Pediatric Annals

Antibiotic Choices: The Critical First Hour

Sara V Sotiropoulos, MD

Abstract

An estimated 40,000 children in the United States present to emergency centers each day with acute infectious diseases. Although most of these children present with mild, self-limiting illnesses, some have serious, life-threatening infections. A child who presents with fever, petechiae, tachycardia, or poor perfusion likely will elicit an appropriate physician response and receive prompt medical therapy. More often, the child with a serious, life-threatening infection will have less obvious findings. Early recognition and treatment of these children may optimize outcomes.1 Therefore, physicians caring for children must have a thorough understanding of the presentations of sepsis in children. Of all children presenting with an acute illness, physicians must be able to identify those at risk for sepsis and rationally approach their initial antibiotic therapy.

This article provides both basic information regarding childhood presentations of life-threatening infections and a practical guide to antibiotic choices that must be made within the first hour of physician contact.

SEPSIS

The signs and symptoms of childhood bacteremia or sepsis are variable and depend on the age of the child, the underlying disease, the presence or absence of a focal infection, and the properties of the etiologic microorganism.

Bacteremia, the presence of viable bacteria in the bloodstream, may be transient and without consequences or may progress to sepsis. Sepsis refers to a clinical state of systemic illness with signs and symptoms of severe infection, most often a result of bacteria or bacterial toxins in the bloodstream. Unrecognized or untreated sepsis likely will progress to septic shock, a condition in which the cardiovascular system fails to adequately perfuse vital organs. The delivery of critical substances and removal of metabolites is impaired. This leads to anaerobic metabolism, acidosis, and ultimately irreversible cell death. Early recognition and treatment of sepsis may prevent shock and the progression to multi-system organ failure and its inherent morbidity and mortality.

Table

Cefotaxime or ceftriaxone is suggested as initial antibiotic therapy in suspected sepsis or meningitis in this age group. Alternative therapy may be ampicillin plus chloramphenicol. On rare occasions (about 1/30,000 courses), chloramphenicol therapy causes nondose-related, idiosyncratic, and often fatal aplastic anemia. Additionally, the liver metabolism of chloramphenicol may be impaired with sepsis, necessitating close monitoring of chloramphenicol levels. Chloramphenicol also may impair myocardial contractility and therefore the dose should be administered slowly over 30 to 60 minutes. Vancomycin should be added to the initial therapy when pneumococcal meningitis is suspected.

PENICILLIN-RESISTANT S PNEUMONIAE

The resistance of S pneumoniae to penicillin and to a lesser extent cephalosporins is increasing at an alarming rate in many parts of the world. Surveillance of nasopharyngeal secretions from children in Tennessee and Kentucky revealed 29% and 33% resistance rates, respectively. Among children in daycare, 61% of pneumococcal isolates were resistant to penicillin.11

The mechanism of resistance in these isolates is altered penicillin-binding proteins. All beta-lactam antibiotics must interact with these penicillin-binding proteins to be effective. Therefore, pneumococci that are resistant to penicillin most often are resistant to ampicillin, amoxicillin-clavulanate, and other extended-spectrum penicillins. Some also are resistant to cephalosporins and other antibiotics. Resistance to vancomycin, as yet, has not been described.12

Because the serum concentrations of cephalosporins are so high, pneumococcal sepsis without meningitis may be adequately treated with a cephalosporin alone. However, if pneumococcal meningitis is suspected, the addition of vancomycin or rifampin to the cephalosporin as initial antibiotic therapy is advised.13 Rifampin may be preferred over vancomycin if dexamethasone is administered.14

SPECIAL CONSIDERATIONS

Several uncommon diseases can present with severe systemic illness and be rapidly fatal if not identified and treated. Many of these require antibiotic therapy outside of the usual third-generation cephalosporin that is suggested…

An estimated 40,000 children in the United States present to emergency centers each day with acute infectious diseases. Although most of these children present with mild, self-limiting illnesses, some have serious, life-threatening infections. A child who presents with fever, petechiae, tachycardia, or poor perfusion likely will elicit an appropriate physician response and receive prompt medical therapy. More often, the child with a serious, life-threatening infection will have less obvious findings. Early recognition and treatment of these children may optimize outcomes.1 Therefore, physicians caring for children must have a thorough understanding of the presentations of sepsis in children. Of all children presenting with an acute illness, physicians must be able to identify those at risk for sepsis and rationally approach their initial antibiotic therapy.

This article provides both basic information regarding childhood presentations of life-threatening infections and a practical guide to antibiotic choices that must be made within the first hour of physician contact.

