Pneumococcal Infections Medication

Antibiotics are the mainstay of treatment in S pneumoniae infections. Until the 1970s, essentially all pneumococcal isolates were sensitive to easily achievable levels of most commonly used antibiotics, including penicillins, macrolides, clindamycin, cephalosporins, rifampin, vancomycin, and trimethoprim-sulfamethoxazole. Beginning in the 1990s, many pneumococcal isolates in the United States showed decreased susceptibility to penicillin and other commonly used antibiotics. Continued increases in these isolates have led to the need for re-establishment of susceptibility standards.

As of 2007, isolates of drug-resistant S pneumoniae have become increasingly common worldwide. The CDC, as well as many state health departments, maintain a population-based surveillance system (the ABC system) that investigates the epidemiology and susceptibility patterns of invasive pneumococcal infections in the United States. In 2008, 24.8% of all isolates obtained showed intermediate or resistant susceptibility patterns to penicillin (down from 25.6% in 2007).^[1] The prevalence of resistance varies greatly among countries, states, counties, and within populations in particular cities and may be as high as 30%-40% in some locations.^{[57, 58]} Resistance rates are generally higher in most European countries, as well as in Hong Kong and Thailand.^{[59, 60]}

Unlike many common bacterial organisms, the method of resistance of pneumococcus to penicillin and cephalosporins is through alteration in the cell wall penicillin-binding proteins (PBPs). By altering these sites (where the antibiotics bind), the antibiotic affinity is decreased, subsequently decreasing the organism's susceptibility to the antibiotic. This type of resistance can be overcome if the serum or site levels of the antibiotic exceed the minimum inhibitory concentration (MIC) of the organism for 40%-50% of the dosing interval.

Penicillin-resistant pneumococci are often also resistant to multiple other classes of antibiotics, including other penicillins, cephalosporins, sulfonamides, trimethoprim-sulfamethoxazole (through amino acid changes), macrolides (through methylation or via an efflux pump), quinolones (through decreased permeability, efflux pumps, and alteration of enzymes), and chloramphenicol (through inactivating enzymes). Resistance is obtained as part of a cassette of genetic information, or a transposon, that encodes resistance to multiple antibiotics.

Resistance rates of pneumococcal isolates in the United States to trimethoprim-sulfamethoxazole, tetracycline, and the macrolides are relatively high. Some isolates (< 10% in the United States) that are resistant to macrolides are also resistant to clindamycin.

Vancomycin-resistant pneumococcal isolates have not been reported in the United States. The phenomenon of tolerance (survival but not growth in the presence of a given antibiotic) has been observed, but its clinical relevance is unknown. Any strain with an in vitro MIC greater than 1 µg/mL to vancomycin should be immediately reported to the state health department and arrangements made for confirmatory testing at the CDC.

In the United States, most pneumococcal isolates remain susceptible to fluoroquinolones. In certain countries and specific populations in whom the use of "respiratory fluoroquinolones" is more prevalent (eg, nursing homes), an increase in resistance has been seen.^{[18, 19, 34]}

Treatment of Specific Infections

Otitis media

The guideline produced by the American Academies of Pediatrics and Family Practitioners for the treatment of otitis media recommends first-line treatment of most patients with amoxicillin 80-90 mg/kg/day.

Patients who do not improve within 48-72 hours should be re-evaluated and their antibiotics switched to amoxicillin-clavulanate or a second- or third-generation oral cephalosporin, although highly resistant pneumococci may require treatment with parenteral ceftriaxone in order to achieve adequate serum levels of antibiotics.

Sinusitis

The typical pathogens that cause sinusitis mimic those of otitis media; therefore, initial therapeutic recommendations are similar. In adult allergic patients and in adults who do not respond to initial therapy, fluoroquinolones provide appropriate coverage. In this clinical situation, this class of antibiotics is not approved for children.

Pneumonia

Most patients treated for community-acquired pneumonia (CAP) are treated as outpatients, and the etiological agent is rarely identified. Clinical studies have shown that, when etiological agents are sought, S pneumoniae is the predominating agent found when a bacterial organism is obtained.

