Pneumococcal disease

Pneumococcal disease is a name for any infection caused by Streptococcus pneumoniae or pneumococcus bacteria ¹. Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium with more than 100 distinct serotypes that differ in their propensity to cause disease overall, as well as their association with case fatality, and antimicrobial resistance ², ³.

Streptococcus pneumoniae or pneumococcus bacteria can cause many types of infections, including:

• Pneumonia (lung infection)
• Meningitis (infection of the lining of the brain and spinal cord)
• Bacteremia (bloodstream infection)
• Otitis media (middle ear infection)
• Sinusitis (sinus infection)

Streptococcus pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections (otitis media) and bacterial meningitis in children, as well as an important cause of sinusitis, bacteremia, septic arthritis, osteomyelitis, peritonitis, and endocarditis and is the leading cause of infectious death in both children and older adults ⁴, ⁵, ⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵. In the United States, prior to the widespread use of 7-valent pneumococcal conjugate vaccine (PCV7), the seven most common serotypes isolated from blood or cerebrospinal fluid (CSF) of children younger than age 5 years accounted for 80% of infections; these seven serotypes accounted for about 50% of isolates from older children and adults ¹⁶.

The pneumococci bacteria are spread from person to person by droplets in the air. People spread pneumococcal bacteria to others through direct contact with respiratory secretions, like saliva or mucus. The pneumococci bacteria are common inhabitants of the human respiratory tract. They may be isolated from the nasopharynx of 5%–90% of healthy people. Many people, especially children, have the bacteria in their nose or throat at one time or another without being ill. Experts call this “carriage,” and it only rarely leads to sickness ⁸. The prominence of Streptococcus pneumoniae as a cause of disease is due to the combination of high carriage rates, its genetic adaptability and its ability to shift from a commensal to a pathogenic interaction with its host ¹⁷. Scientists do not clearly understand the immunologic mechanism that allows pneumococcal disease to occur in a Streptococcus pneumoniae carrier.

Pneumococcal disease can be invasive, meaning a normally sterile part of the body is infected, or non-invasive.

Invasive pneumococcal disease includes bacteremia (blood stream infection), and meningitis (infection of the meninges that surround the brain). They are both caused by infection with the same bacteria but produce different signs and symptoms.

Pneumococcal pneumonia is a common disease caused by Streptococcus pneumoniae infection. Symptoms include abrupt onset of fever, shaking chills or rigors, chest pain, cough, shortness of breath, rapid breathing and heart rate, and weakness. The case-fatality rate is 5%–7% and is higher in adults 65 years and older and people with certain underlying medical conditions ¹⁸. Pneumococcal pneumonia can occur in combination with bacteremia and/or meningitis (invasive pneumococcal pneumonia), or it can occur alone (non-invasive pneumococcal pneumonia). At least 100,000 people were hospitalized each year for pneumococcal pneumonia and at least 30,000 people were hospitalized each year for invasive pneumococcal disease, and about 3,000 people died ¹⁸.

About 4,000 cases of pneumococcal bacteremia without pneumonia occur each year in the United States ¹⁸. Bacteremia is the most common clinical presentation among children less than 2 years of age, accounting for up to 70% of invasive disease in this age group. The overall case-fatality rate of pneumococcal bacteremia is about 20% and may be as high as 60% among older adults ¹⁸.

Footnotes: Pneumococcal disease complications during acute infection occur system-wide. Acute pneumococcal pneumonia and invasive disease can be life-threatening. It can also result in organ damage that results in debilitating long-term sequelae. These sequelae, in turn, contribute to loss of physiological resilience and early mortality

Figure 2. Streptococcus pneumoniae bacteria

Footnote: This digitally-colorized, scanning electron microscopic (SEM) image depicts what were three, round-shaped, Gram-positive, Streptococcus pneumoniae bacteria (lavender), as they were being attacked by an irregularly-shaped white blood cell (WBC) (pink). Note what appeared to be unidentified organisms in the upper left corner.

Figure 3. Streptococcus pneumoniae life cycle

Footnote: Streptococcus pneumoniae colonizes the mucosa of the upper respiratory tract (URT). This carriage is the prerequisite for both transmission to other individuals and invasive disease in the carrier. Carriers can shed Streptococcus pneumoniae in nasal secretions and thereby transmit the bacterium. Dissemination beyond its niche along the nasal epithelium, either by aspiration, bacteraemia or local spread, can lead to invasive diseases, such as otitis media, community-acquired pneumonia, sepsis and meningitis. As all of these diseases are ‘dead ends’ in the life cycle of the organism, the bacterial factors that cause invasive diseases must also be adaptive for colonization and/or transmission.

Figure 4. Streptococcus pneumoniae in blood agar

Footnote: Under an approximate 10X magnification, this image depicts the colonial characteristics displayed by Streptococcus pneumoniae bacterial colonies that were grown on primary isolation medium, consisting of trypticase-soy-agar, containing 5% sheep’s blood, as well as 5mg of gentamicin/ml. Note that the so called doughnut-shaped colonies are those of Streptococcus pneumoniae. Those that do not have depressed centers are not Streptococcus pneumoniae.

Figure 5. Streptococcus pneumoniae optochin test

Footnote: Depicted here, were the results of what is referred to as an optochin (ethylhydrocupreine) test, used to confirm the presence of Streptococcus pneumoniae bacteria, which are optochin-sensitive. In so doing, Streptococcus pneumoniae can then be differentiated from other alpha-hemolytic streptococcal organisms, such as Streptococcus viridans, which are optochin-resistant. The results, revealed that optochin-sensitive, S. pneumoniae, were present on the left, given the zone of inhibition around the optochin imbibed disc, while the optochin-resistant bacteria on the right grew uninhibitedly up to the disc’s edge.

How serious is pneumococcal disease?

Pneumococcal disease is a serious disease that causes much sickness and death. An estimated 30,000 cases and 3,000 deaths from invasive pneumococcal diseases (bacteremia and meningitis) occurred in the United States ¹⁸. Children younger than 2 years of age and adults age 50 years and older have the highest incidence of serious disease ¹⁸. Case-fatality rates are highest for pneumococcal meningitis and bacteremia, and the highest mortality occurs among older adults and patients who have underlying medical conditions.

Pneumococcal vaccine

Pneumococcal vaccines are the best way to protect against serious pneumococcal infections ⁴². Pneumococcal vaccines help protect against some of the more than 100 serotypes of pneumococcal bacteria ⁴³. The Centers for Disease Control and Prevention (CDC) recommends pneumococcal vaccination for children younger than 5 years and adults 65 years or older ²⁶.

