Pediatric Annals

Continuation of Antibiotic Therapy for Serious Bacterial Infections Outside of the Hospital

Kathleen Gutierrez, MD

Abstract

An important determinant of the efficacy of outpatient antibiotic therapy is a child's acceptance of therapy. A child is more likely to be compliant if the antibiotic selected has relatively infrequent dosing and good taste.15,16 Palatability may be a stronger determinant of compliance than frequency of administration.17 In general, cephalosporin suspensions taste and smell better than penicillin suspensions, although Cefpodoxime proxetil and cefuroxime axetil reportedly have a bitter taste.17,18

The bioavailability of some antibiotics is influenced by interactions with concomitant medications (Table 5). Antacids decrease the bioavailability of a number of antibiotics including metronidazole, nitrofurantoin, and fluoroquinolones by decreasing absorption. Acetaminophen decreases the activity of chloramphenicol by increasing its metabolism. The list of all concomitant medications should be reviewed to prevent adverse interactions. Malabsorption of antibiotics is another reason for poor bioavailability. A child with persistent diarrhea, vomiting, or gastrointestinal abnormalities probably is not a candidate for sequential antibiotic therapy.

The optimal time to switch from parenteral to oral antibiotics is dependent on the child's clinical course. In general, the child should be afebrile, symptoms should have improved, cultures (if positive) should indicate the organism is sensitive, and surrogate markers of infection such as white blood cell count, sedimentation rate, or C-reactive protein should be returning to normal.

Following oral therapy and discharge, the child should be evaluated weekly to assure compliance, tolerance of oral medication, and continued clinical improvement. Laboratory tests that may predict therapeutic adequacy include C-reactive protein,19 sedimentation rate, and serum bactericidal titers. The serum bactericidal titer has been used most frequently in monitoring treatment of osteomyelitis and endocarditis. A good response for osteomyelitis has been associated with peak bactericidal titers >1:8 and trough titers 2*1:2.20,21 Families should be educated about the necessity of continuing therapy in a child who is almost back to normal.

HOME INTRAVENOUS ANTIBIOTIC THERAPY

Sequential intravenous to oral antibiotic therapy probably is not appropriate for children with endocarditis or other life-threatening infections. Successful treatment of these infections may require persistent high serum levels of antibiotics maintained over an extended time. Intravenous antibiotic therapy is necessary to achieve drug levels that result in rapid sterilization of the cerebrospinal fluid (CSF). The level of antibiotic achieved in CSF is only 3% to 30% of that achieved in serum, and this percentage decreases as inflammation within the central nervous system resolves.22

Even after CSF is sterile, children with meningitis should be observed for complications including increased intracranial pressure, seizure, stroke, or inappropriate antidiuretic hormone secretion. As a result, most patients with meningitis remain hospitalized until they complete antibiotic therapy. However, children with a good response, an uncomplicated course, and a reliable home situation may be candidates for outpatient antibiotics to complete the last few days of therapy.

Outpatient therapy for meningitis can be given intravenously at home or in the physician's office. For children in whom intravenous access is not possible, once-daily intramuscular ceftriaxone may be an option. Intramuscular ceftriaxone at a dose of 80 to 100 mg/kg/once daily achieves adequate CSF bactericidal levels, provided the child has normal peripheral perfusion23 and the infecting organism is susceptible.

Bacterial endocarditis also generally is treated with a full course of intravenous antibiotics administered in the hospital where close observation is possible. However, some children with endocarditis have a good response to initial inpatient antibiotic treatment and are able to receive at least a portion of their antibiotic therapy as outpatients. Early hospital discharge is more likely with infection by streptococcal species than S aureus, gram-negative organisms, or fungi. The latter tend to have more complications, necessitating closer observation.

A team approach to home intravenous therapy is desirable.…

Serious bacterial infections are an important and frequent cause of hospitalization of infants and children.1 The traditional concept that serious bacterial infections in young children must be treated with prolonged hospitalization for intravenous antibiotics is undergoing révaluation as part of the current focus on medical cost containment. It is apparent that there are strategies available to assure optimal care of children with serious infections while reducing medical costs. Transition of antibiotic therapy from hospital to home can be accomplished once the child demonstrates symptomatic improvement. This article focuses on strategies for continuation of antibiotic therapy for serious bacterial infections outside of the hospital. Requirements for successful transition of therapy, methods for monitoring effectiveness of therapy, and advantages and disadvantages of this approach will be addressed.