In children with CAP treated as outpatients, amoxicillin or amoxicillin-clavulanate at dosages used for the treatment of otitis media are recommended. In school-aged children (>5 y), the addition of a macrolide for coverage of atypical organisms is advised. In children ill enough to warrant hospitalization, the use of penicillin, ampicillin-sulbactam, or ceftriaxone is usually appropriate, and decisions for therapy should account for local resistance patterns. In critically ill or immunocompromised children in whom pneumococcal pneumonia is suspected or possible, vancomycin and a broad-spectrum cephalosporin should be used until or unless organism susceptibilities are available.^[34]

The Infectious Disease Society of America (IDSA) guidelines recommend the initial use of a macrolide (or doxycycline) for outpatient therapy of community-acquired pneumonia in previously healthy adults with no specific risk factors for resistant S pneumoniae infection.^[61] In adult patients with underlying chronic disease, immunosuppression (including asplenia or that caused by immunosuppressive therapies), recent use of antibiotics (the preceding 3 mo), or other specific risk factors for resistant organisms (eg, residence in an area with high rates of resistant pneumococcus), the IDSA guidelines recommend use of either (1) a respiratory fluoroquinolone (moxifloxacin, levofloxacin) or (2) a beta-lactam antibiotic (high-dose amoxicillin, amoxicillin-clavulanate, or, alternatively, a second- or third-generation cephalosporin) plus a macrolide (or doxycycline).

For inpatient treatment of adult pneumonia on a medical ward, treatment recommendations are as above for outpatient treatment of patients with comorbid conditions. For inpatient treatment of adult patients who require ICU care, recommendations are for a beta-lactam antibiotic plus a macrolide or a fluoroquinolone.^[62]

Meningitis

The recommended initial therapy of presumed bacterial meningitis in children is with vancomycin plus ceftriaxone or cefotaxime at meningeal doses. A beta-lactam (penicillin or, more likely, ceftriaxone or cefotaxime [for CSF penetration]) ± vancomycin (adequate CSF levels).

If the isolate is resistant to penicillin cephalosporins, the regimen started initially should be continued despite in vitro resistance) through the completion of therapy, usually 10 days in uncomplicated cases.

For the treatment of pneumococcal meningitis in children who are hypersensitive to beta-lactams, a combination of vancomycin and rifampin should be considered. Monotherapy with vancomycin should not be attempted, as it is difficult to achieve sustained adequate bactericidal concentrations of vancomycin in the CSF. Monotherapy with rifampin should not be attempted due to the concern for development of resistance.

Other potential antibiotics for use in the treatment of pneumococcal meningitis in children include meropenem (meningeal dosed) or chloramphenicol.

In patients infected with rifampin-sensitive pneumococcal isolates, the addition of rifampin to vancomycin should be considered after 48 hours when (1) the clinical condition has worsened despite treatment with vancomycin and cefotaxime/ceftriaxone, (2) repeat lumbar puncture shows persistently positive culture results, and/or (3) the isolate displays an MIC to cefotaxime/ceftriaxone of 4 µg/mL or greater.

The recommendations for treatment of bacterial meningitis in adults are similar to those in children.

• Bacteremia: Treatment of bacteremia should be guided by isolate susceptibilities.
• Other invasive infections: S pneumoniae is not a particularly common cause of other invasive infections, and initial empiric antibiotic coverage may be adequate, although resistant isolates may require a change in antibiotics if pneumococcus is isolated.

Class Summary

Penicillin and its derivatives are inexpensive effective antibiotics for treating pneumococcal infections when they are used against susceptible isolates. Penicillins can be administered orally or parenterally and work by inhibiting cell wall synthesis. Penicillin G is the parenteral drug of choice for susceptible S pneumoniae infections, and other parenteral beta-lactams do not provide additional or improved coverage (nor do beta-lactamase inhibitor combinations).

Typical doses of penicillin provide more than adequate serum and body fluid concentrations for susceptible organisms (usually even with intermediate-susceptible strains), and many studies have shown similar outcomes in patients with penicillin-resistant versus penicillin-susceptible pneumococcal isolates treated with appropriate doses of beta-lactam antibiotics. Levels of CSF penetration are also therapeutic, although, in most cases, vancomycin should be used in addition to a beta-lactam antibiotic until isolate susceptibilities can be determined given the increasing rate of penicillin-resistant strains of S pneumoniae.

Cephalosporins, which are also beta-lactam antibiotics, inhibit pneumococcus in the same way as penicillins and are resisted in the same manner (alteration in the cell wall PBPs). First-generation cephalosporins provide similar coverage in the treatment of penicillin-susceptible strains, although many of them have higher MICs. Most strains of pneumococcus that are not susceptible to penicillin also have some resistance to third-generation cephalosporins, although some may still be susceptible, depending on the particular PBPs affected.

In most cases, macrolides have activity against penicillin-susceptible strains of S pneumoniae. However, half or more of pneumococcal strains that have intermediate resistance or that are resistant to penicillin are also resistant to macrolides. Most macrolide-resistant isolates of S pneumoniae derive their resistance through an efflux pump mechanism, which may be overcome with levels of drug that exceed the MIC for sufficient periods. Macrolides have poor CSF penetration and should not be used to treatment meningitis.^[63]

Most pneumococcal isolates in the United States remain susceptible to certain fluoroquinolones, including moxifloxacin (most effective), levofloxacin, gatifloxacin, and gemifloxacin. Ciprofloxacin and ofloxacin have limited activity against pneumococcal infections. Fluoroquinolones provide broad-spectrum treatment for CAP and achieve excellent serum drug levels and tissue penetration. Specific populations in whom the use of fluoroquinolones is traditionally increased (eg, residents of nursing homes) have shown increased levels of pneumococcal resistance to fluoroquinolones, and their empiric use in respiratory infections should also be tempered by the concern for rapid development of resistance to this class by many organisms.