SEPSIS

The signs and symptoms of childhood bacteremia or sepsis are variable and depend on the age of the child, the underlying disease, the presence or absence of a focal infection, and the properties of the etiologic microorganism.

Bacteremia, the presence of viable bacteria in the bloodstream, may be transient and without consequences or may progress to sepsis. Sepsis refers to a clinical state of systemic illness with signs and symptoms of severe infection, most often a result of bacteria or bacterial toxins in the bloodstream. Unrecognized or untreated sepsis likely will progress to septic shock, a condition in which the cardiovascular system fails to adequately perfuse vital organs. The delivery of critical substances and removal of metabolites is impaired. This leads to anaerobic metabolism, acidosis, and ultimately irreversible cell death. Early recognition and treatment of sepsis may prevent shock and the progression to multi-system organ failure and its inherent morbidity and mortality.

Table

TABLE 1Clinical Signs of Severe Infection In Newborns*

TABLE 1

Clinical Signs of Severe Infection In Newborns*

Table

TABLE 2Suggested Initial Dosages of Intravenous Antibiotics In Children With Sepsis or Meningitis

TABLE 2

Suggested Initial Dosages of Intravenous Antibiotics In Children With Sepsis or Meningitis

When sepsis is suspected, a rapid assessment of the patient and the possible underlying disease should ensue. Initial stabilization of the patient follows the standard prioritized protocol: Airway, Breathing, Circulation. During the process of stabilizing the patient, antibiotics are given. Often, the patient is too ill to delay giving antibiotics until all indicated specimens are obtained for culture. Preferably, at least the blood culture is obtained prior to the delivery of antibiotics. This often is accomplished at the time venous access is established. However, delivery should not be delayed if blood cannot be obtained for culture. Antibiotics may be administered via the intraosseous route.

The choice of antibiotics given during the initial hour of physician contact is based on the probable etiologic agents, the presence of localized infection, the immune status of the patient, and the severity of illness. The diagnosis of meningitis often cannot be ruled out definitively prior to initial antibiotic therapy. Therefore, the empirical regimen should provide adequate coverage for meningitis.

Neonatal Sepsis

Neonatal sepsis (sepsis occurring during the first 28 days of life) may present as early- or late-onset disease. The incidence ranges from 1 to 8 cases per 1000 live births. Early-onset disease refers to sepsis that occurs during the first few days of life. Such cases generally have sudden onset, multisystem involvement, and a mortality rate of 15% to 50%. These infants often have a history of prematurity or obstetrical complications such as premature or prolonged rupture of membranes, fetal distress or hypoxia, or peripartum maternal fever or infection. The etioiogic organism most often is acquired from the maternal genital or gastrointestinal tract during labor and delivery. The most likely pathogens are group B streptococci and aminoglycoside-susceptible coliform bacilli. Lateonset disease occurs after 1 week of age. Although the mortality rate (10% to 20%) is lower than in earlyonset disease, meningitis more often is present and morbidity is high.

The diagnosis of sepsis should be considered in any ill-appearing neonate. Only 50% to 60% of neonates with sepsis or meningitis present with fever (temperature5=38.3°C or 1010F).2 Hypothermia or temperature instability is seen in approximately 15% of neonates with sepsis. Because of the discrepancy noted between tympanic and rectal temperatures, it may be advisable to use rectal temperatures in neonates evaluated for sepsis.3,4 The first sign of sepsis in a neonate often is poor feeding or vomiting. Evaluation of the general appearance of a neonate gives the experienced physician a gestalt of the severity of infection. Physical findings may be subtle, ranging from irritability and hypertonia to lethargy and hypotonia. Focal signs of infection such as an inflamed joint, cellulitis, or pneumonia should be considered indicators of serious systemic disease. Signs of shock, including poor perfusion, tachycardia, and tachypnea may be present. Hypotension, a late finding in shock among neonates and children, is an ominous sign. Although uncommon in this age group, petechia or purpura may be present (Table 1).