Transition of antibiotic therapy from hospital to home may be accomplished in a number of ways. For many types of infection, intravenous antibiotic therapy can be changed to oral antibiotic therapy once the patient shows improvement in symptoms (so-called sequential or "switch" therapy). Alternatively, for more serious infections, intravenous antibiotics given in the hospital may be continued at home or completed with daily visits to a health-care facility. Not only are these strategies cost effective, but they also offer important social and psychological benefits to children and their families.

Table

TABLE 1Infections Amenable to Sequential Intravenous to Oral Antibiotic Therapy

TABLE 1

Infections Amenable to Sequential Intravenous to Oral Antibiotic Therapy

Sequential antibiotic therapy or "switch" therapy refers to the practice of providing the patient with an initial short course of an intravenous antibiotic with completion of therapy by an orally administered agent. The first studies that evaluated sequential intravenous to oral antibiotic therapy for serious bacterial infections were published about 20 years ago.2'4 These studies demonstrated that children with bacterial osteomyelitis or arthritis treated with intravenous antibiotics (range: 3 days to 3 weeks) could safely complete their therapy with appropriate oral antibiotics. Outcomes appeared comparable to those of children hospitalized for prolonged intravenous therapy. Since these initial studies were published, the use of sequential intravenous to oral antibiotic therapy has been used for an increasing variety of infections in children (Table 1).

SEQUENTIAL ANTIBIOTIC THERAPY

Sequential antibiotic therapy provides both economic and patient benefits. An example is illustrated in a study involving almost 800 adults with lower respiratory tract, skin or soft-tissue, bone and joint, or urinary tract infections. Patients were treated initially with a variety of intravenous antibiotics and then switched to oral ciprofloxacin to complete treatment at home. Projected savings of drug plus hospitalization costs was close to $1 million (approximately $1200 per patient enrolled).5 Savings result from reduced acquisition costs of oral drugs, reduced costs associated with preparation and administration of intravenous drugs (eg, pharmacist time, nursing time, supplies, and drug levels), and reduction in number of hospital days. Benefits to the child include earlier return to their familiar home environment and school. In addition, the discomfort and inconvenience of maintaining intravenous access and the risks attendant to prolonged hospitalization such as nosocomial infections and phlebitis are reduced.

Treatment failure or relapse of infection is uncommon if patients are selected carefully for sequential treatment. Failure may occur if patient compliance or absorption of medication is poor. Some children may not be suitable candidates for sequential therapy because their parents are uncomfortable with caring for a young child with a serious infection at home. It can be difficult to give a young child multiple doses of oral antibiotics over a prolonged period.

An important consideration is the type of infection being managed. The prudent physician should first determine if there is sufficient experience in the literature to support the use of sequential antibiotic therapy for a given therapy. A summary of experience with different types of infection follows.

Bone and Joint Infections

Sequential therapy has been studied most extensively in the treatment of bone and joint infections. Staphylococcus aureus is the predominant cause of these infections in children, although other pathogens to consider in normal hosts include Streptococcus pneumoniae, Neisseria meningitidis, group A beta-hemolytic streptococcus, and KingeUa kingae. Hemophilus influenzae type b must be considered in the incompletely vaccinated child especially if younger than 12 to 15 months.

Successful treatment of bone and joint infections is likely if the oral antibiotic is well-tolerated, has good penetration into the bone and synovium, and thus attains concentrations manyfold greater than needed to inhibit growth of the infecting organism.2,4 As a result, sequential intravenous to oral antibiotic therapy has become widely accepted as appropriate care for treatment of uncomplicated bone and joint infections in children.

