eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Pneumococcal Infections

Meera Varman, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Infectious Diseases, Creighton University School of Medicine
Archana Chatterjee, MD, PhD, Professor of Pediatrics, Medical Microbiology and Immunology, and Pharmacy, Division of Pediatric Infectious Diseases, Chief of Division of Pediatric Infectious Diseases, Creighton University School of Medicine; Hospital Epidemiologist and Medical Director of Infection Control, Children's Hospital; Nancy A Wick, MD, Consulting Staff, Department of Emergency Medicine, Section of Pediatrics, Children's at Scottish Rite; Chandy C John, MD, MS, Director, Center for Global Pediatrics, Associate Professor of Pediatrics and Medicine, University of Minnesota Medical School

Updated: Aug 18, 2009

Introduction

Background

Streptococcus pneumoniae colonizes the upper respiratory tract of healthy individuals and is one of the most frequent causes of bacterial infection in children. Common infections caused by this pathogen include otitis media (OM), sinusitis, occult bacteremia, pneumonia, and meningitis. Pneumococci may also cause osteomyelitis, septic arthritis, pericarditis, and peritonitis.

Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.

Pathophysiology

Pneumococci are encapsulated, lancet-shaped, gram-positive diplococci. The bacteria are transmitted person to person via respiratory droplet contact. Pneumococci can cause disease either by direct spread from colonized mucosal surfaces (eg, otitis media) or by hematogenous spread (eg, meningitis following bacteremia). Mucosal irritation resulting from factors such as viral infection or smoke often is a predisposing factor for pneumococcal infection. Ninety serotypes have been identified, with varying degrees of pathogenicity. Serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F cause most invasive disease, and pneumococci with these serotypes are often resistant to penicillin.

Frequency

United States

Invasive disease is most frequent in children younger than 2 years and in adults older than 65 years. Overall annual incidence of invasive disease in the United States is 15 cases per 100,000 individuals but widely varies by age, from 166 cases per 100,000 children younger than 2 years to 5 cases per 100,000 young adults. After the introduction of heptavalent conjugated pneumococcal vaccine, the rate of invasive pneumococcal disease (IPD) has trended down. In an active laboratory surveillance from 1997-2004, the IPD decreased by 40% from 11.8 cases to 7.2 cases per 100,000 live births. Among black infants, a marked decrease was noted in incidence of IPD from 17.1 cases to 5.3 cases per 100,000 live births compared with white infants with a decrease from 9.6 cases to 6.8 cases per 100,000 live births.

From 1999-2007, a 92% reduction in vaccine serotypes has been observed among both invasive and noninvasive isolates; during the same period, a 200% increase has been observed in vaccine-related or nonvaccine serotypes. Among these, serotypes 19A, 6C, 15, and 22F were predominantly noted.¹  The amoxicillin susceptibility was about 70% compared with 50% in macrolides. Serotype 6C is considered to be emerging as well.²  

An increased frequency of disease and increased morbidity and mortality rates are seen in children younger than 2 years and in children with humoral immunodeficiency (eg, HIV infection, agammaglobulinemia, complement deficiency), absent or deficient splenic function (eg, splenectomy, sickle cell anemia), nephrotic syndrome, chronic renal failure, organ transplantation, immunosuppressive therapy, chronic pulmonary disease, cerebral spinal fluid (CSF) leak after skull fracture, cochlear implant, diabetes mellitus, and malignancy. Parental smoking invariably increases acute otitis media by about 64% compared to no history of parental smoking (56%).

Specific Infections

Otitis media

Approximately 30% of children have at least one episode of pneumococcal otitis media by age 3 years. Pneumococci cause approximately 40% of otitis media cases. After the pneumococcal vaccination, nonvaccine serotype is encountered more frequently as a cause of otitis compared with vaccine serotypes.

Bacteremia

Pneumococci are responsible for as many as 85% of occult cases of bacteremia in children. Bacteremia is seen in 3-5% of children aged 3-36 months with fever higher than 102.5°F without another source. In the postvaccine licensure period, the annual episodes of pneumococcal bacteremia decreased from 7.2 episodes to 2.3 episodes per 100,000 emergency department visits in 1999. However, it increased to 2.8 episodes in 2004 and to 3.64 episodes per 100,000 emergency department visits in 2005. The rate of invasive disease due to serotype 19F in the conjugate vaccine has increased.

Pneumonia

S pneumoniae is the most common bacterial cause of childhood pneumonia, especially in children younger than 5 years.

Meningitis/CNS infections

S pneumoniae is the most common cause of bacterial meningitis in children. Yearly incidence in all age groups is 1-2 cases per 100,000 population.

Osteomyelitis/septic arthritis

Pneumococci are responsible for fewer than 10% of all cases of osteomyelitis and septic arthritis.

Other unusual infections caused by pneumococci are sporadic.

Vaccination

International

Pneumococcal pneumonia is estimated to cause 1.2 million deaths per year worldwide in children younger than 5 years.

Mortality/Morbidity

Death resulting from complications of pneumococcal otitis, sinusitis, bacteremia, and pneumonia is rare in otherwise healthy children. As a complication of pneumonia, pneumococcal empyema is not infrequent, even in developed countries, and it remains a significant problem in developing nations.

