When are Oral Antibiotics a Safe and Effective Choice for Bacterial Bloodstream Infections? An Evidence-Based Narrative Review
Bacterial bloodstream infections (BSIs) are a major cause of morbidity and mortality in the United States. Traditionally, BSIs have been managed with intravenous antimicrobials. However, whether intravenous antimicrobials are necessary for the entirety of the treatment course in BSIs, especially for uncomplicated episodes, is a more controversial matter. Patients that are clinically stable, without signs of shock, or have been stabilized after an initial septic presentation, may be appropriate candidates for treatment of BSIs with oral antimicrobials. There are risks and costs associated with extended courses of intravenous agents, such as the necessity for long-term intravenous catheters, which entail risks for procedural complications, secondary infections, and thrombosis. Oral antimicrobial therapy for bacterial BSIs offers several potential benefits. When selected appropriately, oral antibiotics offer lower cost, fewer side effects, promote antimicrobial stewardship, and are easier for patients. The decision to use oral versus intravenous antibiotics must consider the characteristics of the pathogen, the patient, and the drug. In this narrative review, the authors highlight areas where oral therapy is a safe and effective choice to treat bloodstream infection, and offer guidance and cautions to clinicians managing patients experiencing BSI.
© 2018 Society of Hospital Medicine
Although the evidence for treating bacteremic pneumococcal pneumonia using a highly active and absorbable oral agent is fairly robust, S. pneumoniae BSI secondary to other sites of infection sites is less well studied and may require a more conservative approach.
Gram-Positive Cocci, β-hemolytic Streptococcus species
β-Hemolytic Streptococci include groups A to H, of which groups A (S. pyogenes) and B (S. agalactiae) are the most commonly implicated in BSIs.36 Group A Streptococcus (GAS) is classically associated with streptococcal pharyngitis and Group B Streptococcus (GBS) is associated with postpartum endometritis and neonatal meningitis, though both are virulent organisms with a potential to cause invasive infection throughout the body and in all age-groups. Up to 14% of GAS and 41% GBS BSIs have no clear source;37,38 given these are skin pathogens, such scenarios likely represent invasion via microabrasion. As β-hemolytic streptococcal BSI is often observed in the context of necrotizing skin and soft tissue infections, surgical source control is particularly important.39 GAS remains exquisitely susceptible to penicillin, and intravenous penicillin remains the mainstay for invasive disease; GBS has higher penicillin resistance rates than GAS.40 Clindamycin should be added when there is concern for severe disease or toxic shock.41 Unfortunately, oral penicillin is poorly bioavailable (approximately 50%), and there has been recent concern regarding inducible clindamycin resistance in GAS.42 Thus, oral penicillin V and/or clindamycin is a potentially risky strategy, with no clinical trials supporting this approach; however, they may be reasonable options in selected patients with source control and stable hemodynamics. Amoxicillin has high bioavailability (85%) and may be effective; however, there is lack of supporting data. Highly bioavailable agents such as levofloxacin and linezolid have GAS and GBS activity43 and might be expected to produce satisfactory outcomes. Because no clinical trials have compared these agents with intravenous therapy for BSI, caution is advised. Although bacteriostatic against Staphylococcus, linezolid is bactericidal against Streptococcus.44 Fluoroquinolone resistance amongst β-hemolytic Streptococcus is rare (approximately 0.5%) but does occur.45
Gram-Positive Cocci, Staphylococcus Species
Staphylococcus species include S. aureus (including methicillin susceptible and resistant strains: MSSA and MRSA, respectively) and coagulase-negative species, which include organisms such as S. epidermidis. S. aureus is the most common cause of BSI mortality in the United States,1 with mortality rates estimated at 20%–40% per episode.46 Infectious disease consultation has been associated with decreased mortality and is recommended.47 The guidelines of the Infectious Diseases Society of America for the treatment of MRSA recommend the use of parenteral agents for BSI.48 It is important to consider if a patient with S. aureus BSI has infective endocarditis.
Oral antibiotic therapy for S. aureus BSI is not currently standard practice. Although trimethoprim-sulfamethoxazole (TMP-SMX) has favorable pharmacokinetics and case series of using it successfully for BSI exist,49 TMP-SMX showed inferior outcomes in a randomized trial comparing oral TMP-SMX with intravenous vancomycin in a series of 101 S. aureus infections.50 This observation has been replicated.51 Data on doxycycline or clindamycin for S. aureus BSI are limited, and IDSA guidelines advise against their use in this setting because they are predominantly bacteriostatic.48 Linezolid has favorable pharmacokinetics, with approximately 100% bioavailability, and S. aureus resistance to linezolid is rare.52 Several randomized trials have compared oral linezolid with intravenous vancomycin for S. aureus BSI; for instance, Stevens et al. randomized 460 patients with S. aureus infection (of whom 18% had BSI) to linezolid versus vancomycin and observed similar clinical cure rates.53 A pooled analysis showed oral linezolid was noninferior to vancomycin specifically for S. aureus BSI.54 However, long-term use is often limited by hematologic toxicity, peripheral or optic neuropathy (which can be permanent), and induced serotonin syndrome. Additionally, linezolid is bacteriostatic, not bactericidal against S. aureus. Using oral linezolid as a first-line option for S. aureus BSI would not be recommended; however, it may be used as a second-line treatment option in selected cases. Tedizolid has similar pharmacokinetics and spectrum of activity with fewer side effects; however, clinical data on its use for S. aureus BSI are lacking.55 Fluoroquinolones such as levofloxacin and the newer agent delafloxacin have activity against S. aureus, including MRSA, but on-treatment emergence of fluoroquinolone resistance is a concern, and data on delafloxacin for BSI are lacking.56,57 Older literature suggested the combination of ciprofloxacin and rifampin was effective against right-sided S. aureus endocarditis,58 and other oral fluoroquinolone-rifamycin combinations have also been found to be effective59 However, this approach is currently not a standard therapy, nor is it widely used. Decisions on the duration of therapy for S. aureus BSI should be made in conjunction with an infectious diseases specialist; 14 days is currently regarded as a minimum.47,48
Published data regarding oral treatment of coagulase-negative Staphylococcus (CoNS) BSI are limited. Most CoNS bacteremia and up to 80% Staphylococcus epidermidis bacteremia represent blood culture contamination, though true infection from CoNS is not uncommon, particularly in patients with indwelling catheters.60 An exception is the CoNS species Staphylococcus lugdunensis, which is more virulent, and bacteremia with this organism usually warrants antibiotics. Oral antimicrobial therapy is currently not a standard treatment practice for CoNS BSI that is felt to represent true infection; however, linezolid has been successfully used in case series.61