Pneumonia

Recent studies have demonstrated the efficacy of sequential antibiotic therapy in the management of children and adults hospitalized with communityacquired pneumonia.7'10 Most lobar pneumonia in children is caused by S pneumonia*; less common causes include S aureus, group A streptococci, and H influenzae type b in the incompletely immunized child. In two recent studies, children hospitalized with lobar pneumonia were treated initially with intravenous cefuroxime or ceftriaxone until they showed clinical improvement.7,8 Subsequently, they were switched to an oral cephalosporin and evaluated for signs of clinical failure. Cure was achieved in mote than 95% of patients. However, children were excluded if they had an empyema or abscess so it is not known whether sequential intravenous to oral antibiotic therapy is effective in the therapy of complicated pneumonia.

Other serious bacterial infections for which sequential treatment may be appropriate include bacteremia, soft-tissue infections, and pyelonephritis.11'13 Bacteremia

Table

TABLE 2Serious Bacterial Infections That Can Be Treated With Sequential Intravenous to Oral Antibiotic Therapy: Suggested Antibiotic Choices and Duration of Therapy

TABLE 2

Serious Bacterial Infections That Can Be Treated With Sequential Intravenous to Oral Antibiotic Therapy: Suggested Antibiotic Choices and Duration of Therapy

Bacteremia in children older than 3 months usually is caused by S pneumoniae·, N meningitidis and H influenzae type b are less common. Streptococcus pneumoniae bacteremia may be treated initially with parenteral ceftriaxone followed by oral antibiotic oSerapy. In most cases, children do not need to be hospitalized unless there is evidence of focal disease, central nervous system involvement, or progressive illness. Care must be taken to determine t_he susceptibility of S pneumoniae because strains resistant to penicillin and third-generation cephalosporins are becoming increasingly frequent. Vancomycin may be necessary for multiply resistant strains. Hemophilus influenzae type b bacteremia has been treated successfully with sequential intravenous to oral antibiotic therapy,11 and it is probable that some cases of bacteremia caused by N meningits is could be managed with oral antibiotics following initial therapy with parenteral penicillin or a cephalosporin.

Soft-Tissue Infections

Soft-tissue infections generally are caused by S aureus and group A streptococci. Uncomplicated soft tissue infections can be treated with oral antibiotics. More serious infections that warrant initial parenteral therapy include: deep tissue infections caused by group A streptococci; progressive infections of the hand; orbital and periorbital cellulitis; and some infections complicated by abscess formation. Once the infection is controlled and the patient is stable, a switch to an oral antibiotic may be appropriate.

Urinary Tract Infections

Most urinary tract infections can be treated with oral antibiotics. However, children who appear toxic or are very young should be hospitalized and initially treated with parenteral antibiotics. Once the child is afebrile and improving, a switch to an oral antibiotic based on urine culture may be appropriate. Escherichia coli are the most common bacteria infecting the urinary tract. Other organisms include other Enterobacteriaceae, enterococcus, and Pseudomonas aeruginosa in those with urologie abnormalities.

Table

TABLE 3Criteria for Switch From Intravenous to Oral Antibiotic Therapy

TABLE 3

Criteria for Switch From Intravenous to Oral Antibiotic Therapy

Bacterial infections amenable to sequential intravenous to oral antibiotic treatment are listed in Table 2 with recommendations for antibiotics and duration of therapy.

Although sequential therapy is used successfully in the management of a number of pediatric infections, there are fewer data to support sequential therapy for endocarditis, brain abscess, meningitis, or neonatal sepsis. Children with these infections may be more effectively managed with home parenteral therapy.

OPTIMIZING SUCCESS OF SEQUENTIAL ANTIBIOTIC THERAPY

In general, the switch from parenteral to oral therapy should be considered after defervescence and improvement of the signs and symptoms of infection. Several criteria must be met before a child can be considered a candidate for sequential antibiotic therapy (Table 3). There must be an acceptable oral antibiotic to replace the intravenous medication. The antibiotic selected may be the oral form of the intravenous preparation (eg, intravenous clindamycin changed to oral clindamycin), in the same class as the intravenous preparation (intravenous penicillin to oral amoxicillin), or in a different class (intravenous nafcillin to oral cephalexin). The selected oral antibiotic must be active against the suspected or proved infecting organism, well-absorbed, and attain serum and tissue concentrations severalfold higher than the minimum inhibitory concentration of the infecting organism.