The case-fatality rate for pneumococcal meningitis is 5-10%. Between 25-35% of children with pneumococcal meningitis develop permanent neurologic sequelae (eg, hearing deficits, paralysis, hydrocephalus). The risk of fulminant pneumococcal infection and death in the high-risk patient population outlined above (eg, children with humoral immunodeficiency, functional asplenia, nephrotic syndrome) is much higher than the risk in otherwise healthy children.

Race

An increased incidence of invasive pneumococcal disease has been documented in blacks, American Indians (white Mountain Apache, Navajo), and Alaskan Eskimos.

Sex

Pneumococcal disease is slightly more frequent in males than in females, with a male-to-female ratio of 3:2 for pneumococcal bacteremia.

Age

Pneumococcal infections are most common in children aged 1-24 months.

• Otitis media and bacteremia are most common in children aged 6 months to 2 years.
• Sinusitis is most common in children 2 years and older.
• Pneumonia and meningitis are most common in children younger than 5 years.

Clinical

History

Children with pneumococcal infections usually have a temperature higher than 102°F. Children with invasive infections also demonstrate signs and symptoms related to the site of infection. Symptoms of specific infections in addition to fever are as follows:

• Otitis media
  • Otalgia (irritability and ear pulling in younger children)
  • Upper respiratory symptoms
  • Vomiting
• Sinusitis
  • Headache
  • Facial tenderness (much less frequent than in adults)
  • Symptoms of upper respiratory infection (cough, nasal drainage, congestion) lasting for 10 days or longer
• Occult bacteremia - Fever without a localizing source in children aged 2-24 months
• Pneumonia
  • Cough
  • Chest pain, shortness of breath, or respiratory difficulty
  • Malaise and poor appetite
• Meningitis
  • Stiff neck
  • Vomiting
  • Headache (older children)
  • High fever (temperature >103°F)
  • Lethargy
  • Irritability
  • Poor feeding
  • Unconsolable crying

Physical

• Otitis media - Bulging, erythematous, or yellow tympanic membrane with poor mobility and purulent fluid seen behind the tympanic membrane
• Sinusitis
  • Tenderness to palpation over maxillary or frontal sinuses
  • Nasal discharge of any color
  • Swollen nasal turbinates
• Bacteremia - No physical findings except fever (temperature of 102°F or higher) and tachycardia associated with the fever
• Pneumonia
  • Crackles or decreased breath sounds in the area of lobar consolidation on chest auscultation, with egophony in patients with severe consolidation and dullness to percussion
  • Retractions, tachypnea, or both
• Meningitis/CNS infections
  • Ill appearance
  • Nuchal rigidity (may not be present in infants <4 mo)
  • Altered mental status, poorly responsive (patient may present in comatose state)
  • Other neurologic abnormalities possible, such as cranial nerve deficits, ataxia, and weakness
  • Poor perfusion and signs of shock in patients with concurrent pneumococcal sepsis

Differential Diagnoses

Workup

Laboratory Studies

The following studies are indicated in patients with pneumococcal infections:

• WBC count
  • Elevated WBC count and differential showing a high band count or left shift may suggest bacterial infection.
  • Young children with a WBC count greater than 15,000 cells/mL and/or an absolute band count greater than 1500/mcL have an increased likelihood of occult bacteremia.
  • WBC count may be low in children with meningitis and other severe pneumococcal infections.
• Antigen tests
  • The use of CSF and urine antigen tests for pneumococci is limited because of the multitude of S pneumoniae serotypes and the poor sensitivity of the test. At present, these tests should be used only in children in whom blood and CSF cultures were obtained after antibiotic treatment. In these children, antigen test results occasionally are positive when culture results are negative.
  • A negative result on an antigen test does not exclude pneumococcal infection.
• Gram stain
  • Gram stains of usually sterile body fluids (CSF, synovial fluid, pleural fluid) showing gram-positive diplococci strongly suggest the diagnosis of pneumococcal infection, although alpha-hemolytic streptococci and group B streptococci can look like S pneumoniae.
  • Results of CSF Gram stains in younger children with meningitis are positive 90-100% of the time, but the CSF Gram stain technique may be slightly less sensitive in older children.
• Culture
  • Culture of S pneumoniae from usually sterile body fluids (eg, blood, CSF, pleural fluid, middle ear effusion, synovial fluid) establishes the diagnosis definitively.
  • Perform susceptibility testing when an invasive infection is present.
• For each of the following clinical syndromes, specific testing recommendations are as follows:
  • Otitis media or sinusitis
    • Tympanocentesis and bacterial cultures of middle ear fluid should be performed in children with chronic otitis media refractory to antibiotic treatment. This requires technical expertise.
    • Sinus fluid should be obtained and sent for bacterial culture if the sinusitis is refractory to antibiotic treatment.
    • Upper respiratory tract cultures are not reliable in determining infection because of the high rate of asymptomatic children carrying S pneumoniae.
  • Occult bacteremia - Blood culture of sufficient volume (minimum of 2 mL)
• Pneumonia
  • Sputum cultures are difficult to obtain from children, and results may be falsely positive because of the high rates of upper respiratory colonization in this population.
  • Blood cultures should be obtained in all patients, although only 25-30% of patients with pneumococcal pneumonia have positive results on blood culture.
• Meningitis
  • When meningitis is suspected, lumbar puncture should be performed. CSF should be sent for cell count, protein levels, glucose levels, Gram stain, and culture. Antigen tests are needed only if the patient was pretreated with antibiotics.
  • A blood culture also should be obtained to further confirm the diagnosis and the pathogens.
• Osteomyelitis/septic arthritis
  • Procedures include surgical biopsy or joint aspiration; fluid or bone is cultured for the organism.
  • Perform blood culture, since bacteremia often is present as well.

