Pneumococcal Infections (Streptococcus pneumoniae) Medication

Updated: Aug 27, 2018
  • Author: Claudia Antonieta Nieves Prado, MD; Chief Editor: John L Brusch, MD, FACP  more...
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Medication

Medication Summary

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 2010, only 10.6% of all isolates obtained showed intermediate or resistant susceptibility patterns to penicillin (down from 24.8% in 2008; 25.6% in 2007). [6] 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. [87, 88] Resistance rates are generally higher in most European countries, as well as in Hong Kong and Thailand. [89, 90]

The mechanism of pneumococcal resistance to penicillin and cephalosporins is through alteration in the molecular cell wall targets, penicillin-binding proteins (PBPs). Mutations that alter the PBPs result in decreased affinity for binding to these agents, rendering them less effective. This type of resistance can be overcome if the antibiotic concentration at the site of infection exceeds the MIC of the organism for 40%-50% of the dosing interval.

Penicillin-resistant pneumococci are often resistant to multiple additional classes of antibiotics, including other penicillin derivatives, 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 to these agents has been seen. [30, 31, 47]

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 isolated.

In August of 2011, the IDSA released new Clinical Practice Guidelines (CPG) for the treatment for CAP in infants and children. The first line antibiotic recommended is amoxicillin (90 mg/kg/day in 2 doses or 45 mg/kg/day in 3 doses) for previously healthy, appropriately immunized infants, preschool children, school-aged children, and adolescents with mild-to-moderate CAP suspected to be of bacterial origin.

In fully immunized, previously healthy children and adolescents ill enough to warrant hospitalization, ampicillin or penicillin G is recommended for first-line treatment when specific local epidemiology does not show evidence of high-level resistance to penicillin. 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.

The updated guidelines recommend treatment with a third-generation parenteral cephalosporin (ceftriaxone or cefotaxime) for children who are incompletely immunized or live in an area where local susceptibility data show the presence of penicillin resistance, as well as in those children with life-threatening infection and/or complications (to include empyema). In general, non–beta-lactam agents such as vancomycin have proven more effective than third-generation cephalosporins for treatment of pneumococcal pneumonia given the amount of resistance in this country. [91]

The 2007 IDSA guidelines recommend the initial use of a macrolide (alternative, doxycycline [level 3 evidence]) for outpatient therapy of CAP in previously healthy adults with no specific risk factors for drug-resistant S pneumoniae infection. [92] Risk factors include antibiotic use in the preceding 3 months, chronic cardiac/renal/liver/lung disease, immunosuppression (including asplenia, diabetes mellitus, HIV infection, and immunosuppressive therapy), or residence in a region with high rates of drug-resistant pneumococcus. For patients with these risk factors, as well as any adult patient requiring hospital admission, the IDSA guidelines recommend use of either (1) a respiratory fluoroquinolone (ie, moxifloxacin, levofloxacin) or (2) combination therapy with beta-lactam antibiotic (high-dose amoxicillin, amoxicillin-clavulanate, or, alternatively, a second- or third-generation cephalosporin) plus a macrolide. The recommendation in non–critically ill adults admitted with CAP is being called into question by a recent study of non–critically ill hospitalized patients with CAP, which demonstrated noninferiority of beta-lactam monotherapy to both combination therapy (beta-lactam plus macrolide) or fluoroquinolone monotherapy when comparing 90-day mortality rates. [93]

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).

For the treatment of pneumococcal meningitis in children who are allergic 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 also not be attempted owing to the high potential for rapid development of resistance in this setting.

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

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

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Antibiotics

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).

Cephalosporins' mechanism of action and modes of resistance are the same as for all other beta-lactams. First-generation cephalosporins provide similar coverage in the treatment of penicillin-susceptible strains, although many of them have higher MICs.

In most cases, macrolides have activity against penicillin-susceptible strains of S pneumoniae. However, between 1998 and 2011, resistance rates have increased to an estimated 25%-45% in the United States. [94]

Macrolides have poor CSF penetration and should not be used to treatment meningitis.72Hawser SP. Activity of tigecycline against Streptococcus pneumoniae, an important causative pathogen of community-acquired pneumonia (CAP). J Infect.

