems represent one way of automating informatics data, to include potential risk fac-tors for infection with antibiotic-resistant bacteria, for bed-side decision making (74,102). Other specific examples of benefits derived from the use of computerized systems include improvements in the efficiency and costs of existing steward-ship programs, improvements in clinicians’ knowledge regard-ing the treatment of infectious diseases, and improvements in pathogen prediction (102–108). These data suggest that an opportunity exists to employ hospital informatics systems to improve the identification of patients infected with antibiotic-resistant bacteria in order to prescribe more appropriate initial therapy.

Biomarker Guidance of Antibiotic Therapy

When prescribing antimicrobial therapy, clinicians frequently look for objective indicators that antibiotic treatment is appropriate and to determine duration of treatment. Procalci-tonin (PCT), a precursor of calcitonin that is rapidly released into the bloodstream in the presence of an infection, has dem-onstrated utility in guiding decisions regarding antimicrobial therapy (109–111). However, not all experiences with PCT-guided decision making have shown reductions in duration of antibiotic exposure (112,113). A recent comprehensive lit-erature review of PCT-guided antibiotic management in criti-cally ill patients found that the diagnostic value of serum PCT concentrations to discriminate among systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock was unestablished (114). Moreover, although higher PCT concentrations suggest the presence of a systemic bacte-rial infection as opposed to a viral, fungal, or inflammatory etiology of sepsis, serum PCT concentrations did not corre-late with the severity of sepsis or with mortality and therefore should not be employed to dictate the timing and appropriate-ness of escalation of antimicrobial therapy in septic patients (114). On the other hand, at least two meta-analyses suggest that PCT guidance can be used to shorten the duration of anti-microbial therapy in the ICU setting (115,116). The routine use of PCT as an aid in antibiotic decision making should depend on whether or not a particular ICU has an already established culture of successful antimicrobial de-escalation and stewardship (59).• The serum markers, (1,3)-β-D-glucan and galactomannan,

have been used in identifying pathogens associated with invasive fungal infections to assist clinicians in guiding anti-fungal therapy. Fungal infections often present a consider-able diagnostic challenge to clinicians, and mere suspicion of these infections often leads to liberal and prolonged antimicrobial use. Based on their high negative predictive

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value in the appropriate clinical setting, the most suitable use of these markers seems to be in excluding the pres-ence of invasive fungal infections (117,118). However, one study suggests that (1,3)-β-D-glucan may be the most rapid method for the identification of intra-abdominal candidiasis in order to provide timely therapy in such patients (119). In addition, an investigation that measured galactomannan levels in BAL fluid obtained from ICU patients lends sup-port to its use in pathogen identification and early treatment of pulmonary infection (120). Nonetheless, a more recent study only showed modest agreement between galactoman-nan in BAL fluid and validated clinical diagnostic criteria for invasive fungal disease (121). These markers of infec-tion certainly have the potential to enhance stewardship—primarily through de-escalation once a fungal infection has been excluded—and future clinical experience with these markers will determine if this potential can be fully realized.

summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010. Infect Con-trol Hosp Epidemiol. 2013;34:1–14.

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9. Rello J, Sa-Borges M, Correa H, et al. Variations in etiology of ventilator-associated pneumonia across four treatment sites: implications for antimicro-bial prescribing practices. Am J Respir Crit Care Med. 1999;160:608–613.

10. Masterton RG, Kuti JL, Turner PJ, et al. The OPTIMA programme: utiliz-ing MYSTIC (2002) to predict critical pharmacodynamic target attain-ment against nosocomial pathogens in Europe. J Antimicrob Chemother. 2005;55:71–77.

11. Namias N, Samiian L, Nino D, et al. Incidence and susceptibility of patho-genic bacteria vary between intensive care units within a single hospital: implications for empiric antibiotic strategies. J Trauma. 2000;49:638–645.

12. Kollef MH, Fraser VJ. Antibiotic resistance in the intensive care unit. Ann Intern Med. 2001;134:298–314.

13. Kollef MH, Micek ST. Strategies to prevent antimicrobial resistance in the intensive care unit. Crit Care Med. 2005;33:1845–1853.

