Stewardship and Emerging Resistance

Introduction

Emergence of antibiotic resistance is potentiated by all antibiotic use. Careful antibiotic use is essential to preserving the armamentarium. Among outpatient visits, 12.6% are associated with antibiotic prescriptions, and 30% of those prescriptions are considered inappropriate. Most prescriptions are for acute respiratory infections (usually caused by viruses) and asymptomatic bacteriuria not requiring antibiotic treatment. One fifth of emergency department visits for adverse drug events are related to antibiotics. Inpatient antibiotic use accounts for 38.5% of all antibiotic use; half of hospitalized patients receive antibiotics, and half of these medications are considered unnecessary or inappropriate. The World Health Organization has named carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa and carbapenem-resistant and extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae as priority-one pathogens, for which new antibiotics are critically needed.

Antimicrobial Stewardship and the Value of Infectious Disease Consultation

Antibiotic stewardship refers to coordinated interventions to improve antibiotic use and clinical outcomes by promoting optimal antibiotic regimens. Goals include minimizing adverse events (5% risk per antibiotic per patient), risk of Clostridium difficile infection, and emergence of resistance. A key aspect of stewardship is avoiding antibiotic administration when not indicated. Antibiotic selection, dosing, therapy duration, and route of administration are also considered. Furthermore, antimicrobial stewardship programs include simplifying unnecessary combination therapy, avoiding redundant double anaerobic coverage, converting intravenous to oral agents, streamlining de-escalation, and minimizing duration of therapy.

Combination therapy does not prevent the emergence of resistance. However, it may be considered in specific circumstances, such as empiric therapy regimens, to broaden the spectrum of activity or provide coverage for potential antimicrobial-resistant organisms pending culture and susceptibility results. Antibiotic combination therapy may also provide synergistic activity in limited situations, such as enterococcal endocarditis and bacteremia caused by carbapenem-resistant Enterobacteriaceae (CRE).

Conversion from an intravenous to an oral antimicrobial agent should be considered for ease of administration and to limit intravenous catheter access and use, thereby decreasing the risk of catheter-related bloodstream infection. Factors supporting readiness for conversion include a temperature of 38 °C (100.4 °F) or less, an improving leukocyte count, clinical stability and improvement of signs and symptoms related to infection, a functioning gastrointestinal tract and ability to swallow medications or having a nasogastric tube in place, no diagnostic indication for intravenous therapy (endocarditis, Staphylococcus aureus bacteremia), and availability of a suitable oral alternative with good oral bioavailability (fluoroquinolones, oxazolidinones, metronidazole, clindamycin, trimethoprim-sulfamethoxazole, fluconazole, doxycycline, voriconazole).

Antimicrobial stewardship programs use various interventions to optimize antimicrobial use. Interventions that have been shown to be effective in improving outcomes, decreasing resistance, and decreasing costs include preauthorization and prospective audit with feedback to the prescriber, targeting antibiotics associated with a high risk of C. difficile infection (such as clindamycin, broad-spectrum antibiotics, and fluoroquinolones), using dedicated pharmacokinetic monitoring and adjustment programs, increasing the use of oral antimicrobial agents, and reducing antimicrobial therapy to the shortest effective duration.

Newer Antibacterial Drugs

Two newer cephalosporin antibiotics, ceftazidime-avibactam and ceftolozane-tazobactam, have enhanced activity against β-lactamase–producing organisms, particularly ESBLs, and against some carbapenemase-producing CRE.

Colistin is an older antimicrobial agent that has made a resurgence because of its bactericidal activity against pan-resistant gram-negative organisms (including carbapenem-resistant, gram-negative organisms). Half of patients who are administered colistin develop nephrotoxicity, which limits the drug's usefulness in many cases. Kidney function should be closely monitored during administration, and colistin should be dose adjusted for patients with kidney disease. Paresthesias are a commonly reported neurotoxicity. Unfortunately, colistin resistance has been reported and appears to be increasing.