Initial Antibiotic Therapy. For suspected sepsis with or without meningitis in the first 28 days of life, a combination of ampicillin (effective against common pathogens such as group B streptococci and uncommon pathogens such as Listeria monocytogenes and Neisseria meningitidis) and gentamicin (an aminoglycoside effective against pathogens such as Escherichia coli and other gram-negative bacilli, as well as synergistic with ampicillin against group B streptococci) is preferred therapy (Tables 2 and 3). An alternative therapeutic regimen would be ampicillin plus either cefotaxime or ceftriaxone.5,6 Many experts prefer the use of cefotaxime over ceftriaxone in neonates because ceftriaxone can displace bilirubin from albumin-binding sites, thus potentially exaggerating hyperbilirubinemia.7

A third antibiotic is required in the treatment of certain patients. Vancomycin should be added in neonates with suspected pneumococcal meningitis. Although this is a rare pathogen in this age group, the prevalence of penicillin- and cephalosporin-resistant strains continues to increase. This diagnosis should be suspected when the Gram's stain reveals gram-positive cocci and the latex agglutination test is negative for group B streptococci. Methicillin-resistant Staphylococcus epidermidis is a leading isolate among neonatal intensive care unit (NICU) patients. Therefore, vancomycin should be added to the empirical antibiotic regimen of neonates with a history of a central venous catheter or recent NICU stay. An antimicrobial agent such as clindamycin or metronidazole with broad anaerobic coverage should be added when an intra-abdominal infection is suspected.

Sepsis in the 4- to 8- Week-Old infant

Immediately following the neonatal period, identification of the baby with sepsis remains difficult. Fever, listlessness, or poor feeding may be the first sign of bacterial sepsis. Bonadio et al8 evaluated febrile infants ages 0 to 8 weeks and found that changes in affect, peripheral perfusion and respiratory status/effort best distinguished infants with serious bacterial infections from those with aseptic meningitis or viral syndromes. The evaluation and therapy of such infants should be individualized. Empirical antibiotic therapy may be necessary after appropriate specimens are collected for cultures and other laboratory tests. This certainly is indicated in any ill-/toxic-appearing infant and any infant with a suspected localized bacterial infection.

Initial Antibiotic Therapy. Infants 4 to 8 weeks of age are susceptible to neonatal pathogens as well as pathogens seen in the older infant and child. This includes, among others, group B streptococci, L mono' cytogenes, gram-negative bacilli, Streptococcus pneumoniae, N meningitidis, and Hemophilus influenzae. Preferred empirical therapy includes ampicillin plus either cefotaxime or ceftriaxone. If pneumococcal meningitis is suspected, vancomycin should be added to the empirical antibiotic regimen.

Sepsis in the Older Infant and Child

The presence of persistent irritability despite optimal environmental conditions in a previously healthy child should alert the physician to the possibility of sepsis or meningitis.9,10 High fever, tachycardia, chills, nausea, vomiting, and petechial or purpuric rash may be present. Often, patients are flushed during this "warm shock" phase. In time, altered mental status may be observed. This may be manifested by the infant's or child's lack of eye contact with their parents or by decreased awareness of procedures and surroundings. Hyperventilation may occur as a compensatory mechanism for metabolic acidosis. As shock progresses, cold clammy extremities and weak peripheral pulses will be noted, and the patient may develop severe respiratory distress. At this point, the clinician must recognize impending cardiopulmonary arrest and act accordingly.

Infants and children less than 2 years of age may have "occult bacteremia." Most studies indicate the risk of bacteremia increases with the degree of fever present. Although identification, therapy, and close follow-up is necessary for these patients, the majority do not require hospitalization. The intricacies of this clinical condition will not be discussed in this text.

Initial Antibiotic Therapy. Beyond the first 8 weeks of life, the spectrum of bacterial pathogens in sepsis changes. Although occasionally seen, group B streptococcus is not commonly isolated in older infants and children. Streptococcus pneumoniae, N meningitidis, and H influenzae are the most frequently identified etiologic agents. Although the extensive use of the H influenzae vaccines has led to a marked reduction in serious infections due to H influenzae, it remains a possible pathogen and should be given consideration when choosing antibiotics. Gram-negative organisms may be isolated in urosepsis, Salmonella gastroenteritis, an intra-abdominal infectious process, or an immunocompromised host. Group A streptococcus, Staphylococcus aureus, or coagulase-negative staphylococcus may be the etiologic agent in specific clinical scenarios discussed below.

Table

TABLE 3Initial Antibiotic Choices for Otherwise Healthy Children With Suspected Sepsls/Menlngltls*

TABLE 3

Initial Antibiotic Choices for Otherwise Healthy Children With Suspected Sepsls/Menlngltls*

Cefotaxime or ceftriaxone is suggested as initial antibiotic therapy in suspected sepsis or meningitis in this age group. Alternative therapy may be ampicillin plus chloramphenicol. On rare occasions (about 1/30,000 courses), chloramphenicol therapy causes nondose-related, idiosyncratic, and often fatal aplastic anemia. Additionally, the liver metabolism of chloramphenicol may be impaired with sepsis, necessitating close monitoring of chloramphenicol levels. Chloramphenicol also may impair myocardial contractility and therefore the dose should be administered slowly over 30 to 60 minutes. Vancomycin should be added to the initial therapy when pneumococcal meningitis is suspected.