Vancomycin is the only glycopeptide antibiotic that has demonstrated effectiveness against pneumococcal infections. To date, no clinical or in vitro evidence of pneumococcal resistance to vancomycin has been reported in the United States, and it is the drug of choice (with a third-generation cephalosporin) in the treatment of pneumococcal meningitis.

The increased number of pneumococcal isolates resistant to trimethoprim-sulfamethoxazole precludes its use unless susceptibilities are known and beta-lactam use is contraindicated.

Clindamycin may also be used to treat nonmeningeal S pneumoniae infections. Penicillin or macrolide resistance may also be associated with clindamycin resistance in individual isolates.

Carbapenems are also effective against S pneumoniae but should be reserved for specific cases given their broad coverage and the potential for development of resistance by multiple organisms.

Cefotaxime (Claforan)

Third-generation cephalosporin with broad gram-negative spectrum, lower efficacy against gram-positive organisms, and higher efficacy against resistant organisms. Arrests bacterial cell wall synthesis by binding to one or more of the PBPs, in turn inhibiting bacterial growth. Safety profile is more favorable than aminoglycosides. DOC for meningitis (all ages), inpatient treatment of pneumonia, bacteremia, and other invasive infections.

Penicillin G (Pfizerpen)

DOC for severe infections, including meningitis attributed to susceptible strains of S pneumoniae. DOC for severe infections, excluding meningitis attributed to strains of S pneumoniae with intermediate susceptibility to penicillin.

Amoxicillin (Trimox, Amoxil)

Has better absorption than penicillin VK and administration is q8h instead of q6h. For minor infections, some authorities advocate administration q12h. Probably most active of the penicillins for non–penicillin-susceptible S pneumoniae.

Ampicillin (Marcillin, Omnipen)

No advantage over penicillin G in the treatment of pneumococcal infections. Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.

Cefazolin (Ancef, Kefzol, Zolicef)

Alternative choice for parenteral treatment of pneumococcal infection outside CNS. Best beta-lactam for IM administration. Poor capacity to cross blood-brain barrier precludes use for treatment of meningitis.

Ceftriaxone (Rocephin)

May be used to treat pneumococci that have reduced susceptibility to penicillin. Generally not preferred for infections caused by high-level penicillin-resistance pneumococci. For empiric treatment of meningitis, use in conjunction with vancomycin or rifampin.

Azithromycin (Zithromax)

Approximately 25% of S pneumoniae strains naturally resistant. Generally better tolerated than erythromycin. Because of long half-life, treatment duration is reduced.

Vancomycin (Vancocin, Lyphocin)

Always active against strains of S pneumoniae. DOC for the treatment of meningitis caused by non–penicillin-susceptible S pneumoniae. Has suboptimal capability to cross blood-brain barrier and should be administered with cefotaxime or ceftriaxone for the treatment of meningitis. In adults, glucocorticoids may decrease penetration of vancomycin in the CNS; avoid this medication unless specific indications exist. Vancomycin is frequently the preferred drug for the treatment of severe penicillin-resistant pneumococcal infections outside the CNS and for patients with an IgE-type allergy to penicillin. Only IV administration is effective.

The maintenance dose can be estimated using the following formula: 150 + 15 times the creatinine clearance in mL/min = mg of vancomycin to be administered daily.

Clindamycin (Cleocin)

Lincosamide for treatment of serious skin and soft-tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Meropenem (Merrem IV)

A carbapenem antibiotic alternative for patients allergic to penicillin with meningitis or other severe invasive infections (good CSF penetration). Has been used successfully in patients with meningitis caused by penicillin-resistant pneumococci.

Linezolid (Zyvox)

Prevents formation of functional 70S initiation complex, which is essential for bacterial translation process. Bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci. Used as alternative in patients allergic to vancomycin and for treatment of vancomycin-resistant enterococci.

Tigecycline (Tygacil)

A glycylcycline antibiotic that is structurally similar to tetracycline antibiotics. Inhibits bacterial protein translation by binding to 30S ribosomal subunit and blocks entry of amino-acyl tRNA molecules in ribosome A site. Indicated for complicated skin and skin structure infections caused by E coli, E faecalis (vancomycin-susceptible isolates only), S aureus (methicillin-susceptible and methicillin-resistant isolates), S agalactiae, S anginosus group (includes S anginosus, S intermedius, and S constellatus), S pyogenes, and B fragilis.