Imaging Studies

• Chest radiographs may reveal lobar or segmental consolidation or typical findings of round pneumonia.
• In many centers, a head CT scan is performed in older children with meningitis to exclude increased intracranial pressure prior to performing lumbar puncture. No compelling evidence exists that CT findings are better than physical examination at predicting complications from lumbar puncture, and, in most patients, a CT scan causes unnecessary delay of lumbar puncture. In young children with an open fontanelle, a head CT scan is unnecessary unless physical findings suggest complications or a diagnosis other than meningitis. In children with persistent fevers despite appropriate antimicrobial therapy, a head CT scan, or preferably an MRI, should be performed to exclude subdural empyema. MRI is more sensitive than CT in the detection of subdural or epidural empyema.

Procedures

• Lumbar puncture

Treatment

Medical Care

• Antibiotic therapy (see Medication)
• Supportive care

Consultations

• Surgeon: Children with septic arthritis, osteomyelitis, subdural effusion with meningitis, mastoiditis, or other unusual invasive infections require appropriate surgical consultation.
• Infectious disease specialist: A specialist in pediatric infectious diseases should be consulted when treating children with complicated pneumococcal infections or invasive pneumococcal disease caused by drug-resistant S pneumoniae.

Medication

Many pneumococcal strains are resistant to penicillin (8-40%, depending on geographic location), and resistance to ceftriaxone is also increasing. Therapy must be altered accordingly. Nonsusceptibility to penicillin and trimethoprim/sulfamethoxazole has increased from 25% and 18%, respectively, in the prepneumococcal vaccine era (ie, prior to availability of pneumococcal vaccine 7 [PCV7]) to 39% and 29%, respectively, in the postvaccination period.

When a strain is resistant to penicillin and cephalosporins, it is often also resistant to erythromycin, trimethoprim-sulfamethoxazole, and tetracyclines. Resistance is seen most often in serotypes 6, 9, 14, 19, and 23.

Penicillin-resistant strains are defined as intermediately resistant (minimum inhibitory concentration [MIC] >0.1-1 mcg/mL) or highly resistant (MIC >2 mcg/mL). The susceptibility to cefotaxime or ceftriaxone is based on location of isolation of the organism.

The key to successful antibiotic therapy of pneumococcal disease is achieving drug concentrations in the affected area of the body that are several times higher than the MIC of the organism.

Beta-lactam antibiotics (eg, amoxicillin, cefuroxime) achieve high levels in middle ear fluid and in the respiratory tract. For this reason, they remain the drugs of choice for otitis media and sinusitis, even when these infections are caused by penicillin-resistant pneumococci. Amoxicillin is the drug of choice for susceptible strains causing most noninvasive disease (eg, otitis media, sinusitis) and for outpatient treatment of pneumonia. High-dose amoxicillin (80-90 mg/kg/d) can also be used for otitis media, sinusitis, and pneumonia caused by penicillin-resistant pneumococci with intermediate resistance. If otitis media fails to respond after high-dose amoxicillin, the next options include amoxacillin/clavulanate (Augmentin), cefdinir, cefpodoxime, or intramuscular ceftriaxone. If the patients fail with these regimens myringotomy may be required.

Eradication of meningitis requires a drug concentration of 8-fold to 15-fold higher than the minimum bactericidal concentration (MBC) in the CNS. Initial empiric therapy should include cefotaxime (225-300 mg/kg/d divided every 8 h) or ceftriaxone (100 mg/kg/d divided every 12-24 h) along with vancomycin (60 mg/kg/d divided every 6 h). Vancomycin should be discontinued if the organism is susceptible to ceftriaxone. Ceftriaxone is the drug of choice for meningitis caused by ceftriaxone-susceptible pneumococci (MIC <0.5 mcg/mL).

Meropenem may be an alternative to ceftriaxone for ceftriaxone-resistant pneumococcal meningitis. If the MIC to meropenem is more than 0.12 mcg/mL, vancomycin should be used in addition to meropenem.

For nonmeningeal invasive pneumococcal disease including disease caused by penicillin- and ceftriaxone-resistant pneumococci, ceftriaxone is the drug of choice if the organism's MIC to ceftriaxone is less than 4 mcg/mL. For organisms with an MIC of 4 mcg/mL or higher, vancomycin probably should be used in addition to ceftriaxone.