Several oral antibiotics have bioavailability close to or equivalent to that of their intravenous counterparts. These include clindamycin, metronidazole, chloramphenicol, and ciprofloxacin. Other antibiotics with good oral bioavailability include trimethoprim sulfamethoxazole and erythromycin. Serum and tissue levels of many oral beta-lactam antibiotics are lower than those attained after intravenous administration (Table 4). Low serum levels may be overcome by increasing the usual oral dose of beta-lactam antibiotics two to three times die "normal" dosage.14 For example, 75 to 100 mg/kg/day of dicloxacillin and 100 mg/day of penicillin V, cephalexin, or amoxicillin are well-tolerated in patients treated for bone and joint infections. However, care must be taken when the usual dose of a beta-lactam antibiotic is increased. Some components of the drug may be increased safely while increases in others may cause significant adverse effects. For example, doubling or tripling the usual recommended dose of amoxicillin causes few adverse effects; however, an increased dose of clavulanic acid is associated with significant adverse effects.

Table

TABLE 4Peak Serum Levels of Antibiotics Commonly Used in Sequential Intravenous to Oral Therapy

TABLE 4

Peak Serum Levels of Antibiotics Commonly Used in Sequential Intravenous to Oral Therapy

Table

TABLE 5Medications That Alter the Bioavailability of Oral Antibiotics*

TABLE 5

Medications That Alter the Bioavailability of Oral Antibiotics*

An important determinant of the efficacy of outpatient antibiotic therapy is a child's acceptance of therapy. A child is more likely to be compliant if the antibiotic selected has relatively infrequent dosing and good taste.15,16 Palatability may be a stronger determinant of compliance than frequency of administration.17 In general, cephalosporin suspensions taste and smell better than penicillin suspensions, although Cefpodoxime proxetil and cefuroxime axetil reportedly have a bitter taste.17,18

The bioavailability of some antibiotics is influenced by interactions with concomitant medications (Table 5). Antacids decrease the bioavailability of a number of antibiotics including metronidazole, nitrofurantoin, and fluoroquinolones by decreasing absorption. Acetaminophen decreases the activity of chloramphenicol by increasing its metabolism. The list of all concomitant medications should be reviewed to prevent adverse interactions. Malabsorption of antibiotics is another reason for poor bioavailability. A child with persistent diarrhea, vomiting, or gastrointestinal abnormalities probably is not a candidate for sequential antibiotic therapy.

The optimal time to switch from parenteral to oral antibiotics is dependent on the child's clinical course. In general, the child should be afebrile, symptoms should have improved, cultures (if positive) should indicate the organism is sensitive, and surrogate markers of infection such as white blood cell count, sedimentation rate, or C-reactive protein should be returning to normal.

Following oral therapy and discharge, the child should be evaluated weekly to assure compliance, tolerance of oral medication, and continued clinical improvement. Laboratory tests that may predict therapeutic adequacy include C-reactive protein,19 sedimentation rate, and serum bactericidal titers. The serum bactericidal titer has been used most frequently in monitoring treatment of osteomyelitis and endocarditis. A good response for osteomyelitis has been associated with peak bactericidal titers >1:8 and trough titers 2*1:2.20,21 Families should be educated about the necessity of continuing therapy in a child who is almost back to normal.

HOME INTRAVENOUS ANTIBIOTIC THERAPY

Sequential intravenous to oral antibiotic therapy probably is not appropriate for children with endocarditis or other life-threatening infections. Successful treatment of these infections may require persistent high serum levels of antibiotics maintained over an extended time. Intravenous antibiotic therapy is necessary to achieve drug levels that result in rapid sterilization of the cerebrospinal fluid (CSF). The level of antibiotic achieved in CSF is only 3% to 30% of that achieved in serum, and this percentage decreases as inflammation within the central nervous system resolves.22

Even after CSF is sterile, children with meningitis should be observed for complications including increased intracranial pressure, seizure, stroke, or inappropriate antidiuretic hormone secretion. As a result, most patients with meningitis remain hospitalized until they complete antibiotic therapy. However, children with a good response, an uncomplicated course, and a reliable home situation may be candidates for outpatient antibiotics to complete the last few days of therapy.