Most pneumococcal isolates in the United States remain susceptible to respiratory fluoroquinolones. In the United States, less than 1% of S pneumoniae isolates are resistant to levofloxacin, moxifloxacin, or gemifloxacin. [95] Ciprofloxacin and ofloxacin have limited activity against pneumococcal infections. Fluoroquinolones achieve excellent serum drug levels and tissue penetration. Specific populations in whom the use of fluoroquinolones is traditionally increased (eg, nursing home residents) have shown increased rates of pneumococcal resistance to fluoroquinolones, serving as a reminder that consideration of their empiric use in uncomplicated respiratory infections should be tempered by concern for the promotion of further antimicrobial resistance.

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 penicillin-resistant pneumococcal meningitis.

The increasing 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. Approximately 5%-10% of S pneumoniae strains in the United States are resistant to clindamycin. [26] As such, clindamycin should be used only after susceptibility testing has confirmed activity on clinical isolates. 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 (Moxatag)

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

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

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)

Generally better tolerated than erythromycin. Because of long half-life, treatment duration is reduced. Should not be used for meningitis owing to poor CSF penetration.

Vancomycin

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.

Ceftaroline (Teflaro)

Appears to be effective in vitro against pneumococcal isolates. A study in US medical centers from 2009 through 2012 that evaluated multidrug-resistant S pneumoniae (not susceptible to penicillin, ceftriaxone, erythromycin, tetracycline, trimethoprim-sulfamethoxazole, and levofloxacin) showed that ceftaroline was 16 times more potent than ceftriaxone. [93]

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.

Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Sulfatrim Pediatric)

Sulfamethoxazole and trimethoprim is a sulfonamide derivative antibiotic. This agent inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic acid, thereby inhibiting folic acid synthesis and resulting in inhibition of bacterial growth.

Levofloxacin (Levaquin)

Levofloxacin is rapidly becoming a popular choice in pneumonia; this agent is a fluoroquinolone used to treat CAP caused by S aureus, S pneumoniae (including penicillin-resistant strains), H influenzae, H parainfluenzae, Klebsiella pneumoniae, M catarrhalis, C pneumoniae, Legionella pneumophila, or M pneumoniae.

Levofloxacin is the L stereoisomer of the D/L parent compound ofloxacin, the D form being inactive. It has good monotherapy with extended coverage against Pseudomonas species and excellent activity against pneumococcus. Levofloxacin acts by inhibition of DNA gyrase activity. The oral form has a bioavailability that is reportedly 99%.

The 750-mg dose is as well tolerated as the 500-mg dose, and it is more effective. Other fluoroquinolones with activity against S pneumoniae may be useful and include moxifloxacin, gatifloxacin, and gemifloxacin.

Moxifloxacin (Avelox, Moxifloxacin Systemic)

Moxifloxacin is a fluoroquinolone that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication and transcription. Use caution in prolonged therapy, and perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic). Note that superinfections may occur with prolonged or repeated antibiotic therapy, and fluoroquinolones have induced seizures in patients with CNS disorders and caused tendinitis or tendon rupture.

Gemifloxacin (Factive)

Gemifloxacin is a fluoroquinolone that inhibits the A subunits of DNA gyrase, resulting in inhibition of bacterial DNA replication, DNA repair, recombination, transposition, and transcription.

Clarithromycin (Biaxin, Biaxin XL)

Clarithromycin is another initial drug of choice that is used in otherwise uncomplicated pneumonia. It is used to treat CAP caused by H influenzae, M pneumoniae, S pneumoniae, M catarrhalis, H parainfluenzae, or C pneumoniae (TWAR strain). Clarithromycin appears to cause more GI symptoms (eg, gastric upset, metallic taste) than azithromycin.

This agent is a semisynthetic macrolide antibiotic that reversibly binds to the P site of the 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

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Vaccines

Class Summary

Pneumococcal vaccines are recommended as part of routine prophylaxis in young children (aged < 5 y) and adults aged 65 y or older. These vaccines are also recommended for individuals who are immunocompromised (eg, HIV, cancer, renal disease) or have functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear implants.

Pneumococcal vaccine 13-valent (Prevnar 13)

Capsular polysaccharide vaccine against 13 strains of S pneumoniae, conjugated to nontoxic diphtheria protein, including serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F.

Pneumococcal vaccine polyvalent (Pneumovax 23)

S pneumoniae capsular antigens stimulate active immune response, resulting in production of endogenously produced antibodies. The 23 serotypes contained in the vaccine include : 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F.

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