Antibiotic agents

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Amoxicillin (Trimox, Amoxil, Biomox)

DOC for OM, sinusitis, and outpatient treatment of pneumonia. Interferes with synthesis of cell wall mucopeptides during active multiplication resulting in bactericidal activity against susceptible bacteria.

Dosing

Adult

250-500 mg/dose PO tid

Pediatric

Standard dose: 20-50 mg/kg/d PO divided tid
High dose: 80-90 mg/kg/d PO divided tid for unresponsive OM and sinusitis; not to exceed 2-3 g/d
Note: May need to start with high-dose treatment in areas with high prevalence (>30%) of penicillin-resistant pneumococci

Interactions

Reduces efficacy of PO contraceptives

Contraindications

Documented hypersensitivity; Epstein-Barr virus infection

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dose adjustment needed in renal failure; diarrhea may occur

Ceftriaxone (Rocephin)

Third-generation cephalosporin. DOC for meningitis (age >1 mo), inpatient treatment of pneumonia, occult bacteremia, and other invasive infections. Alternative for outpatient treatment of occult bacteremia and OM unresponsive to standard antibiotics.

Dosing

Adult

1-4 g/d IV/IM divided q12-24h; not to exceed 4 g/24 h

Pediatric

50-75 mg/kg/d IM/IV divided q12-24h
Meningitis (including penicillin-resistant strains): 100 mg/kg/d IV divided q12h administered with vancomycin
Non-CNS infections caused by penicillin-resistant strains: 80-100 mg/kg/d IV divided q12-24h
Acute OM: 50 mg/kg IM as single dose
Acute OM refractory to prior antibiotic treatment: 50 mg/kg/d IM for 3 d
Occult bacteremia: 50 mg/kg/d IM
Note: Not to exceed 1 g/dose

Interactions

Probenecid may increase ceftriaxone levels; coadministration with ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust in renal impairment; caution in infants <4 wk because of risk of hyperbilirubinemia (consider alternative cephalosporin, eg, cefotaxime)

Cefotaxime (Claforan)

Third-generation cephalosporin. DOC for meningitis (all ages), inpatient treatment of pneumonia, bacteremia, and other invasive infections.

Dosing

Adult

Standard dose: 1-2 g/dose IV/IM q6-8h
Meningitis or other severe infection: 2 g/dose IV/IM q4-6h
Note: Not to exceed 12 g/d

Pediatric

Neonates (dose based on postnatal age and weight):
<7 days and <2000 g: 100 mg/kg/d IV/IM divided q12h
<7 days and >2000 g: 100-150 mg/kg/d IV/IM divided q8-12h
7-28 days and <1200 g: 100 mg/kg/d IV/IM divided q12h
7-28 days and >1200 g: 150 mg/kg/d IV/IM divided q8h
Infants age >4 weeks and children:
100-200 mg/kg/d IV/IM divided q8h
Meningitis: 200 mg/kg/d IV/IM divided q6h
Non-CNS penicillin-resistant infections: 150-225 mg/kg/d
IV/IM divided q6-8h
Penicillin-resistant CNS/meningitis: 225-300 mg/kg/d IV/IM divded q6-8h administered with vancomycin

Interactions

Probenecid may increase cefotaxime levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Possible neutropenia, thrombocytopenia, eosinophilia, positive Coombs test result, elevated BUN level, creatinine level, and liver enzyme level; dose adjustment needed in renal failure

Vancomycin (Vancocin)

DOC for initial treatment of all meningitis (with cefotaxime or ceftriaxone) until susceptibilities are known. Continue in addition to ceftriaxone if the organism's ceftriaxone MIC is >0.25 mcg/mL. Also consider adding for non-CNS invasive infections if not responding to standard treatment because the infection may be caused by highly penicillin-resistant strains. DOC for patients allergic to penicillin with meningitis (with rifampin) or other invasive infections (alone).

Dosing

Adult

2 g/d IV divided q6-12h

Pediatric

Neonates (dose based on postnatal age and weight):
<7 days and <1200 g: 15 mg/kg/dose/d IV
<7 days and 1200-2000 g: 10-15 mg/kg/dose IV q12-18h
<7 days and >2000 g: 10-15 mg/kg/dose IV q8-12h
7-28 days and <1200 g: 15 mg/kg/dose/d IV
7-28 days and 1200-2000 g: 10-15 mg/kg/dose IV q8-12h
7-28 days and >2000 g: 15-20 mg/kg/dose IV q8h
Infants age >4 weeks and children: 40 mg/kg/d IV divided q6-8h
CNS infections: 60 mg/kg/d IV divided q6-8h
Note: Not to exceed 2 g/24 h

Interactions

Erythema, histaminelike flushing, and anaphylactic reactions may occur when administered with anesthetic agents; taken concurrently with aminoglycosides, risk of nephrotoxicity may increase above risk with aminoglycoside monotherapy; effects in neuromuscular blockade may be enhanced when coadministered with nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Possibility of ototoxicity and nephrotoxicity; possible exacerbation by concurrent aminoglycosides; dose adjustment needed in renal failure; possible red man syndrome with rapid IV infusion; infuse over 60-120 min for safety; monitor serum levels to avoid toxicity and ensure therapeutic levels (obtain trough level 30 min prior to dose 3, obtain peak level 60 min after dose 5); desired peak level is 25-40 mg/L and desired trough level is <10 mg/L; for meningitis, desired peak level is a minimum of 30 mg/L; when coadministered with aminoglycosides, monitor serum levels of both drugs and creatinine daily

Azithromycin (Zithromax)

Alternative for patients allergic to penicillin with OM, sinusitis, or outpatient treatment of pneumonia.