Outpatient therapy for meningitis can be given intravenously at home or in the physician's office. For children in whom intravenous access is not possible, once-daily intramuscular ceftriaxone may be an option. Intramuscular ceftriaxone at a dose of 80 to 100 mg/kg/once daily achieves adequate CSF bactericidal levels, provided the child has normal peripheral perfusion23 and the infecting organism is susceptible.

Bacterial endocarditis also generally is treated with a full course of intravenous antibiotics administered in the hospital where close observation is possible. However, some children with endocarditis have a good response to initial inpatient antibiotic treatment and are able to receive at least a portion of their antibiotic therapy as outpatients. Early hospital discharge is more likely with infection by streptococcal species than S aureus, gram-negative organisms, or fungi. The latter tend to have more complications, necessitating closer observation.

A team approach to home intravenous therapy is desirable. The team could include a physician, home pharmacist, case manager, and visiting nurse. Parents must be willing and able to learn to care for the child's intravenous line, the correct storage of antibiotics, and manage the infusion pump. In some cases, arrangements must be made with a child's school, day care, or baby-sitter. Parents and caregivers should have good access to medical care, a telephone, a refrigerator, and ready transportation. The home infusion company used must have pharmacists and nurses experienced in pediatrics and should have appropriate accreditation.

Good intravenous access is necessary, and prolonged access may be especially difficult in children younger than I year. Heparin-locked peripheral intravenous catheters may be left in place for 72 hours and are appropriate for shorter courses of therapy. If duration is anticipated to be longer than a week, consideration should be given to placement of a percutaneous intravenous central catheter. Children who require many weeks of intravenous therapy may benefit from a central indwelling catheter. A variety of infusion systems are available. Sophisticated electronic programmable infusion pumps facilitate administration of antibiotics that require frequent administration while simple mechanical pumps are adequate for once- or twice-daily administration. Every effort should be made to simplify the regimen.

The use of outpatient parenteral antibiotics offers many of the same advantages to children and families as a switch from intravenous to oral therapy. In properiy selected cases, outpatient intravenous antibiotic therapy is safe, clinically effective, and cost effective. The cost savings varies widely, but there are direct and indirect cost benefits.24 Although home treatment still requires intravenous antibiotics, pumps, other equipment, and home nursing care, significant direct savings result compared with hospital care. Indirect benefits include ability to return to school, work, and a normal family life.

SUMMARY

Many children hospitalized with serious bacterial infections are candidates for either home oral antibiotic therapy or outpatient parenteral antibiotic therapy. Outpatient antibiotic therapy offers the potential for excellent medical treatment, reduced costs, and improved quality of life for ill children. However, cost considerations must not override good medical judgment. Certain children simply are not candidates for outpatient therapy because of the seriousness of their infection, poor compliance, lack of intravenous access, or poor social situation. In addition, although the few published studies to date all show that outpatient antibiotic therapy is effective, there is further need for properly designed clinical trials to evaluate the efficacy and safety of outpatient antibiotic therapy for serious bacterial infections in children.

REFERENCES

1. Grossman M, Applehaum MN. Demographics of community-acquired bacterial infection» in hospitalized children. Pediarr Infect Dis i. 1992;! 1:139-142.

2. Bryson Y], Connor JD1 LcClerc M, Giammona ST. High-dose oral dicloxacillln treatment of acute staphylococcal osteomyelitis in children. J Pediatr. 1 979;9f673-fS?5.

3. Rodrigue: W, Ross S1 Khan W et al. Clindamycin In the treatment of osteomyelitis in children. Am/ Dis Olili 1977;131:1088-1093.

4. Tetzlaff TR Jr1 McCracken GH Jr, Nelson JD. Ora! antibiotic therapy for skeletal Infections in children, II: therapy of osteomyelitis and suppurative arthritis. J Pediatr. 1978;92:485-490.

5. Orasele TH Jr, Paladino JA, Schentag JJ, et al. Clinical and economic impact of ora! ciprofloxacin as follow-up to parenteral antibiotics. Ami Pharmacoúyer. 1991 i25:857 862.

6. Mandel! LA. Bergeron MG, Gribble MJ, et al: Sequential antibiotic therapy: effec tive cost management and patient care. Canadian Journal of Infectious Diseases 1995i6:306.

