TREATMENT Pneumococcal Infections
Historically, the activity of penicillin against pneumococci made parenteral penicillin G the drug of choice for disease caused by susceptible organisms, including community-acquired pneumonia. For susceptible strains, penicillin G remains the most commonly used agent, with daily doses ranging from 50,000 U/kg for minor infections to 300,000 U/kg for meningitis. Other parenteral β-lactam drugs, such as ampicillin, cefotaxime, ceftriaxone, and cefuroxime, can be used against penicillin-susceptible strains but offer little advantage over penicillin. Macrolides and cephalosporins are alternatives for penicillin-allergic patients. While agents such as clindamycin, tetracycline, and trimethoprim-sulfamethoxazole exhibit some activity against pneumococci, resistance to these agents is frequently encountered in different parts of the world.
Penicillin-resistant pneumococci were first described in the mid-1960s, at which point tetracycline- and macrolide-resistant strains had already been reported. Multidrug-resistant strains were first described in the 1970s, but it was during the 1990s that pneumococcal drug resistance reached pandemic proportions. The use of antibiotics selects for resistant pneumococci, and strains resistant to β-lactam agents and to multiple drugs are now found all over the world. The emergence of high rates of macrolide and fluoroquinolone resistance also has been described.
The molecular basis of penicillin resistance in S. pneumoniae is the alteration of penicillin-binding protein (PBP) genes by transformation and horizontal transfer of DNA from related streptococcal species. Such alteration of PBPs results in lower affinity for penicillins. Depending on the specific PBP(s) and the number of PBPs altered, the level of resistance ranges from intermediate to high. For many years, penicillin susceptibility breakpoints have been defined by MICs as follows: susceptible, ≤0.06 μg/mL; intermediate, 0.12–1.0 μg/mL; and resistant, ≥2.0 μg/mL. However, in vitro results often were not predictive of the response of a patient to treatment for pneumococcal diseases other than meningitis. New recommendations have been based on the revised penicillin G breakpoints established in 2008 by the Clinical and Laboratory Standards Institute. For IV treatment of meningitis with at least 24 million units per day in 8 divided doses, the susceptibility breakpoint remains ≤0.06 μg/mL, and MICs of ≥0.12 μg/mL indicate resistance. For IV treatment of nonmeningeal infections with 12 million units per day in 6 divided doses, the breakpoints are ≤2 μg/mL for susceptible organisms, 4 μg/mL for intermediate organisms, and ≥8 μg/mL for resistant organisms; a dosage of 18–24 million units per day is recommended for strains with MICs in the intermediate category. The original breakpoints remain the same for oral treatment of nonmeningeal infections with penicillin V.
Although guidelines for antibiotic therapy should be driven in part by local patterns of resistance, guidelines from national organizations in many countries (e.g., the Infectious Diseases Society of America/American Thoracic Society, the British Thoracic Society, and the European Respiratory Society) lay out evidence-based approaches. The following guidelines for the treatment of individual sepsis syndromes are based on those advocated by the American Academy of Pediatrics and published in the 2012 Red Book. MENINGITIS LIKELY OR PROVEN TO BE DUE TO S. PNEUMONIAE
As a result of the increased prevalence of resistant pneumococci, first-line therapy for persons ≥1 month of age is a combination of vancomycin (adults, 30–60 mg/kg per day; infants and children, 60 mg/kg per day) and cefotaxime (adults, 8–12 g/d in 4–6 divided doses; children, 225–300 mg/kg per day in 1 dose or 2 divided doses) or ceftriaxone (adults, 4 g/d in 1 dose or 2 divided doses; children, 100 mg/kg per day in 1 dose or 2 divided doses). If children are hypersensitive to β-lactam agents (penicillins and cephalosporins), rifampin (adults, 600 mg/d; children, 20 mg/d in 1 dose or 2 divided doses) can be substituted for cefotaxime or ceftriaxone. A repeat lumbar puncture should be considered after 48 h if the organism is not susceptible to penicillin and information on cephalosporin sensitivity is not yet available, if the patient’s clinical condition does not improve or deteriorates, or if dexamethasone has been administered and may be compromising clinical evaluation. When antibiotic sensitivity data become available, treatment should be modified accordingly. If the isolate is sensitive to penicillin, vancomycin can be discontinued and penicillin can replace the cephalosporin, or cefotaxime or ceftriaxone can be continued alone. If the isolate displays any resistance