Dosing

Adult

500 mg PO on day 1, then 250 mg/d PO on days 2-5

Pediatric

10 mg/kg/dose PO day 1, then 5 mg/kg/d PO on days 2-5; not to exceed 250 mg/d

Interactions

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine

Contraindications

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in hospitalized, geriatric, or debilitated patients

Clindamycin (Cleocin)

Alternative treatment for OM or sinusitis unresponsive to standard treatment. Alternative also for OM, sinusitis, and inpatient or outpatient treatment of pneumonia and treatment of invasive infections other than CNS infections in patients who are allergic to penicillin.

Dosing

Adult

150-450 mg/dose PO q6-8h; not to exceed 1.8 g/d
1200-1800 mg/d IM/IV divided q6-12h; not to exceed 4.8 g/d

Pediatric

Neonates: 5 mg/kg/dose q6-12h (longer interval if weight <2 kg)
Infants age >4 weeks and children:
30 mg/kg/d PO divided q6-8h
40 mg/kg/d IV/IM divided q6-8h

Interactions

Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium; erythromycin may antagonize effects of clindamycin; antidiarrheals may delay absorption of clindamycin

Contraindications

Documented hypersensitivity; hepatic impairment; antibiotic-associated colitis; CNS infections

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Possibility of pseudomembranous colitis up to several weeks after cessation of therapy; possible diarrhea, rash, Stevens-Johnson syndrome, granulocytopenia, thrombocytopenia, or sterile abscess at injection site; not to exceed infusion rate of 30 mg/min; possible hypotension or cardiac arrest; do not use in CNS infections (poor CNS penetration)

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.

Dosing

Adult

1.5-3 g/d IV divided q8h
Meningitis and severe infections: 6 g/d IV divided q8h

Pediatric

<3 months: Not established
>3 months and children: 60 mg/kg/d IV divided q8h; not to exceed 3 g/d
Meningitis: 120 mg/kg/d IV divided q8h; not to exceed 6 g/d

Interactions

Probenecid may inhibit renal excretion of meropenem, increasing meropenem levels

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Possible diarrhea, rash, vomiting, PO moniliasis, glossitis, pain and irritation at IV injection site, and headache; possible hepatic enzyme elevation, bilirubin elevation, leukopenia, and neutropenia; dose adjustment needed in renal impairment; use in meningitis only if organism is susceptible to meropenem (MIC <0.12 mcg/mL)

Rifampin (Rifadin)

Used in conjunction with vancomycin for patients allergic to penicillin with meningitis.

Dosing

Adult

600-1200 mg/d IV divided q12h

Pediatric

20 mg/kg/d IV divided q12h

Interactions

Induces CYP450 microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations occur in LFTs)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Obtain CBC counts and baseline clinical chemistry panels prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Amoxicillin-clavulanic acid (Augmentin)

Antibiotic with beta-lactam inhibitor. Alternative for OM or sinusitis unresponsive to standard treatment.
In children >3 mo, base dosage protocol on amoxicillin content. As a result of different amoxicillin–to–clavulanic acid ratios in 250-mg tab (250/125) vs 250-mg chewable tab (250/62.5), do not use 250-mg tab until child weighs >40 kg.

Dosing

Adult

250-500 mg/dose PO tid or 750 mg/dose PO bid

Pediatric

Based on amoxicillin component:
<3 months: 30 mg/kg/d PO divided bid
>3 months: 20-40 mg/kg/d PO divided tid or 25-45 mg/kg/d PO divided bid

Interactions

Coadministration with warfarin or heparin increases risk of bleeding

Contraindications

Documented hypersensitivity; sensitivity to phenylketonurics (bid dosage form contains phenylalanine)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dose adjustment needed with renal impairment

Cefprozil (Cefzil)

Alternative for OM or sinusitis unresponsive to standard treatment or in patients with penicillin allergy but no cephalosporin allergy. Alternative outpatient treatment for pneumonia.

Dosing

Adult

500-1000 mg/d PO divided q12h

Pediatric

30 mg/kg/d PO divided q12h; not to exceed 1 g/d

Interactions

Probenecid increases effect of cefprozil; coadministration with furosemide and aminoglycosides increases nephrotoxic effects of cefprozil

Contraindications

Documented hypersensitivity; caution with penicillin allergy

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dose adjustment needed with renal failure

Cefepime (Maxipime)

Fourth-generation cephalosporin with good gram-negative coverage. Similar to third-generation cephalosporins but has better gram-positive coverage. Has good pneumococcal coverage and penetrates the CSF well, thus, can be used as alternative to ceftriaxone.