There are 2 types of pneumococcal vaccines used in the United States ⁴⁴, ⁴⁵:

1. Pneumococcal conjugate vaccines (PCVs). A conjugate vaccine is a type of vaccine that joins a protein to an antigen (in the case of pneumococcal vaccines, the protein is connected to unique polysaccharides [long chains of sugar molecules] from the surface of each of the pneumococcal serotypes). The conjugate vaccines have the polysaccharides for different serotypes attached (or conjugated) to a carrier protein. The protein helps improve the quality of the immune system response to the vaccine compared to the response to an unconjugated polysaccharide (PPV). Immune response to pneumococcal conjugate vaccine (PCV) is a T-cell dependent response that produces memory B-cells and reduces carriage of the bacteria in the respiratory track. Pneumococcal conjugate vaccines (PCVs) are given to children younger than 5 years old and to older children who need it. Vaccine providers also give pneumococcal conjugate vaccines (PCVs) to adults 65 years or older and other adults who need it.
   • PCV15 (Vaxneuvance) helps protect against 15 types of Streptococcus pneumoniae bacteria ⁴⁶.
   • PCV20 (Prevnar 20) helps protect against 20 types of Streptococcus pneumoniae bacteria ⁴⁷.
   • PCV21 (Capvaxive) helps protect against 21 types of Streptococcus pneumoniae bacteria ⁴⁸.
2. Pneumococcal polysaccharide vaccine (PPV). A polysaccharide vaccine is a type of vaccine that is composed of long chains of sugar molecules called polysaccharides, that resemble the surface of certain serotypes of pneumococcal bacteria in order to help the immune system mount a response. The immune response to the Pneumovax23 (PPSV23) vaccine is a T-cell independent immune response but does not reduce bacterial carriage. Vaccine providers may give Pneumovax23 (PPSV23) to children 2 through 18 years old with certain medical conditions. Vaccine providers give it to adults who receive PCV15 (Vaxneuvance). They also may give it to adults who have received an earlier vaccine called PCV13 (Prevnar 13). PCV13 (Prevnar 13) is FDA-licensed and may still be available in some clinics. PCV13 (Prevnar 13) is no longer routinely recommended; however, CDC guidance allows for its use as previously recommended in situations where PCV15, PCV20, or PCV21 is indicated but unavailable and the alternative is that the patient would not be vaccinated ⁴⁹.
   
   • PPSV23 (Pneumovax23) helps protect against 23 types of Streptococcus pneumoniae bacteria ⁵⁰. Following the 2022 changes to the pneumococcal vaccination schedule for adults, PPSV23 (Pneumovax23) is no longer recommended alone, however PPSV23 (Pneumovax23) is recommended for adults following PCV13 (Prevnar 13) or PCV15 (Vaxneuvance) vaccination. PPSV23 (Pneumovax23) is not recommended for people who have previously received a PCV20 (Prevnar 20) or PCV21 (Capvaxive) vaccination.

Each of these vaccines helps protect against specific serotypes, or strains of Streptococcus pneumoniae bacteria. The number at the end of the vaccine name tells how many serotypes the pneumococcal vaccine includes.

The Centers for Disease Control and Prevention (CDC) recommends pneumococcal vaccination for ⁵¹:

• Children
  • All children younger than 5 years old
  • Children 5 through 18 years old with certain risk conditions
• Adults
  • All adults 65 years or older
  • 19 through 64 years old with certain risk conditions

Pneumococcal vaccine schedule for children

The Centers for Disease Control and Prevention (CDC) recommends routine pneumococcal vaccination for all children younger than 5 years old ²⁶.

Administer a 4-dose pneumococcal conjugate vaccine series (PCV15 [Vaxneuvance] or PCV20 [Prevnar 20]), 1 dose at each of the following ages ²⁶:

• 2 months
• 4 months
• 6 months
• with a booster at age 12 through 15 months

Catch-up guidance

Vaccinate children younger than 5 years of age who miss their shots or start the pneumococcal conjugate vaccine series later than recommended. The number of doses recommended and the intervals between doses will depend on the child’s age when vaccination begins. Otherwise healthy children who fall behind should be given catch-up vaccination through age 59 months; if they have certain underlying medical conditions they should be given catch-up vaccination through age 71 months.

Children may be at increased risk for febrile seizures if a pneumococcal conjugate vaccine is administered with inactivated influenza vaccine. However, clinicians may give either pneumococcal conjugate vaccine at the same time as an influenza vaccine.

Currently, no data from clinical trials are available for co-administration of Pneumovax23 (PPSV23) with other childhood vaccines during the same visit.

Pneumococcal vaccine schedule for adults 65 years or older

The Centers for Disease Control and Prevention (CDC) recommends PCV15 (Vaxneuvance), PCV20 (Prevnar 20) or PCV21 (Capvaxive) for all adults 65 years or older ²⁶:

• Who have never received any pneumococcal conjugate vaccine (PCV)
• Whose previous vaccination history is unknown

If PCV15 (Vaxneuvance) is used, administer a dose of Pneumovax23 (PPSV23) one year later, if needed. Only one dose of Pneumovax23 (PPSV23) is indicated. If previously administered, another dose isn’t needed. If Pneumovax23 (PPSV23) is not available, one dose of PCV20 (Prevnar 20) or PCV21 (Capvaxive) may be given. Their pneumococcal vaccinations are complete ²⁶.

The minimum interval is 8 weeks and can be considered in adults with ²⁶:

• An immunocompromising condition
• A cochlear implant
• A cerebrospinal fluid leak

If PCV20 (Prevnar 20) or PCV21 (Capvaxive) is used, a dose of Pneumovax23 (PPSV23) isn’t indicated. Regardless of which vaccine is used (PCV20 or PCV21), their pneumococcal vaccinations are complete ²⁶.

Recommendation for shared clinical decision-making

Based on shared clinical decision-making, adults 65 years or older have the option to get no additional pneumococcal vaccines, PCV20 (Prevnar 20) or PCV21 (Capvaxive). They can get PCV20 (Prevnar 20) or PCV21 (Capvaxive) if they have received both ²⁶:

• PCV13 (Prevnar 13) (but not PCV15, PCV20, or PCV21) at any age and
• Pneumovax23 (PPSV23) at or after the age of 65 years old

Pneumococcal vaccine administration

Use a needle length appropriate for the age and size (22–25 Gauge) of the person receiving the pneumococcal vaccine. NEVER administer a pneumococcal conjugate vaccine (PCV15, PCV20, or PCV21) and Pneumovax23 (PPSV23) during the same visit ⁵². If someone is indicated to receive PCV15 (Vaxneuvance) and Pneumovax23 (PPSV23), administer PCV15 (Vaxneuvance) first followed by Pneumovax23 (PPSV23).

• Administer pneumococcal polysaccharide vaccine Pneumovax23 (PPSV23) intramuscularly or subcutaneously ⁵².
• Administer pneumococcal conjugate vaccines (PCV15 [Vaxneuvance] or PCV20 [Prevnar 20]) intramuscularly ⁵².
• For infants and young children, use the vastus lateralis muscle in the anterolateral thigh.
• For older children and adults, use the deltoid muscle.
• Administer pneumococcal conjugate vaccine (PCV21 [Capvaxive]) to adults intramuscularly using the deltoid muscle.

The primary series of PCV15 (Vaxneuvance) or PCV20 (Prevnar 20) consists of 3 doses routinely given at 2, 4, and 6 months of age. You can administer the first dose as early as 6 weeks of age. CDC recommends a fourth (booster) dose at 12 through 15 months of age. For children vaccinated when they are younger than 12 months of age, the minimum interval between doses is 4 weeks. Separate doses given at 12 months of age and older by at least 8 weeks.

The number and timing of doses for older children and adults depends on the medical indication, prior pneumococcal vaccination, and age.

For children (2 through 18 years old), the interval between PCV15 (Vaxneuvance) and Pneumovax23 (PPSV23) should be at least 8 weeks. If Pneumovax23 (PPSV23) is inadvertently administered first, wait at least 8 weeks to administer PCV15 (Vaxneuvance).