14. Kollef MH, Micek ST. Methicillin-resistant Staphylococcus aureus: a new community-acquired pathogen. Curr Opin Infect Dis. 2006;19:161–168.

15. Chastre J, Wolff M, Fagon JY, et al; PneumA Trial Group. Comparison of 15 vs. 8 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003;290:2588–2598.

16. Dennesen PJ, van der Ven AJ, Kessels AG, et al. Resolution of infectious parameters after antimicrobial therapy in patients with ventilator-associ-ated pneumonia. Am J Respir Crit Care Med. 2001;163:1371–1375.

17. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate anti-microbial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118:146–155.

18. Kollef MH. Inadequate antimicrobial treatment: an important determinant of outcome for hospitalized patients. Clin Infect Dis. 2000;31:S131–S138.

19. Micek ST, Lloyd AE, Ritchie DJ, et al. Pseudomonas aeruginosa blood-stream infection: importance of appropriate initial antimicrobial treat-ment. Antimicrob Agents Chemother. 2005;49:1306–1311.

20. Dhainaut JF, Laterre PF, LaRosa S, et al. The clinical evaluation commit-tee in a large multicenter phase 3 trial of drotrecogin alfa (activated) in patients with severe sepsis (PROWESS): role, methodology, and results. Crit Care Med. 2003;31:2291–2301.

21. Harbarth S, Garbino JK, Pugin J, et al. Inappropriate initial antimicrobial therapy and its effects on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003;115:529–535.

22. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, et al. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med. 2003;31: 2742–2751.

23. Kollef MH, Ward S. The influence of mini-BAL cultures on patient out-comes: implications for the antibiotic management of ventilator-associated pneumonia. Chest. 1998;113:412–420.

24. Rello J, Ollendorf DA, Oster G, et al. Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Chest. 2002;122:2115–2121.

25. Shorr AF, Combes A, Kollef MH, Chastre J. Methicillin-resistant Staphy-lococcus aureus prolongs intensive care unit length of stay in ventilator-associated pneumonia—despite initially appropriate antibiotic therapy. Crit Care Med. 2006;34:700–706.

26. Anhalt JP, Fenselau C. Identification of bacteria using mass spectrometry. Anal Chem. 1975;47(2):219–225.

27. La Scola B, Raoult D. Direct identification of bacteria in positive blood culture bottles by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. PLoS One. 2009;4(11):e8041.

28. Huang A, Newton D, Kunapuli A, et al. Impact of rapid organism identi-fication via matrix-assisted laser desorption/ionization time-of-flight com-bined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis. 2013;57(9):1237–1245.

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• Initial treatment with an appropriate antibiotic regi-men is one of the most important factors influencing the outcome of critically ill patients with infection.• Infection with antibiotic-resistant microorganisms

increases the likelihood that inappropriate initial antibiotic therapy will be prescribed to critically ill patients.

• The prevalence of antibiotic resistance varies locally and regionally.

• Host factors influence the likelihood that a patient will be infected with antibiotic-resistant pathogens (e.g., prior hospitalization or antibiotic treatment, admission from a nursing home or other high-risk environment).

• Efforts should be made to rapidly identify the source and site of infection and to obtain specimens for cul-ture, antimicrobial susceptibility testing, and rapid diagnostic tests. Obtaining these specimens should not delay initial empiric therapy in a critically ill patient.

• Avoidance of unnecessary antibiotic exposure in the ICU setting is important to reduce the emergence of and subsequent infection with antibiotic-resistant microorganisms.

• Optimization of antibiotic regimens using pharmaco-kinetic and pharmacodynamic principles to minimize organism exposure to sublethal antimicrobial concen-trations could play a role in the reduction of antibiotic resistance.

key Points

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Antibiotics in the Management of Serious Hospital-Acquired ... · niques and biomarkers may aid in optimizing antimicrobial therapy, these technologies are not currently widely available