Dosing

Adult

1-2 g IV q12h for 10 d

Pediatric

50 mg/kg IV q8h; not to exceed 2 g/dose

Interactions

At high doses, probenecid decreases cefepime clearance; when used concurrently, aminoglycosides increase nephrotoxic potential of cefepime

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Adjust dose in severe renal insufficiency; prolonged use of cefepime may predispose patients to superinfection

Cefuroxime (Zinacef, Ceftin)

Second-generation cephalosporin good for treatment of non-CNS pneumococcal disease

Dosing

Adult

250-500 mg PO bid
750 mg to 1.5 g IV q8h

Pediatric

30 mg/kg/d PO divided bid; not to exceed 1 g/d
150 mg/kg/d IV divided q8h; not to exceed adult dose

Interactions

Disulfiramlike reactions may occur when alcohol is consumed within 72 h after taking cefuroxime; may increase hypoprothrombinemic effects of anticoagulants; may increase nephrotoxicity in patients receiving potent diuretics, such as loop diuretics; coadministration with aminoglycosides increase nephrotoxic potential

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Administer one-half dose if creatinine clearance is 10-30 mL/min and one-quarter dose if <10 mL/min; fungal and microorganism overgrowth may occur with prolonged therapy

Follow-up

Further Inpatient Care

The following is recommended in patients with bacterial meningitis due to pneumococcal infection:

• ICU admission is initially recommended for all patients with bacterial meningitis.
• Consider a second lumbar puncture at 24-48 hours to evaluate therapy if patient is not improving. A repeat lumbar puncture should be performed in all patients with penicillin-resistant pneumococcal meningitis.
• If the pneumococcal isolate is found to be susceptible to ceftriaxone (MIC <0.5), discontinue vancomycin. If the isolate is resistant to ceftriaxone, continue vancomycin and ceftriaxone.
• Daily fluid intake and output should be recorded in children with meningitis, and daily electrolyte levels tested during the acute phase of the illness, since children are at risk for syndrome of inappropriate antidiuretic hormone secretion and resultant hyponatremia. Most experts now agree that children with meningitis should receive regular maintenance intravenous or oral fluids rather than fluid restriction, but fluid intake and output still should be recorded carefully.
• Children with meningitis should be observed for signs of hydrocephalus. In the young child with an open fontanelle, daily head circumference measurements and palpation of the fontanelle should be performed. Older children should be observed for signs and symptoms of hydrocephalus.
• All children with meningitis should undergo hearing tests.
• Dexamethasone therapy started prior to antibiotics and administered for 4 days decreased the frequency of hearing loss in children with meningitis caused by Haemophilus influenzae.⁵ Smaller studies have documented a decreased frequency of hearing loss in children and adults with pneumococcal meningitis who were treated with dexamethasone. If dexamethasone is given, it should be done prior to the first dose of antibiotics. Dexamethasone dosing is 0.6 mg/kg/d divided every 6 hours for 4 days. However, dexamethasone may decrease CSF concentrations of vancomycin; therefore, use of dexamethasone in regions with a high prevalence of penicillin-resistant pneumococci is controversial.

Further Outpatient Care

• Discharged patients treated for invasive disease should have outpatient follow-up care at 24-48 hours.

Inpatient & Outpatient Medications

• Initial treatment of otitis media or sinusitis: Administer amoxicillin for 5-10 days (otitis media) or 10-21 days (sinusitis).
• Treatment of otitis media or sinusitis that has failed to improve clinically using standard-dose amoxicillin treatment: Administer high-dose amoxicillin, amoxicillin-clavulanic acid (Augmentin), cefuroxime, or ceftriaxone (intramuscularly).
• Occult bacteremia (with positive culture results): See Pneumococcal Bacteremia.
• Outpatient pneumonia: Administer amoxicillin for 10 days.
• Inpatient pneumonia
  • Administer intravenous ceftriaxone until the child has improved clinically, with a subsequent outpatient regimen for a total of 10 days of treatment.
  • For critically ill patients, the addition of vancomycin should be considered, but most pneumococci causing non-CNS disease, even penicillin-resistant strains, should respond to high-dose ceftriaxone.
• Other invasive pneumococcal diseases
  • Administer third-generation or fourth-generation parenteral cephalosporins (ceftriaxone, cefotaxime, cefepime).
  • If a patient is critically ill at presentation or not clinically improving, consider adding vancomycin until susceptibilities are known.
• Meningitis in children older than 1 month
  • Ceftriaxone or cefotaxime are the drugs of choice because they have the best CSF penetration.
  • For meningitis, always add vancomycin until susceptibilities are known.
  • After 24-48 hours of therapy, adding rifampin to vancomycin therapy may be considered if (1) clinical worsening is noted, (2) the follow-up CSF does not show eradication of organism or decrease in bacterial load, or (3) minimum inhibitory concentration (MIC) of pneumococci to cefotaxime is 4 or higher.
• Patients allergic to penicillin
  • Otitis media, sinusitis, outpatient treatment of pneumonia: Administer azithromycin (or other macrolide), clindamycin (if not allergic to cephalosporins), cefuroxime, or cefprozil.
  • Inpatient treatment of pneumonia or other invasive infections: Administer intravenous ceftriaxone if the patient is not allergic to cephalosporins. If the patient is allergic to cephalosporins, administer intravenous clindamycin or meropenem. Meropenem has 5-10% cross-reactivity with beta-lactams; therefore, hypersensitivity testing may need to be performed if the allergy is severe. Consider adding vancomycin if the patient is severely ill and organism susceptibility is not known.
  • Meningitis: Administer vancomycin plus rifampin or meropenem (patients age >3 mo).