For adults, the recommended interval is at least 1 year. An 8-week minimum interval can be considered for adults with an immunocompromising condition, cochlear implant, or cerebrospinal fluid leak. If Pneumovax23 (PPSV23) is inadvertently administered first, wait at least 1 year to administer PCV15 (Vaxneuvance).

In adults, you can administer a pneumococcal vaccine (PCV15, PCV20, PCV21, or PPSV23) during the same visit with influenza vaccination or other recommended vaccines. Administer each vaccine with a separate syringe and, if feasible, at a different injection site. Annual influenza vaccination is important to help prevent the flu. Additionally, since having the flu increases the risk of getting pneumococcal disease, receiving a flu vaccine is important for preventing pneumococcal disease.

Side effects of pneumonia vaccine

Redness, swelling, pain, or tenderness where the pneumonia vaccine is given, and fever, loss of appetite, fussiness (irritability), feeling tired, headache, muscle aches, joint pain, and chills can happen after pneumococcal conjugate vaccination (PCV) ⁵³.

PCV15 (Vaxneuvance), PCV20 (Prevnar 20) or PCV21 (Capvaxive) side effects:

• Redness, swelling, pain, or tenderness where the vaccine provider gave the shot
• Fever or chills
• Loss of appetite
• Fussiness (irritability) in young children
• Feeling tired
• Headache
• Muscle aches or joint pain

Pneumovax23 (PPSV23) side effects:

• Redness or pain where the vaccine provider gave the shot
• Feeling tired
• Fever
• Muscle aches

Young children may be at increased risk for seizures caused by fever after a pneumococcal conjugate vaccine (PCV) if it is administered at the same time as inactivated influenza vaccine. Ask your doctor for more information.

People sometimes faint after medical procedures, including vaccination. Tell your doctor if you feel dizzy or have vision changes or ringing in the ears. As with any medicine, there is a very remote chance of a vaccine causing a severe allergic reaction, other serious injury, or death ⁵³.

An allergic reaction could occur after the vaccinated person leaves the clinic. If you see signs of a severe allergic reaction (hives, swelling of the face and throat, difficulty breathing, a fast heartbeat,
dizziness, or weakness), call your local emergency services number and get the person to the nearest hospital. For other signs that concern you, see your doctor.

Pneumonia vaccine contraindications

You shouldn’t get PCV15 (Vaxneuvance), PCV20 (Prevnar 20) or PCV21 (Capvaxive) if you’ve:

• Had a life-threatening allergic reaction after any type of pneumococcal conjugate vaccination (PCV)
• Had a life-threatening allergic reaction to any vaccine containing diphtheria toxoid (DTaP)
• Have a severe allergy to any part of these vaccines

You shouldn’t get Pneumovax23 (PPSV23) if you:

• Are younger than 2 years old
• Had a life-threatening allergic reaction after getting Pneumovax23 (PPSV23)
• Have a severe allergy to any part of Pneumovax23 (PPSV23)

Which underlying medical conditions indicate that a child age 6 through 18 years should receive additional doses of pneumococcal vaccine beyond the routine schedule?

Medical conditions that increase the risk of pneumococcal disease and are indications for additional pneumococcal vaccine doses beyond the routine schedule are broken down into two categories: non-immunocompromising (non-IC) and immunocompromising (IC) ¹⁸. Recommendations differ slightly under certain circumstances by non-immunocompromising (non-IC) or immunocompromising (IC) category.

Non-immunocompromising (non-IC) conditions include ¹⁸:

• Cerebrospinal fluid (CSF) leak
• Chronic heart disease (especially cyanotic congenital heart disease and heart failure)
• Chronic kidney disease (except as specified in the immunocompromising (IC) list below)
• Chronic liver disease
• Chronic lung disease (including moderate persistent or severe persistent asthma)
• Diabetes mellitus
• Cochlear implant

Immunocompromising (IC) conditions include ¹⁸:

• Kidney disease and on maintenance dialysis
• Kidney disease with nephrotic syndrome
• Asplenia or splenic dysfunction
• Congenital or acquired immunodeficiency, including B-(humoral) or T-lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3, and C4 deficiency; and phagocytic disorders (excluding chronic granulomatous disease)
• Treatment with immunosuppressive drugs or radiation therapy (including treatment for Hodgkin disease, leukemias, lymphomas, malignant neoplasm, and solid organ transplant)
• HIV infection
• Sickle cell disease or other hemoglobinopathies

An older child through age 18 years with any high-risk condition who completed a pneumococcal conjugate vaccine (PCV) series before age 6 years that included any dose of PCV20 (Prevnar 20), is not recommended to receive any additional pneumococcal conjugate vaccine (PCV) doses.

Children with non-immunocompromising (non-IC) or immunocompromising (IC) conditions who completed a pneumococcal conjugate vaccine (PCV) series before age 6 years with PCV13 (Prevnar 13) or PCV15 (Vaxneuvance) but who have not received PCV20 (Prevnar 20) or pneumococcal polysaccharide vaccine Pneumovax23 (PPSV23) should receive additional pneumococcal vaccination with a single dose of PCV20 at least 8 weeks after the most recent pneumococcal conjugate vaccine (PCV) dose. If PCV20 (Prevnar 20) is not available, a non-IC or IC child in this circumstance may, alternatively, receive a single dose of Pneumovax23 (PPSV23) at least 8 weeks after the most recent pneumococcal conjugate vaccine (PCV) dose. An immunocompromised (IC) child given Pneumovax23 (PPSV23) in this circumstance would also be due for a dose of either PCV20 (Prevnar 20) or a second dose of Pneumovax23 (PPSV23) at least 5 years after the first Pneumovax23 (PPSV23).

Doses of the PCV7 (Prevnar 7) do not count toward pneumococcal conjugate vaccine (PCV) vaccination when determining the current pneumococcal vaccination needs of a child or teen with a qualifying non-IC or IC condition.

When feasible, administer any needed pneumococcal vaccination at least two weeks before initiating planned interventions that place a child at high risk (such as a cochlear implant or spleen removal).

What are the different serotypes of Streptococcus pneumoniae targeted by different pneumococcal vaccines?

Streptococcus pneumoniae bacteria are serotyped based on the polysaccharides in the outer capsule of the bacteria. Serotypes vary in how common they are and in what percentage of pneumococcal disease they cause.

Among the pneumococcal conjugate vaccines (PCVs), PCV13 (Prevnar 13) includes serotypes: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. PCV15 (Vaxneuvance) includes all PCV13 serotypes plus 22F and 33F. PCV20 (Prevnar 20) includes all PCV15 serotypes plus 8, 10A, 11A, 12F, and 15B.

Pneumovax23 (PPSV23) vaccine does not contain serotype 6A, but contains 19 other serotypes present in PCV20, plus serotypes 2, 9N, 17F, and 20.

PCV21 (Capvaxive) is designed to target additional Streptococcus pneumoniae serotypes causing a significant proportion of disease in adults that are not prevented by the vaccines approved for children. PCV21 (Capvaxive)does not contain 10 serotypes found in other pneumococcal vaccines approved for children (1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F, 15B, or 2). Instead, it contains an additional 11 serotypes not found in PCV20 (Prevnar 20): 9N, 17F, 20, 15A, 15C, 16F, 23A, 23B, 24F, 31, and 35B. Because of these differences, CDC estimates that PCV20 (Prevnar 20) targets serotypes that cause between 54% and 65% of invasive pneumococcal disease in adults, and PCV21 (Capvaxive) targets serotypes that cause between 77% and 85% of invasive pneumococcal disease in adults ¹⁸.