PENICILLIN-RESISTANT S PNEUMONIAE

The resistance of S pneumoniae to penicillin and to a lesser extent cephalosporins is increasing at an alarming rate in many parts of the world. Surveillance of nasopharyngeal secretions from children in Tennessee and Kentucky revealed 29% and 33% resistance rates, respectively. Among children in daycare, 61% of pneumococcal isolates were resistant to penicillin.11

The mechanism of resistance in these isolates is altered penicillin-binding proteins. All beta-lactam antibiotics must interact with these penicillin-binding proteins to be effective. Therefore, pneumococci that are resistant to penicillin most often are resistant to ampicillin, amoxicillin-clavulanate, and other extended-spectrum penicillins. Some also are resistant to cephalosporins and other antibiotics. Resistance to vancomycin, as yet, has not been described.12

Because the serum concentrations of cephalosporins are so high, pneumococcal sepsis without meningitis may be adequately treated with a cephalosporin alone. However, if pneumococcal meningitis is suspected, the addition of vancomycin or rifampin to the cephalosporin as initial antibiotic therapy is advised.13 Rifampin may be preferred over vancomycin if dexamethasone is administered.14

SPECIAL CONSIDERATIONS

Several uncommon diseases can present with severe systemic illness and be rapidly fatal if not identified and treated. Many of these require antibiotic therapy outside of the usual third-generation cephalosporin that is suggested for suspected sepsis in patients older than 8 to 12 weeks. Rocky Mountain spotted fever, the most common rickettsial disease in the United States, is characterized by fever, headache, myalgias, and a maculopapular or petechial rash that commonly involves the palms and soles. Transmitted by ticks, it exhibits a spring/summer predominance. Treatment within the first 6 days of illness is associated with a better prognosis. The drug of choice is tetracycline or doxycycline, even in children younger than 8 years.15 Ehrlichiosis, a tick-borne disease with a presentation similar to Rocky Mountain spotted fever, also requires tetracycline or doxycycline for adequate therapy.16 Tularemia, transmitted by ticks or rabbit exposure, can present as sepsis. Streptomycin (30 mg/kg/day administered intramuscularly in two divided doses) remains the drug of choice. If streptomycin is unavailable, therapy can be initiated with gentamicin.17

An antistaphylococcal penicillin should be initiated if toxic shock syndrome is suspected. Although antibiotic therapy likely will not have a profound immediate effect in this exoprotein-driven syndrome, some patients are bacteremic at presentation.

The addition of clindamycin to a penicillin or cephalosporin may be advantageous in the initial therapy of patients with aggressive group A streptococcal infections such as necrotizing fascitis or myositis. Clindamycin is effective against group A streptococci and may act by suppressing the synthesis of bacterial toxins.28

INITIAL THERAPY OF SEPSIS WITH LOCALIZING SIGNS

The child who presents with sepsis but who has signs of a localized infection deserves special consideration. Among children with community-acquired infectious syndromes commonly caused by S aureus (osteomyelitis, septic arthritis, bacterial tracheitis, and preorbitai cellulitis), an antistaphylococcal penicillin or vancomycin should be added to ceftriaxone or cefotaxime. Children with central lines or other foreign bodies should be treated with antibiotics effective against coagulase-negative and coagulase-positive staphylococci, alphahemolytic streptococci, and gram-negative organisms. Vancomycin plus ceftazidime is an appropriate initial therapeutic regimen in such patients.

Sepsis following a rodent bite may be due to Streptobacillus momliformis or Spirillum minus, both of which are susceptible to penicillin. Sepsis following cat or dog bites may be due to penicillin-sensitive Posturelk multocida. Ampiciilin-clavulanate may be used if additional coverage for S aureus is desired.

Although decreased in incidence since the widespread use of the H influenzae type b vaccines in infants, epiglottitis should be considered in any child with stridor and fever. After securing the child's airway in a controlled setting, an antibiotic effective against H influenzae, such as cefuroxime, should be administered.

INFECTIONS IN IMMUNOCOMPROMISED CHILDREN

Infection remains the leading cause of death among children with cancer. With the emergence of gram-positive organisms as the most commonly isolated bacteria in this patient population, vancomycin often is added to ceftazidime for empirical therapy.