Transfer

• In hospitals without a pediatric ICU, consider transfer of patients with meningitis or critically ill patients with other invasive disease.
• Also consider transfer if subspecialty surgical consultation may be needed (osteomyelitis, septic arthritis, mastoiditis, other unusual invasive disease).

Deterrence/Prevention

• In March 2000, the US Food and Drug Administration approved a heptavalent protein-conjugate vaccine (PVC7) safe for use in children as young as 6 weeks. The new heptavalent conjugate vaccine has been recommended by the American Academy of Pediatrics Advisory Committee on Immunization Practices for all children younger than 2 years and for high-risk children (see Frequency) aged 2-5 years. The vaccine has been shown in several large-scale trials to markedly reduce the number of cases of meningitis and bacteremic pneumonia. The vaccine was less efficacious in reducing OM. Children should receive the pneumococcal vaccine at age 2, 4, 6, and 12-15 months.
• The older 23-valent pneumococcal polysaccharide vaccine is effective and safe in children older than 2 years. It can be used in children at high risk for invasive pneumococcal disease who have not received the conjugate vaccine. Children older than 24 months who are at high risk of pneumococcal infection should have received 4 doses of PCV7; recommendations suggest administration of Pneumovax (PPV23), which is a 23-valent vaccine, followed by another dose after 3-5 years to give additional protection. Further study is required to determine whether revaccination is necessary in later years and which vaccine should be administered if revaccination is necessary.
• Pneumococcal vaccination with PCV7 and/or PPV 23 is recommended 2 weeks prior to splenectomy, cochlear implant, or immunosuppressive therapy. Children who are diagnosed with invasive pneumococcal disease should still complete their pneumococcal vaccine series.
  • Although the World Health Organization (WHO) recommends global implementation of PCV7, only a few countries have introduced PCV7 because of difficulty with completion of the 3 + 1 dose schedule (ie, doses at 2 mo, 4 mo, 6 mo, and 12-15 mo).
  • van Gils et al conducted a study to examine reduced pneumococcal carriage with vaccination schedules of 2 doses (administered at age 2 mo and 4 mo) or 2 + 1 dose (administered at age 2 mo, 4 mo, and 11 mo).⁶ Vaccine serotype pneumococcal carriage rates were measured during the second year of life. 
    • Vaccine serotype pneumococcal carriage was significantly decreased after both PCV7 schedules at age 12 months; 25% in the 2-dose schedule and 20% in the 2 + 1-dose schedule, compared with 38% in the control group who did not receive the vaccine (both P <0.001).
    • At 18 months, the 2 + 1–dose schedule group had further decreased to 16% and, at 24 months, decreased to 14% (both P <0.001).
    • The 2-dose schedule group remained stable at 18 months (24%), but at 24 months had further decreased to 15% (both P <0.001).
    • In the control group, vaccine serotype pneumococcal carriage remained around 36-38% until 24 months.
    • Results showed that significant reductions of vaccine serotype pneumococcal carriage occurred in the second year of life for those on the 2 + 1–dose or 2-dose schedule for PCV7 vaccination compared with those who did not receive pneumococcal vaccination.
• Further recommendations for prevention include restricting antibiotic use to reduce the resistance, adding more antigen to the pneumococcal vaccine, and improving the vaccination coverage.

Complications

• Meningitis - Subdural empyema, hydrocephalus, hearing loss, developmental delay, spasticity, mental retardation, and neurologic weakness
• Otitis media - Mastoiditis and cavernous sinus thrombosis
• Sinusitis - Intracranial abscess, periorbital/orbital cellulitis, subperiosteal abscess, cavernous sinus or sagittal sinus thrombosis, and meningitis
• Bacteremia - Osteomyelitis, endocarditis, and meningitis

Prognosis

• See Mortality/Morbidity.

Miscellaneous

Medicolegal Pitfalls

• The major medical-legal pitfall in pneumococcal infections is failure to diagnose meningitis. With the exception of very young children (<6 wk), the diagnosis is usually strongly evident by history and physical examination. In addition, osteomyelitis and septic arthritis occasionally are difficult to diagnose and can be overlooked. Fortunately, pneumococci is not a frequent cause of these conditions.

Multimedia

Media file 1: Sputum Gram stain from a patient with a pneumococcal pneumonia. Note the numerous polymorphonuclear neutrophils and gram-positive, lancet-shaped diplococci. Courtesy of C. Sinave, MD, personal collection.

References

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2. Jacobs MR, Bajaksouzian S, Bonomo RA, et al. Occurrence, distribution and origins of serotype 6C Streptococcus pneumoniae, a recently recognized serotype. J Clin Microbiol. Oct 29 2008;[Medline].