How effective are pneumococcal conjugate vaccines at preventing pneumococcal carriage or disease?

The United States Food and Drug Administration (FDA) licensed the first pneumococcal conjugate vaccine (PCV) against seven pneumococcus bacteria serotypes (PCV7, Prevnar 7) in 2000. A large clinical trial showed PCV7 (Prevnar7) reduced invasive disease caused by vaccine serotypes by 97%. Compared to unvaccinated children, children who received PCV7 (Prevnar 7) ¹⁸:

• Had 20% fewer episodes of chest X-ray confirmed pneumonia
• Had 7% fewer episodes of acute otitis media
• Underwent 20% fewer tympanostomy tube placements

FDA licensed PCV13 (Prevnar 13) based on studies comparing the serologic response of children who received PCV13 (Prevnar 13) to those who received PCV7 (Prevnar 7). Substantial evidence demonstrates that routine infant PCV7 and PCV13 vaccination reduces the carriage and transmission of vaccine serotypes.

Researchers conducted a randomized placebo-controlled trial (CAPiTA trial) in the Netherlands among approximately 85,000 adults 65 years or older from 2008 through 2013 ⁵⁴. The Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA trial) evaluated the clinical benefit of PCV13 (Prevnar 13) in the prevention of pneumococcal pneumonia. The results of the CAPiTA trial demonstrated ⁵⁴:

• 46% efficacy against vaccine-type pneumococcal pneumonia
• 45% efficacy against vaccine-type non-bacteremic pneumococcal pneumonia
• 75% efficacy against vaccine-type invasive pneumococcal disease (IPD, i.e., bacteremia or meningitis)

FDA licensed PCV15 (Vaxneuvance) and PCV20 (Prevnar 20) in 2021 based on studies comparing the serologic response of adults who received either PCV15 or PCV20 to those who received PCV13 (Prevnar 13). These studies showed PCV15 (Vaxneuvance) and PCV20 (Prevnar 20) induced antibody levels comparable to those induced by PCV13 (Prevnar 13) and shown to be protective against invasive disease. FDA subsequently expanded the indication for use of PCV15 and PCV20 to include children starting at age 6 weeks in 2022 and 2023, respectively, based on serologic studies. PCV21 (Capvaxive) was licensed in 2024 based on a similar evaluation of serologic response to vaccination.

How effective is pneumococcal polysaccharide vaccine at preventing pneumococcal carriage or disease?

According to CDC, more than 80% of healthy adults who receive Pneumovax23 (PPSV23) develop antibodies against the serotypes contained in the vaccine that persist for at least 5 years ¹⁸. Older adults and people with some chronic illnesses or immunodeficiency may not respond as well and their antibody levels may decline more quickly.

Overall, the Pneumovax23 (PPSV23) vaccine is 60% to 70% effective in preventing invasive pneumococcal disease caused by serotypes in the vaccine ¹⁸. Pneumovax23 (PPSV23) shows less effectiveness among immunocompromised people; however, because of their increased risk of invasive pneumococcal disease, CDC recommends Pneumovax23 (PPSV23) for people in these groups who receive PCV15 (Vaxneuvance). There has not been consensus regarding the ability of Pneumovax23 (PPSV23) to prevent non-bacteremic pneumococcal pneumonia; however, recent observational studies reported 21%–46% effectiveness against Pneumovax23 (PPSV23)-type pneumococcal pneumonia when PPSV23 was given less than 5 years before illness onset.

Unlike pneumococcal conjugate vaccines (PCVs), Pneumovax23 (PPSV23) vaccination has not been shown to decrease nasal carriage of pneumococcal bacteria among those vaccinated ¹⁸.

Pneumococcal disease cause

Pneumococcal disease is caused by Streptococcus pneumoniae or pneumococcus bacteria infection. Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium with more than 100 distinct serotypes that differ in their propensity to cause disease overall, as well as their association with case fatality, and antimicrobial resistance ², ³. Streptococcus pneumoniae or pneumococcus bacteria are encapsulated within a polysaccharide capsule, which is an important virulence factor ⁵⁵. These Streptococcus pneumoniae (pneumococcus) serotypes have been defined based on differences in their capsular polysaccharide composition ⁵⁶. The main way people spread Streptococcus pneumoniae bacteria to others is through direct contact with respiratory droplets in the air. People spread pneumococcal bacteria to others through direct contact with respiratory secretions, like saliva or mucus. Streptococcus pneumoniae bacteria often spread within households and in crowded conditions.

The pneumococci bacteria are common inhabitants of the human respiratory tract. They may be isolated from the nasopharynx of 5%–90% of healthy people. Many people, especially children, have the bacteria in their nose or throat at one time or another without being ill. Experts call this “carriage,” and it only rarely leads to sickness. The prominence of Streptococcus pneumoniae as a cause of disease is due to the combination of high carriage rates, its genetic adaptability and its ability to shift from a commensal to a pathogenic interaction with its host ¹⁷. Scientists do not clearly understand the immunologic mechanism that allows pneumococcal disease to occur in a Streptococcus pneumoniae carrier.

Transmission of Streptococcus pneumoniae occurs through ⁵⁷:

• Direct person-to-person contact via respiratory droplets
• Autoinoculation in persons carrying the bacteria in their upper respiratory tract

The pneumococcal serotypes most often responsible for causing infection are those most frequently found in carriers. Although carriage does not necessarily lead to disease, it is an important precursor for pneumococcal disease.

The following factors influence the spread of the organism within a family or household:

• Crowding
• Season. Pneumococcal infections are more common during the winter and in early spring when respiratory diseases are more prevalent.
• Presence of upper respiratory infections or pneumococcal disease, such as pneumonia or otitis media.

The period of communicability for pneumococcal disease is unknown. Presumably, transmission can occur as long as the organism appears in respiratory secretions.

Streptococcus pneumoniae bacterium most often resides asymptomatically in the nasopharynx but can be aspirated into the lungs to cause pneumonia ⁸. From the airway, the pneumococcus can gain access to the bloodstream and spread to other sites, where it can cause disseminated organ damage ⁵⁸, ⁵⁹, ⁶⁰. Young children with underdeveloped immune systems, those with immunodeficiencies, adults over the age of 65 with multiple medical conditions, and individuals experiencing or who have recently experienced a respiratory viral infection have increased susceptibility to both becoming infected with and dying from pneumococcal disease ⁵, ⁶⁰, ⁶¹, ⁶².

Pneumococcal disease risk factors

Many health conditions and other factors can increase someone’s risk for pneumococcal disease, including severe infections.

Conditions and other factors that increase the risk for invasive pneumococcal disease include ⁶³:

• Alcoholism
• Cerebrospinal fluid leak
• Chronic heart, lung, liver, or renal disease
• Cigarette smoking
• Cochlear implant
• Decreased immune function from disease or drugs
• Diabetes
• Functional or anatomic asplenia, including sickle cell disease

Conditions associated with decreased pulmonary clearance, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), viral infections, and active/passive cigarette smoke exposure, also predispose to Streptococcus pneumoniae infection.

Chronic lung conditions that increase someone’s risk include chronic obstructive pulmonary disease (COPD), emphysema, and asthma (in adults) or asthma treated with high-dose steroids (in children).

Persons with a cochlear implant appear to be at increased risk of pneumococcal meningitis.