Children with human immunodeficiency virus infection are at risk for serious disease with common pathogens. When they present with signs of sepsis, antibiotics as discussed above are indicated. However, when they present febrile, but nontoxic, the clinician must assess the potential for rapid progression and act accordingly.

Children with sickle cell disease have an estimated incidence of invasive S pneumoniae infection that is 30 to 100 times that in healthy children. Although fever may be caused by viral illnesses or vaso-occlusive crises, children with sickle cell disease and fever require a thorough evaluation for possible sepsis ana may require prophylactic antibiotic therapy.

CONCLUSION

It is important for clinicians to recognize those infants and children at risk for serious bacterial infections. Empirical antibiotic therapy, when deemed necessary, should be chosen based on the age of the child, the most likely etiologic agents, the presence or absence of localized infection, the immunocompetency of the patient, and the severity of illness.

During the past decade, two significant developments have occurred in sepsis and meningitis of childhood: the decline of disease due to H influenzae and the emergence of resistant S pneumoniae. Meningitis due to penicillin- or cephalosporin-resistant organisms requires the addition of vancomycin for adequate therapy. Vancomycin should be included in the antibiotic regimen of any child or infant with suspected pneumococcal meningitis.

REFERENCES

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2. Klein JO, Marcy SM. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, eck Infectious Diseases of the Fetus, Neuborn & Infant. Philadelphia, Pa: WB Saunders Co; 1995:835-890.

3. Brennen DF, Fallt JL, Rothrock SG. Kerr RB. Reliability of infrared tympanic therraometry in the detection of rectal fever in children. Ann Emerg Med. 1995;25:2130.

4. Ericluon RS, Woo TM. Accuracy of Infrared ear thermometry and traditional temperature methods in young children. Heart Lung. 1994;23:181-195

5. Nelson JD. Therapy for neonatal sepsis. Seminar, in Pediatric Infectious Diseases. 1994;5:15-19.

6. Klein JO. Antimicrobial agent*. In: Feigin RD, Cherry JD, eck. Textbook of Pediatric Infectious Distasa. Philadelphia, Pa: WB Saunders Co: 1992:2179-2199.

7. Fink S1 Karp W, Robertson A· Ceftriaajne effect on bilirubin-albumin binding. Pediatrics. 1987:80:873-875.

8. Bonadio WA, Henncs H, Smith D, et al. Reliability of observation variables in distinguishing infectious outcome of febrile young infants. Pediatr Infect Dis }. 1993:12:111-117.

9. McCarthy PL Controversies in pediatrics: what tests are indicated for the child under 2 with fever. Pediatr Rev. 1979;1:51-56.

10. Smith AL Commentary: die febrile infant. Pediatr Rev. 1979;1:35-36.

11. Drug-resistant Streptococcus pneumoniae - Kentucky and Tennessee, 1993. MMWR Morb Mortal Wkh/ Rep. 1994:43:23-26,31.

12. Friedland IR, Med M, McCracken GH Jr. Management of infections caused by antibiotic-resistant Streptococcus pneumonia. N Engl J Med. 1994;331:377-382.

13. Bradley JS, Kaplan SL, Klugman KP, Leffiadro RJ. Consensus: management of infections in children caused by Streptococcus pneumoniae with decreased susceptibility to penicillin. Pediatr Infect Dis J. 1995;14:1037-1041.

14. Pub MM, Hkkey SM, Uscher Ml, Shelton S, McCracken GH jr. Effect of dexamethasone on therapy of experimental penicillin and cephalosporin-resistant pneumococcal meningitis. Antímicrob Agents ChemoAer. 1994;38:1320-1324.

15. Abramson JS, Oivner LB. Rocky mountain spotted fever. Seminars m Pediatric Infectious Diseases. 1994;5:131-136.

16. Edwards MS. Ehrlichiosis in children. Seminars in Pediatric Infectious Diseases. 1994;5:143-147.

17. Sotiropoulos SV. Tularemia. Seminars m Pediatric infectious Diseases. 1994:5:102107.

18. Bisno AL, Stevens DL, Streptococcal Infections of skin and soft tissues, N En|i J Mei 1996:334:240-245.

TABLE 1

Clinical Signs of Severe Infection In Newborns*

TABLE 2

Suggested Initial Dosages of Intravenous Antibiotics In Children With Sepsis or Meningitis

TABLE 3

Initial Antibiotic Choices for Otherwise Healthy Children With Suspected Sepsls/Menlngltls*

10.3928/0090-4481-19960601-10

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