Three agents are available in the lipoglycopeptide class of antibiotics with activity against aerobic gram-positive organisms, such as S. aureus (including methicillin-resistant S. aureus), streptococci, and vancomycin-susceptible Enterococcus faecalis. Ceftaroline is a fifth-generation cephalosporin with a unique spectrum of activity that covers methicillin-resistant S. aureus. Delafloxacin is a new anionic fluoroquinolone with gram-positive (including methicillin-resistant S. aureus) and gram-negative activity (Table 69).

Antibiotics for Antibiotic-Resistant Organisms

Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter species, Pseudomonas aeruginosa, and Enterobacter species are particularly problematic antibiotic-resistant organisms. This group includes ESBL and carbapenemase-producing CRE (Klebsiella pneumoniae carbapenemases and New Delhi metallo-β-lactamase) that destroy carbapenems. Few effective antibiotics are available to treat infections with these pathogens. However, several older, less commonly used antibiotics retain their activity. Infectious disease consultation should be considered for infections with organisms in this group.

Minocycline

Resurgence in the use of minocycline, available in intravenous and oral forms, is partly because of its activity against multidrug-resistant Acinetobacter. In vitro susceptibility to minocycline can be inferred from susceptibility to tetracycline; however, some tetracycline-resistant strains are sensitive to minocycline. Minocycline has been used to treat ventilator-associated pneumonia with an 80% clinical response rate and is also useful for treating infections caused by Stenotrophomonas maltophilia, a problematic ICU pathogen with intrinsic antibiotic resistance. The adverse effects of minocycline are similar to those of tetracycline, including photosensitivity, gastrointestinal disturbance, and skin pigmentation changes with prolonged use.

Fosfomycin

Fosfomycin (available in the United States) is a bactericidal oral antibiotic with gram-negative and gram-positive activity (including methicillin-resistant S. aureus and vancomycin-resistant enterococci). It achieves high concentrations in the urine and may be used to treat cystitis caused by vancomycin-resistant enterococci and other multidrug-resistant uropathogens such as carbapenemase-producing K. pneumoniae.

Colistin

Colistin (polymyxin E) is a bactericidal agent used to treat multidrugand pan-resistant aerobic gram-negative infections, including P. aeruginosa. Proteus, Providencia, Burkholderia, Morganella, and Serratia species are resistant to colistin. Colistin resistance has been described in some multidrug-resistant gram-negative infections (mostly carbapenemase-producing K. pneumoniae), leading to completely untreatable infections. Colistin can be administered by nebulized aerosol or intravenously. The most common adverse effect is nephrotoxicity (up to 50% of patients), which is usually reversible.

Outpatient Parenteral Antibiotic Therapy

Outpatient parenteral antibiotic therapy (OPAT) is defined as administration of at least two doses of intravenous antibiotics on different days without intervening hospitalization. Approximately 250,000 patients per year in the United States are treated with OPAT. OPAT allows patients to complete parenteral antibiotic therapy at home or in other outpatient settings when an oral antibiotic is not appropriate or available. Bone and joint infections compose most of the infections treated with OPAT; other candidates include endocarditis, cardiac device infections, abdominal infections, skin and soft tissue infections, and antibiotic-resistant infections for which parenteral antibiotics are the only option (such as urinary tract infection).

Patients should be clinically stable and their infection improving before starting OPAT; OPAT is not appropriate if the patient's care needs would be better met in the hospital. When considering OPAT, it is important to assess the type of infection being treated, the prescribed antibiotic and dosing frequency, the planned therapy duration, the administration site, the intravenous catheter type, and the monitoring process for possible complications. Increasingly, OPAT is being started without initial hospitalization after careful medical assessment by a well-established and organized OPAT program. OPAT requires close monitoring, including antibiotic levels (vancomycin, aminoglycosides), complete blood count, creatinine level, liver chemistry tests, and coagulation tests if relevant for the antibiotic; patients receiving daptomycin therapy in particular should undergo baseline measurement of kidney function and creatine kinase level, followed by weekly monitoring. Antibiotic doses and timing should be adjusted based on monitoring results. Treatment failure may result from relapse or progression of primary infection (60% and 21%, respectively) and therapeutic complications (19%). Successful OPAT requires patient participation; supervised infectious disease OPAT programs have been shown to be safe, efficient, and clinically effective.