7. Dagan R, Syrogiannopoulos G, Ashkenazi S, et al. Parenteral-oral switch in the man agement of paediatric pneumonía. Divi?. I994;47(supple 3):43-51.

8. Shalit I, Dagan R, Engelhard D, et al. Cefuroxime efficacy in pneumonia: sequential short-course IV/oral suspension therapy. 1st] Med Sd. 1994;30:684-689.

9. Vogel R Sequential therapy In the hospital management of lower respiratory infections. Am ; Med. I995;99(suppl 6B):14S-19S.

10. Ramirez J, Srinath L. Ahkee S, et al. Early twitch from intravenous to oral cephalosporins in the treatment of hospitalized patients wich community- acquired pneumonia. Attri Intern Med. 1995;155:1273-1276.

11. Bradley JS, Ching DK, Hart CL Invasive bacterial disease in childhood; efficacy of oral antibiotic therapy following short course parenteral therapy in non-central nervous system infections. Pediatr Infect Dis J. 1987;6:821-825.

12. McCarthy Pl, Grundy GW. Spiesel SZ, et al. Bacteremia in children: an outpatient clinical review. Pediatrics. 1976;56:861-868.

13. Baron MA, Fink HD. Bacteremia in private pediatric practice. Pediatrics. 1980*6:171-175.

14. Nelson JD. Options for outpatient management of serious infections. Pediatr Infect Dis J. 1992;! 1:175-178.

15. Cockbum J, Gibberd RW, Reid AL, Sanson-Fisher RW. Determinants of non-compliance with short-term antibiotic regimens. Br Med J. 1987;295:814-818.

16. Ruff ME, Schotik DA, Bass JW, Vincent JM. Antimicrobial drug suspensions: a blind companion of taste of 14 common pediatric drugs. Pediatr infect Dis ). 1991;10:30-33.

17. Dagan R, Shvareman P. Liss Z. Variation in acceptance of common oral antibiotic suspensions. Pediatr Infect Dis). 1994;13:686-690.

18. Démets DM, Chan DS, Bass JW Antimicrobial drug suspensions: a blinded comparison of taste of 1 2 common pediatric drugs including Cefixime, Cefpodoxime, cefprozil, and lorcarbef. Pediarr Infect Dis}. 1994:13:87.

19. U nkila-Kallio L, KaIlIo M, Eslcola J, Peltola H. Serum C-reacti ve protein, erythrocyte sedimentation rate, and white blood cell count in acute hematogenous osteomyelitis of children. Pediatrics. 1994;93:59-62.

20. Weinstein MP, Stratton CW, Hawley HB, et al. Multicenter collaborative evaluation of a standardized serum bactericidal test as a predictor of therapeutic efficacy in acute and chronic osteomyelitis. AmJ Met 1987:83:218-222.

21. Prober CG, Yeager AS. Use of the serum bactericidal titer to assess the adequacy of oral antibiotic therapy in the treatment of acute hematogenous osteomyelitis. J PedW. 1979;95:131-135.

22. Risruccia AM, LeFrock JL. Cerebrospinal fluid penetration of antimicrobials. Anofctot CriemoAer. 1992:45:118-152.

23. Bradley JS, Farhat C1 Stamboulian D, et al. Ceftriaxone therapy of bacterial meningitis: cerebrospinal fluid concentrations and bactericidal activity after intramuscular injection in children treated with dexamethasone. Pediatr infect Dis J. 1994:13:724728.

24. Balinsky W, Nesbitt S. Cost-effectiveness of outpatient parenteral antibiotics: review of the literature. AmJ Med. 1989;87:301-305.

TABLE 1

Infections Amenable to Sequential Intravenous to Oral Antibiotic Therapy

TABLE 2

Serious Bacterial Infections That Can Be Treated With Sequential Intravenous to Oral Antibiotic Therapy: Suggested Antibiotic Choices and Duration of Therapy

TABLE 3

Criteria for Switch From Intravenous to Oral Antibiotic Therapy

TABLE 4

Peak Serum Levels of Antibiotics Commonly Used in Sequential Intravenous to Oral Therapy

TABLE 5

Medications That Alter the Bioavailability of Oral Antibiotics*

10.3928/0090-4481-19961101-10

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