3. Invasive pneumococcal disease in children 5 years after conjugate vaccine introduction--eight states, 1998-2005. MMWR Morb Mortal Wkly Rep. Feb 15 2008;57(6):144-8. [Medline]. [Full Text].

4. Ulloa-Gutierrez R, Avila-Aguero ML. 6th International Symposium on Pneumococci and Pneumococcal Diseases. Expert Rev Vaccines. Aug 2008;7(6):725-8. [Medline]. [Full Text].

5. Arditi M, Mason EO Jr, Bradley JS, et al. Three-year multicenter surveillance of pneumococcal meningitis in children: clinical characteristics, and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics. Nov 1998;102(5):1087-97. [Medline].

6. van Gils EJ, Veenhoven RH, Hak E, et al. Effect of reduced-dose schedules with 7-valent pneumococcal conjugate vaccine on nasopharyngeal pneumococcal carriage in children: a randomized controlled trial. JAMA. Jul 8 2009;302(2):159-67. [Medline].

7. AAPCID. Pneumococcal infections. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. American Academy of Pediatrics; 2000:452-60.

8. AAPCID. Pneumococcal infections. In: Pickering LK, ed. 2006 Red Book: Report of the Committee on Infectious Diseases. 27^th ed. American Academy of Pediatrics; 2006:525-37.

9. AAPCID. Therapy for children with invasive pneumococcal infections. American Academy of Pediatrics Committee on Infectious Diseases. Pediatrics. Feb 1997;99(2):289-99. [Medline].

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13. Dagan R. The potential effect of widespread use of pneumococcal conjugate vaccines on the practice of pediatric otolaryngology: the case of acute otitis media. Curr Opin Otolaryngol Head Neck Surg. Dec 2004;12(6):488-94. [Medline].

14. Deeks SL, Palacio R, Ruvinsky R, et al. Risk factors and course of illness among children with invasive penicillin-resistant Streptococcus pneumoniae.The Streptococcus pneumoniae Working Group. Pediatrics. Feb 1999;103(2):409-13. [Medline].

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17. Klein JO. The pneumococcal conjugate vaccine arrives: a big win for kids. Pediatr Infect Dis J. Mar 2000;19(3):181-2. [Medline].

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Keywords

pneumococcus, Streptococcus pneumoniae, S pneumoniae, pediatric infections, otitis media, osteomyelitis, septic arthritis, pericarditis, peritonitis, pneumococcal disease, pneumococcal pneumonia, pneumococcal infection, invasive pneumococcal disease, IPD, HIV infection, agammaglobulinemia, complement deficiency, splenectomy, sickle cell anemia, nephrotic syndrome, chronic renal failure, organ transplantation, immunosuppressive therapy, chronic pulmonary disease, cerebral spinal fluid leak after skull fracture, cochlear implant, diabetes mellitus, malignancy, otalgia, cough, meningitis

Contributor Information and Disclosures

Author

Meera Varman, MD, Assistant Professor, Department of Pediatrics, Section of Pediatric Infectious Diseases, Creighton University School of Medicine
Meera Varman, MD is a member of the following medical societies: American Academy of Pediatrics, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society
Disclosure: phamaceutical companies Honoraria Speaking and teaching; phamaceutical companies Grant/research funds clinical trials

Coauthor(s)

Archana Chatterjee, MD, PhD, Professor of Pediatrics, Medical Microbiology and Immunology, and Pharmacy, Division of Pediatric Infectious Diseases, Chief of Division of Pediatric Infectious Diseases, Creighton University School of Medicine; Hospital Epidemiologist and Medical Director of Infection Control, Children's Hospital
Archana Chatterjee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Society for Microbiology, International Society for Infectious Diseases, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: GlaxosmithKline Honoraria Speaking and teaching; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; Sanofi-Pasteur Honoraria Speaking and teaching; Wyeth Honoraria Speaking and teaching; GlaxoSmithKline Grant/research funds Other; MedImmune  Other; Merck Grant/research funds Other; Novartis Grant/research funds Other; Sanofi-Pasteur Grant/research funds Other

Nancy A Wick, MD, Consulting Staff, Department of Emergency Medicine, Section of Pediatrics, Children's at Scottish Rite
Nancy A Wick, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, American Medical Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chandy C John, MD, MS, Director, Center for Global Pediatrics, Associate Professor of Pediatrics and Medicine, University of Minnesota Medical School
Chandy C John, MD, MS is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

David Jaimovich, MD, Chief Medical Officer, Joint Commission International and Joint Commission Resources
David Jaimovich, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Larry I Lutwick, MD, Professor of Medicine, State University of New York, Downstate Medical School; Director, Infectious Diseases, Veterans Affairs New York Harbor Health Care System, Brooklyn Campus
Larry I Lutwick, MD is a member of the following medical societies: American College of Physicians and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

CME Editor

Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine
Robert W Tolan Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, Phi Beta Kappa, and Physicians for Social Responsibility
Disclosure: GlaxoSmithKline Honoraria Speaking and teaching; MedImmune Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching; sanofi pasteur Honoraria Speaking and teaching; Baxter Healthcare Honoraria Speaking and teaching

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
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