to penicillin but is susceptible to the cephalosporins, vancomycin can be discontinued and cefotaxime or ceftriaxone continued. If the isolate exhibits any resistance to penicillin and is not susceptible to cefotaxime and ceftriaxone, vancomycin and high-dose cefotaxime or ceftriaxone can be continued; rifampin may be added as well if the isolate is susceptible and the patient’s clinical condition is worsening, if the CSF remains positive for bacteria, or if the MIC of the cephalosporin in question against the infecting strain is high. Some physicians advocate the use of glucocorticoids in children >6 months old, but this recommendation remains controversial and is not universally considered the standard of care. Glucocorticoids significantly reduce rates of mortality, severe hearing loss, and neurologic sequelae in adults and should be administered to those with community-acquired bacterial meningitis. If dexamethasone is given to either adults or children, it should be administered before or in conjunction with the first antibiotic dose. INVASIVE INFECTIONS (EXCLUDING MENINGITIS)
In previously well children with noncritical illness, therapy with a recommended antibiotic should be instigated at the following dosages: penicillin G, 250,000–400,000 units/kg per day (in divided doses 4–6 h apart); cefotaxime, 75–100 mg/d (doses 8 h apart); or ceftriaxone, 50–75 mg/d (doses 12–24 h apart). For critically ill children, including those who have myocarditis or multilobular pneumonia with hypoxia or hypotension, vancomycin may be added if the isolate may possibly be resistant to β-lactam drugs, with its use reviewed once susceptibility data become available. If the organism is resistant to β-lactam agents, therapy should be modified on the basis of clinical response and susceptibility to other antibiotics. Clindamycin or vancomycin can be used as a first-line agent for children with severe β-lactam hypersensitivity, but vancomycin should not be continued if the organism is shown to be sensitive to other non-β-lactam antibiotics.
For outpatient management, amoxicillin (1 g every 8 h) provides effective treatment for virtually all cases of pneumococcal pneumonia. Neither cephalosporins nor quinolones, which are far more expensive, offer any advantage over amoxicillin. Levofloxacin (500–750 mg/d as a single dose) and moxifloxacin (400 mg/d as a single dose) also are highly likely to be effective in the United States except in patients who come from closed populations where these drugs are used widely or who have themselves been treated recently with a quinolone. Clindamycin (600–1200 mg/d every 6 h) is effective in 90% of cases and azithromycin (500 mg on day 1 followed by 250–500 mg/d) or clarithromycin (500–750 mg/d as a single dose) in 80% of cases. Treatment failure resulting in bacteremic disease due to macrolide-resistant isolates has been amply documented in patients given azithromycin empirically. As noted above, rates of resistance to all these antibiotics are relatively low in some countries and much higher in others; high-dose amoxicillin remains the best option worldwide.
The optimal duration of treatment for pneumococcal pneumonia is uncertain, but its continuation for at least 5 days once the patient becomes afebrile appears to be a prudent approach. Cases with a second focus of infection (e.g., empyema or septic arthritis) require longer therapy. ACUTE OTITIS MEDIA
Amoxicillin (80–90 mg/kg per day) is recommended for children with acute otitis media except in situations where observation and symptom-based treatment without antibiotics are advocated. These situations include nonsevere illness and an uncertain diagnosis in children 6 months to 2 years of age and nonsevere illness (even if the diagnosis seems certain) in children >2 years of age. Although the optimal duration of therapy has not been conclusively established, a 10-day course is recommended for younger children and for children with severe disease at any age. For children >6 years old who have mild or moderate disease, a course of 5–7 days is considered adequate. Patients whose illness fails to respond should be reassessed at 48–72 h. If acute otitis media is confirmed and antibiotic treatment has not been started, administration of amoxicillin should be commenced. If antibiotic therapy fails, a change is indicated. Failure to respond to second-line antibiotics as well indicates that myringotomy or tympanocentesis may need to be undertaken in order to obtain samples for culture.
The above recommendations can also be followed for the treatment of sinusitis. Detailed information on the further management of these conditions in children has been published by the American Academy of Pediatrics and the American Academy of Family Physicians.