Conditions that cause immune deficits, including HIV infection, malignancy, diabetes mellitus, functional or anatomic asplenia, humoral immunity defects, complement deficiencies, and neutrophil dysfunction, are associated with an increased risk of disease.

Children with HIV infection or functional or anatomic asplenia, particularly sickle cell disease, are at high risk for invasive pneumococcal disease. Some studies report rates more than 50 times higher than those among children of the same age without these conditions.

Experts do not know why, but children of certain racial and ethnic groups also have increased rates of disease:

• Alaska Native people
• African American people
• Certain American Indian people

Research shows that young children attending childcare are at increased risk for invasive pneumococcal disease and acute otitis media.

Children younger than 5 years, particularly aged 2 years or younger, are at an increased risk of pneumococcal disease ⁶⁴. In addition, absence of breastfeeding, exposure to cigarette smoke, daycare attendance, and lack of immunization with the pneumococcal conjugate vaccine further increase the risk of disease. Adults older than 55-65 years are also at an increased risk of pneumococcal disease ⁶⁴.

Children at risk for pneumococcal disease

Children at increased risk for pneumococcal disease include those younger than 2 years old and those with:

• Chronic heart, lung, or kidney disease
• Cerebrospinal fluid (CSF) leak (a health problem where fluid surrounding and protecting the brain and spinal cord leaks)
• Cochlear implant (a small electronic device that is surgically implanted to help people with severe hearing loss be able to hear)
• Diabetes
• HIV infection, cancer, solid organ transplant, or another condition or taking medicine that weakens the immune system
• Nephrotic syndrome (a kidney disorder)
• Sickle cell disease, a damaged spleen, or no spleen

Children with functional or anatomic asplenia, particularly those with sickle cell disease, and children with immunocompromising conditions are at very high risk for invasive disease, with rates in some studies more than 50 times higher than those among children of the same age without these conditions (i.e., incidence rates of 5,000 to 9,000 per 100,000 population). Other conditions that increase the risk of invasive pneumococcal disease in children include chronic heart disease, lung disease (including asthma if treated with high-dose oral corticosteroid therapy), liver disease, CSF leak, and having a cochlear implant. Rates are also increased among children of certain racial and ethnic groups, including Alaska Natives, African Americans, and certain American Indian groups (Navajo and White Mountain Apache). The reason for this increased risk by race and ethnicity is not known with certainty but has also been noted for invasive Haemophilus influenzae infection (also an encapsulated bacterium). Attendance at a childcare center has also been shown to increase the risk of invasive pneumococcal disease and acute otitis media 2- or 3-fold among children younger than age 5 years. Children with a cochlear implant are at increased risk for pneumococcal meningitis.

Adults at risk for pneumococcal disease

Adults 65 years or older are at increased risk for pneumococcal disease.

Adults of all ages are also at increased risk for pneumococcal disease if they have:

• Alcoholism
• Chronic heart, lung, kidney, or liver disease
• Cochlear implant
• CSF leak
• Diabetes
• HIV infection, cancer, solid organ transplant, or another condition or taking medicine that weakens the immune system
• Nephrotic syndrome
• Sickle cell disease, a damaged spleen, or no spleen

Adults with certain medical conditions are at highest risk for invasive pneumococcal disease. Adults who smoke cigarettes are also at increased risk for pneumococcal disease.

For adults age 18 through 64 years with hematologic cancer, the rate of invasive pneumococcal disease in 2013–2014 was 129 per 100,000 population. Other conditions that place adults at highest risk for invasive pneumococcal disease include other immunosuppressive conditions from disease or drugs, functional or anatomic asplenia, and renal disease. Other conditions that increase the risk of invasive pneumococcal disease in adults include chronic heart disease, chronic lung diseases (including chronic obstructive lung disease, emphysema, and asthma), liver disease, smoking cigarettes, alcoholism, CSF leak, and having a cochlear implant.

Pneumococcal disease symptoms

Pneumococcal disease symptoms depend on the part of the body that’s infected. It usually takes 1 to 3 days for pneumonia symptoms to appear after Streptococcus pneumoniae bacteria enter someone’s body. Experts don’t know how long it takes for symptoms to appear for other types of pneumococcal disease. Generally, the symptoms are similar to other bacterial infections in that part of the body.

Pneumonia

Symptoms of pneumococcal pneumonia, a lung infection, include:

• Chest pain
• Cough
• Fever and chills
• Rapid breathing or difficulty breathing

Older adults may experience confusion or low alertness, rather than the more common symptoms listed above.

Meningitis

Symptoms of pneumococcal meningitis, an infection of the lining of the brain and spinal cord, include:

• Confusion
• Fever
• Headache
• Photophobia (eyes being more sensitive to light)
• Stiff neck

In babies, meningitis may cause poor eating and drinking, low alertness, and vomiting.

Bacteremia (bloodstream infection)

Symptoms of pneumococcal bacteremia, a bloodstream infection, include:

• Chills
• Fever
• Low alertness

Ear infection

Symptoms of ear infections include:

• A red, swollen ear drum
• Ear pain
• Fever
• Sleepiness

Streptococcus pneumoniae are a common cause of middle ear infection (acute otitis media). Clinical manifestations may depend on the age of the patient. In young children, ear pain may be shown as irritability, change in sleeping or eating habits, or holding or tugging at the ear. Fever, ear drainage, and hearing loss may be present. Complications of pneumococcal otitis media may include mastoiditis and meningitis. Streptococcus pneumoniae infection is the most common cause of mastoiditis, a complication of middle ear infection (acute otitis media) that was more common in the pre-antibiotic era; this complication is now more commonly associated with untreated or improperly treated cases.

Several early studies demonstrated that middle ear infection (acute otitis media) due to Streptococcus pneumoniae is usually accompanied by fever and pain; the fever associated with pneumococcal otitis media tends to be higher than that caused by other common bacterial pathogens ⁶⁵. Pneumococcal disease is less likely to resolve spontaneously.

Pneumococcal acute otitis media U.S. statistics: 

• Causes up to 20% of all acute otitis media infections, which are the most frequent reasons for pediatric medical visits and pediatric antibiotic prescriptions

Sinus infection

Symptoms of sinus infections include:

• Bad breath
• Cough
• Facial pain or pressure
• Headache
• Post-nasal drip (mucus dripping down the throat)
• Runny or stuffy nose
• Sore throat

Conjunctivitis

Conjunctivitis also called “pink eye”, is an inflammation or infection of the transparent membrane (conjunctiva) that lines your eyelid and covers the white part of your eyeball. When small blood vessels in the conjunctiva become inflamed, they’re more visible. This is what causes the whites of your eyes to appear reddish or pink. Conjunctivitis is commonly caused by a bacterial or viral infection, an allergic reaction, or — in babies — an incompletely opened tear duct.

Bacterial conjunctivitis is more likely to be bilateral and purulent than viral conjunctivitis.

Streptococcus pneumoniae is found in up to one third of patients with bacterial conjunctivitis; the rate of isolates that are not susceptible to penicillin is increasing.

Osteomyelitis and septic arthritis

Streptococcus pneumoniae infection is an uncommon cause of osteomyelitis (bone infection) and septic arthritis (joint infection), causing approximately 4% and 20% of cases in children, respectively.

• Septic arthritis: Pneumococcal septic arthritis usually manifests as painful, swollen, and hot joints. The ankles and knees are most commonly involved, and one or more joints may be affected. Blood or synovial cultures usually grow S pneumoniae. Up to half of patients with pneumococcal septic arthritis have concomitant osteomyelitis.
• Osteomyelitis: The femur and humerus are most often involved in cases of pneumococcal osteomyelitis in children; the vertebral bones are often involved in adult patients. Up to 20% of patients with pneumococcal osteomyelitis develop long-term sequelae, a figure similar to that of rates of osteomyelitis of other causes. One clinical study performed by the Pediatric Multicenter Pneumococcal Surveillance Study Group ⁶⁶ showed that more than 40% of patients with joint and bone pneumococcal infections had associated bacteremia. Patients with joint prostheses or rheumatic fever are at increased risk for joint disease.

Soft tissue infections

Although uncommon, Streptococcus pneumoniae infection can be a cause of mild-to-serious soft tissue infections, including cellulitis, myositis, periorbital cellulitis, and abscess, particularly in some immunocompromised hosts (eg, those with SLE). Most patients have white blood cell counts greater than 15,000 cells/μL and elevated temperatures. Physical findings are related to the site of infection and usually include redness, warmth, and tenderness of the involved area. Movement may be limited by pain and/or swelling. The incidence of soft tissue infections is increased in persons with HIV infection or underlying connective tissue disease; however, most affected individuals are otherwise healthy and respond well to antibiotic therapy ⁶⁵.

Peritonitis

Peritonitis is an inflammation (irritation) of the peritoneum. This is the thin tissue that lines the inner wall of the abdomen and covers most of the abdominal organs. Overall, primary peritonitis (peritonitis caused by the spread of organisms via blood or lymph to the peritoneal cavity) is rare, accounting for less than 20% of peritonitis cases.

Streptococcus pneumoniae is the most commonly isolated organism in patients with primary peritonitis. Primary peritonitis in children is usually associated with underlying conditions such as nephrotic syndrome or other immunocompromising diseases. In adults, primary peritonitis is usually associated with cirrhosis.

Females with severe pelvic inflammatory disease due to Streptococcus pneumoniae infection may develop peritonitis. In such cases, organisms may gain access to the peritoneum via the fallopian tubes from the female genital tract. This is the only invasive disease caused by Streptococcus pneumoniae infection that is more common in females. Other persons at risk for peritonitis include persons with gastrointestinal injury, ulcers, or malignancy.

Presenting symptoms of peritonitis include abdominal pain, anorexia, emesis, diarrhea, and fever. Children may present atypically with right lower quadrant abdominal pain that may be mistaken for appendicitis.

Heart infections

In the antibiotic era, pneumococcal cardiac infections are rare.

• Endocarditis: Involvement of native aortic and mitral valves are most common; infection can lead to valve destruction, heart failure, and embolization. Presenting signs and symptoms are typical of those seen in other causes of endocarditis and include fever, new or changing murmurs, muscle and/or joint pains, sweating, fatigue, anorexia, and skin findings. In alcoholics, may be part of the triad of endocarditis, pneumonia, and meningitis.
• Pericarditis: Prior to the widespread use of antibiotics, S pneumoniae infection was the most common cause of purulent pericarditis in children; now, infection in childhood is extremely rare, and nearly all cases of pneumococcal pericarditis occur in adults. Symptoms, signs, and examination findings may include chest and/or pleuritic pain; radiating pain to the neck, abdomen, shoulder, or back; orthopnea; dry cough; extremity swelling; anxiety; fatigue; fever; pericardial rub; and muffled heart sounds.

Acute exacerbations of chronic bronchitis

Acute exacerbations of chronic bronchitis manifest as a change from baseline chronic symptoms. Symptoms include shortness of breath, increased production and/or purulence of sputum, increased sputum tenacity, and cough.

An estimated 80% of cases of acute exacerbations of chronic bronchitis are caused by infection, with about one half of those caused by aerobic bacteria, of which Streptococcus pneumoniae is the most commonly isolated organism.

Symptoms such as sore throat, rhinorrhea, nasal congestion, and dyspnea (shortness of breath) may indicate a viral cause ⁶⁷.

Pneumococcal disease complications

Serious pneumococcal infections can result in sepsis, long-term problems, or death. Sepsis is a life-threatening emergency resulting from the body’s extreme response to infection.

Pneumonia

Pneumonia can cause:

• Airway blockage, collapsed lungs, and lung abscesses (pus)
• Empyema (infection around the lungs and in the chest cavity)
• Pericarditis (inflammation of the outer lining of the heart)

Pneumococcal pneumonia kills about 1 in 20 people who get it.

Meningitis

Meningitis can cause developmental delay or hearing loss. About 1 in 12 children and 1 in 6 older adults who get pneumococcal meningitis dies of the infection.

Bacteremia

Bacteremia can result in loss of limbs. About 1 in 30 children with pneumococcal bacteremia die of it. Pneumococcal bacteremia kills about 1 in 8 adults who get it.

Minor infections

Complications are rare and not usually severe for mild infections like ear and sinus infections.

Pneumococcal disease diagnosis

How the pneumococcal disease diagnosis is made depends upon where the infection is. Your doctor will do a physical exam and ask about your medical history. If Streptococcus pneumoniae infection is suspected or considered, Gram stain and culture of appropriate specimens should be obtained, when possible. Potential specimens may include 1 or more of the following ¹⁵:

• Blood
• Cerebrospinal fluid (CSF)
• Sputum
• Pleural fluid or lung aspirate
• Joint fluid
• Bone
• Other abscess or tissue specimens

Specimens should be obtained prior to the initiation of antibiotic therapy and inoculated directly into blood-culture bottles, when possible.

Antibiotic susceptibilities should be obtained routinely on all cultures with growth of Streptococcus pneumoniae. Note that minimum inhibitory concentration (MIC) breakpoints are different depending on the specimen type.

Other laboratory values that may be helpful in diagnosis and treatment include a complete blood cell (CBC) count and differential, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP).

In children who do not produce sputum and in adults with a nonproductive cough, the diagnosis may be made based on urine antigen testing for Streptococcus pneumoniae. As with urinary antigen testing for Legionella, antigenuria may not be present in early infection or in patients without bacteremia, but, if present, may persist after clinical resolution of infection. Evaluation of sputum via a combination of culture, Gram stain, and pneumococcal antigen was found to be the most useful way of achieving an etiologic diagnosis of community acquired pneumonia. Pneumococcal antigen detection in sputum has been shown to have high sensitivity (90%), even compared with urinary antigen detection essays, in early and mild community acquired pneumonia in pretreatment patients whose sputum specimens can be obtained ⁶⁸. The pneumococcal urinary antigen assay may augment the standard diagnostic methods of blood culture and sputum culture, as it provides rapid results ⁶⁹.

A commercially available urinary antigen test can detect the C-polysaccharide antigen of Streptococcus pneumoniae as a cause of community-acquired pneumonia. The urinary antigen test:

• Is rapid and simple to use
• Has a reasonable specificity in adults
• Can detect pneumococcal pneumonia after initiation of antibiotic therapy

In the diagnosis of Streptococcus pneumoniae community acquired pneumonia, the urinary antigen test has a sensitivity of 77%-88% and a specificity of 67%-100% ⁷⁰. However, the clinical usefulness of this pneumococcal urinary antigen test is not well defined. The urinary antigen test is unable to provide antimicrobial susceptibility data, so it does not supplant traditional culture methods. The 2019 Infectious Diseases Society of America community acquired pneumonia guidelines do not recommend routine urinary testing for pneumococcal antigen in adults with community acquired pneumonia, except in adults with severe pneumonia ⁷¹.

The role of fiberoptic bronchoscopy is best done in the absence of adequate sputum for culture or when the patient is not responding to current therapy ⁷².

Culture and sensitivity

Antimicrobial susceptibility testing should be performed on all isolates of Streptococcus pneumoniae, regardless of the isolation site, because of the increasing prevalence of antibiotic resistant isolates. All isolates should be tested for susceptibility to penicillin and either cefotaxime or ceftriaxone. In addition, cerebrospinal fluid (CSF) isolates should be tested for susceptibility to vancomycin and meropenem. Cerebrospinal fluid (CSF) isolates that are found to be nonsusceptible to penicillin should also be tested for susceptibility to rifampin.

Microbiology laboratories should follow established guidelines regarding inoculum size and media (Mueller-Hinton agar with sheep, horse, or lysed horse red blood cells). Isolates from patients with invasive disease should undergo testing with quantitative minimal inhibitory concentration (MIC) techniques (eg, broth microdilution, antibiotic gradient strips).

The Clinical and Laboratory Institute (CLSI) (2010) has defined Streptococcus pneumoniae susceptibility as follows ⁷³, ⁷⁴:

• Pneumonia: For penicillin-sensitive Streptococcus pneumoniae (MIC < 2 μg/mL), penicillin G or amoxicillin is considered first-line therapy. For penicillin-resistant Streptococcus pneumoniae (MIC ≥2 μg/mL), the choice of antimicrobial agent should be directed by susceptibility testing.
• Cefotaxime or ceftriaxone considerations are as follows:
  • Susceptible (non-CNS/CNS): MIC is ≤1/0.5 µg/mL, respectively.
  • Intermediate (non-CNS/CNS): MIC is 2/1 µg/mL, respectively.
  • Resistant (non-CNS/CNS): MIC is ≥4/2 µg/mL, respectively.

Strains with intermediate or resistant susceptibility patterns should be considered nonsusceptible and alternate therapy used.

Imaging studies

• Chest radiography: Chest radiography should be performed in most patients with evidence of invasive pneumococcal infection and in those with pneumococcal pneumonia. The typical chest radiography finding in adolescents and adults with pneumococcal pneumonia is lobar consolidation. Infants and young children with pneumococcal pneumonia more often have a pattern of scattered parenchymal consolidation and bronchopneumonia. Other chest radiography findings may include air bronchograms, pleural effusions/empyema, pneumatoceles, and, rarely, abscesses. Cavitation is not a feature of Streptococcus pneumoniae pneumonia and, if present, should prompt investigation for other pathogens.
• Ultrasonography/CT scanning:
  • Chest ultrasonography or chest CT scanning may be obtained to provide information on the presence and/or extent of pleural effusion/empyema and parenchymal disease. Studies investigating the diagnostic utility of lung ultrasonography to diagnose pneumonia have also been promising ⁷⁵.
  • Echocardiography should be performed in patients in whom endocarditis is suspected.
  • Sinus CT scanning may provide information about the presence and extent of sinus disease. Positive findings include opacification or air-fluid levels.
  • Facial CT scanning should be obtained in patients with periorbital or orbital cellulitis to look for evidence of soft tissue swelling, bony involvement, cranial nerve impingement, or proptosis.
• MRI/CT scanning:
  • MRI or CT scanning of affected bones or joints should be obtained to evaluate for evidence of joint destruction, periosteal elevation, or a mass.
  • An MRI of the brain may be obtained in patients with meningitis to determine the location and extent of involvement but is not required by Infectious Disease Society of America (IDSA) guidelines.

Procedures

• Middle ear fluid aspiration
• Pleural fluid aspiration
• Chest tube thoracostomy or catheter placement
• Video-assisted thoracoscopy (VATS) or pleural decortication
• Lumbar puncture
• Joint fluid aspiration and/or wash-out of joint space
• Bone biopsy
• Soft tissue/muscle biopsy

Pneumococcal disease treatment

Antibiotics are the mainstay of treatment in Streptococcus pneumoniae infections ⁷⁶, ⁷⁷, ⁷⁸, ⁷⁹, ⁸⁰, ⁸¹, ⁸², ⁸³, ⁸⁴. The first dose of antibiotics should be given as quickly as possible after the definitive diagnosis. Early administration of antibiotics is associated with a better prognosis and the failure to use antibiotics has been associated with an increased risk of in-hospital mortality and more than a five-fold increase in 30-day mortality ²⁸, ²⁹, ³⁰, ³¹, ³², ³³, ³⁴, ³⁵, ³⁶, ³⁷.

Antibiotic treatment for serious pneumococcal infections typically includes ‘broad-spectrum’ antibiotics until results of antibiotic sensitivity testing are available. Antibiotic sensitivity testing shows which antibiotics will be most successful at treating a bacterial infection. Broad-spectrum antibiotics work against a wide range of bacteria. Once the sensitivity of the bacteria is known, doctors may choose a more targeted (or ‘narrow-spectrum’) antibiotic.

Streptococcus pneumoniae bacteria are resistant to one or more antibiotics in more than 30% of cases ⁸⁵. The CDC, as well as many state health departments, maintain a population-based surveillance system (the Active Bacterial Core surveillance system) that investigates the epidemiology and susceptibility patterns of invasive pneumococcal infections in the United States. In 2019, Active Bacterial Core surveillance estimated there were about 30,300 cases of invasive pneumococcal disease ⁸⁶. 3.8% and 2.4% of the isolates obtained showed intermediate or resistant susceptibility patterns to penicillin and cefotaxime, respectively ⁸⁶. One hundred percent of the isolated were susceptible to vancomycin  ⁸⁶. 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. Resistance rates are generally higher in most European countries, as well as in Hong Kong and Thailand ⁸⁸.

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 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.

State and local health departments have reported outbreaks of drug-resistant Streptococcus pneumoniae in ⁸⁹:

• Long-term care settings
• Institutions for people living with HIV
• Childcare centers

Streptococcus pneumoniae antibiotics

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 Streptococcus 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. Penicillin- and cefotaxime-susceptible strains of Streptococcus pneumoniae were estimated at 96.2% and 97.6%, respectively ⁸⁶.

In most cases, macrolides have activity against penicillin-susceptible strains of Streptococcus pneumoniae. However, between 1998 and 2011, resistance rates have increased to an estimated 25%-45% in the United States ⁹⁰. In 2019, the CDC’s active bacterial core surveillance report found the erythromycin resistance rate to be 29.3% ⁸⁶.

Macrolides have poor CSF penetration and should not be used to treatment meningitis ⁹¹.

Most pneumococcal isolates in the United States remain susceptible to respiratory fluoroquinolones. In the United States, less than 1% of Streptococcus pneumoniae isolates are resistant to levofloxacin, moxifloxacin, or gemifloxacin ⁹². 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, dalbavancin, and telavancin are glycopeptide antibiotics that have demonstrated efficacy against pneumococcal infections ⁹³. 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 Streptococcus pneumoniae infections. Approximately 5%-10% of Streptococcus pneumoniae strains in the United States are resistant to clindamycin ⁹⁴. 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 Streptococcus pneumoniae but should be reserved for specific cases given their broad coverage and the potential for development of resistance by multiple organisms.

Pneumococcal pneumonia

Pneumococcal pneumonia treatment is antibiotic therapy and supportive care including mechanical ventilation if necessary. Treatment of community-acquired pneumonia varies based on the area of practice and severity of the disease. In 2019, the Infectious Disease Society of America (IDSA) guidelines for diagnosis and treatment of community-acquired pneumonia were published ⁷¹. In healthy outpatient adults without comorbidities (eg, chronic heart, lung, liver or renal disease; diabetes mellitus, alcoholism, malignancy and asplenia), monotherapy with amoxicillin, doxycycline, or a macrolide (clarithromycin or azithromycin) is recommended; however, the use of macrolides should be limited to areas with less than 25% pneumococcal resistance to macrolides. Outpatients with the comorbidities listed above should receive either (1) combination therapy with amoxicillin/clavulanate or a cephalosporin (cefpodoxime or cefuroxime) plus a macrolide or doxycycline or (2) monotherapy with a respiratory fluoroquinolone (moxifloxacin, levofloxacin, or gemifloxacin). Regarding the treatment of hospitalized patients with CAP, the recommended regimens consist of (1) combination therapy with a beta-lactam and a macrolide or (2) monotherapy with a respiratory fluoroquinolone. There was not enough evidence to support beta-lactam monotherapy over fluoroquinolone therapy or combination beta-lactam/macrolide in hospitalized patients.

A recent Cochrane review shows the non-superiority of any outpatient antibiotic regimen for community-acquired pneumonia concerning the other drug classes ⁹⁵, ⁹⁶.

The first dose of antibiotics should be given as quickly as possible after the definitive diagnosis. The American College of Emergency Physicians policy statement gives a level B recommendation that there is not enough evidence to establish a benefit in mortality or morbidity from starting the antibiotics in less than 4, 6, or 8 hours ⁹⁷. The American College of Emergency Physicians clinical policy also notes that there is not enough evidence to determine if there is a benefit in morbidity or mortality from antibiotics being administered within any specific time course but recommends to begin antibiotics as soon as the diagnosis is made.

Patients with pneumococcal pneumonia who do not respond or respond slower than usual to initial treatment should undergo follow-up chest radiography. Worsening disease and/or the presence of a pleural effusion may indicate the need for consultation with a pulmonologist, an infectious disease specialist, and/or a surgeon for further intervention. Oral therapy can be initiated when patients have clinically improved and become afebrile. Repeat chest radiography should be performed 4-8 weeks after therapy is completed to ensure resolution of disease. Chest radiography findings may remain abnormal for weeks to months, particularly following severe disease or complicated pneumonias.

Patients with complicated pneumonia having parapneumonic effusion may need a tube thoracostomy and if it further progresses to empyema and is resistant to drainage by tube thoracostomy then decortication is required with video-assisted thoracoscopic surgery (VATS).

Pneumococcal meningitis

Patients with pneumococcal meningitis should be admitted to the hospital and treated with parenteral antibiotics. Per Infectious Disease Society of America guidelines, the initial treatment for pneumonococcal meningitis should be vancomycin and a third-generation cephalosporin ⁹⁸.

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 minimum inhibitory concentration (MIC) to cefotaxime/ceftriaxone of ≥4 µg/mL.

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

The use of systemic steroids within 15 minutes of initiating infusion of antibiotics in adult patients with bacterial meningitis is usually recommended with caution, as they may decrease cerebrospinal fluid (CSF) antibiotic concentration; patients with meningitis treated with steroids should be monitored closely ⁹⁹.

Steroids can be considered prior to antibiotic therapy in children aged 6 weeks and older with possible pneumococcal meningitis. If used, they should be given before or at the time of the first dose of antibiotics.

A repeat lumbar puncture should be considered after 48 hours of therapy in the following circumstances:

• Patients whose isolates are not susceptible to penicillin based on oxacillin disc diffusion testing or minimum inhibitory concentration (MIC) testing without pending results of cefotaxime and/or ceftriaxone susceptibilities
• Patients whose condition has worsened or has not improved
• Patients who received steroid therapy (which could alter the ability to observe clinical improvement/worsening)

Intravenous fluids, parenteral/enteral nutrition, and other medications should be used as indicated in appropriate clinical instances.

Pneumococcal bacteremia and sepsis

Patients with pneumococcal bacteremia should be treated with appropriate antibiotics and supportive care.

Repeat blood cultures should always be obtained in patients with Streptococcus pneumoniae bacteremia until culture results are negative.

Patients with signs or symptoms of sepsis should be admitted to the hospital and treated aggressively with antibiotics and other medical therapies, as indicated.

Pneumococcal conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis

Most patients with conjunctivitis, otitis media, sinusitis, bronchitis, and tracheobronchitis due to Streptococcus pneumoniae infection can be treated on an outpatient basis with appropriate antibiotics. Compliance and follow-up should be ensured.

Infants and elderly patients, as well as those with immunodeficiencies, underlying disease, or signs of severe disease, should be treated more aggressively and hospitalized when indicated.

Otitis media

The guideline produced by the American Academies of Pediatrics and Family Practitioners for the treatment of pneumococcal otitis media recommends first-line treatment of most patients with amoxicillin 80-90 mg/kg/day or amoxicillin-clavulanate (amoxicillin 90 mg/kg/day with clavulanate 6.4 mg/kg/day). Alternatives include cefdinir, cefuroxime, cefpodoxime, or ceftriaxone. These alternative antibiotics vary in their efficacy against the different pathogens known to cause otitis media. US data on in vitro susceptibility of Streptococcus pneumoniae to cefdinir and cefuroxime are 70% to 80%, respectively, compared with 84% to 92% to amoxicillin ¹⁰⁰.

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.

Other invasive pneumococcal infections

Purulent pneumococcal pericarditis and endocarditis are serious diseases and should be treated aggressively with appropriate courses of parenteral antibiotics.

Blood cultures should be obtained until multiple negative sets are documented. Repeat chest radiography, echocardiography, and other imaging tests may be repeated as recommended to monitor disease resolution.

Patients with osteomyelitis and joint infections caused by S pneumoniae infection should be monitored closely for a decrease in pain and inflammatory markers and improved use of the affected limb or joint. Failure to improve should prompt re-evaluation of the area via aspiration, washout, biopsy, or repeat imaging.

Surgical care

Patients with complicated pneumonia may require a chest tube for drainage of pleural fluid; video-assisted thoracoscopic surgery (VATS) or decortication may be required in more severe cases or in those with empyema.

In patients with suspected septic arthritis or osteomyelitis, synovial fluid or bone tissue should be obtained for Gram stain, cell count, histology, and culture.

Patients with recurrent or chronic otitis media, periorbital or orbital cellulitis, or facial cellulitis may require surgical intervention.

Pneumococcal disease prognosis

Pneumococcal conjunctivitis, otitis media, and sinusitis in developed countries where appropriate antibiotics are available usually carry an excellent prognosis ¹⁰¹.

The prognosis of pneumococcal pneumonia depends largely on underlying factors, including age, immunosuppression, availability of antibiotics, and extent of lung involvement. It appears that most adults (mean age, 64.6 years) who survive invasive pneumococcal pneumonia lose a mean 9.9 years of longevity ¹⁰².

The prognosis of pneumococcal meningitis is also related in part to host factors. Most studies have shown that morbidity rates in otherwise healthy US children with meningitis are usually less than 10%; however, neurological complications are common ¹⁰¹.

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