Sequential therapy in the hospital management of lower respiratory infections

Sequential Therapy in the Hospital Management of Lower Respiratory FRIEDRICH

VOGEL,

DR. MED.,

Hofheim,Germany

Conventional treatment for patients hospitalized with lower respiratory infections, such as pneumonia or bronchitis, typically consists of parenteral antibiotic therapy for 7-10 days. The clinical evidence, however, shows that in most patients the objective and subjective indicators of infection are substantially improved within the first 2 days of treatment. Thus, many of these patients can be switched to oral antibiotics after 2-3 days of parenteral therapy, with no loss in efficacy of treatment and with substantial savings in terms of cost of care and length of hospital stay. P-La&am antibiotics are a frequent choice for the oral component following short-term intravenous therapy. The results of recent, large-seale comparative clinical trials support the usefulness of this treatment approach, known as sequential therapy.

From the Medizinische Klinik, Klinlken des MaIn-Taunus-Kreises, Hofhelm am Taunus, Germany. Requests for reprints should be addressed to F. Vogel, M.D.. Kliniken des MawTaunus-Kreises, Llndenstrasse 10, D65719 Hofheim am Taunus, Germany.

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ower respiratory tract infections are among the most common bacterial infections and account for up to 30% of all antibiotic prescriptions written in the hospital and in the community at large.le3 In the current health economics environment, clinicians must consider not only the efficacy of antibiotic treatment but also how to administer it in a cost-effective manner?B The following discussion, while emphasizing the clinical aspects of treatment, also views therapeutic options from an economic perspective.

LIMITATIONS OF CONVENTIONALAPPROACHES One of the biggest problems in the hospital treatment of patients with lower respiratory infection is the absence of rapid diagnostic capabilities that could indicate immediately which patients would benefit from antibiotic therapy. Many respiratory infections have a viral etiology; but with current diagnostic tools it may take up to several days before the pathogen is identified. In fact, frequently, the causative agent is never isolated at all. Empiric antibiotic therapy is, therefore, the standard approach to treatment. Oral antibiotics generally suffice for the management of most mild-to-moderate severe respiratory infections. Parenteral antibiotic therapy is typically reserved for the more difficult eases, such as in patients with severe infection or underlying chronic disease. These patients need to be stabilized acutely with intravenous therapy; they often respond quickly and are well enough to be sent home after a brief hospital stay. Yet, they must remain in hospital in order to complete the requisite ‘i-10 day course of intravenous antibiotic therapy, Recognizing the high cost of these extended hospital stays, various centers in Europe and, to a lesser extent, in the United States have begun to adopt a regimen of relatively brief intravenous antibiotic therapy-no more than 2-3 days-followed by oral treatment. This approach is referred to as “sequential therapy” in t,his discussion, but it is also variously known as “switch therapy,” “follow-on therapy,” ‘(step-down therapy,” and “deescalation therapy.” The principle in each case is the same: if patients can be treated effectively with a short course of intravenous therapy and subsequently

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switched to oral antibiotics, then the length of hospital stay and overall cost of treatment can be reduced substantially without compromising clinical outcome.“‘4~”

TABLE I Antibiotics Used in Sequential Therapy

SEQUENTIALTHERAPY-TREATMENT OPTIONS Sequential therapy for lower respiratory infections embraces a broad range of treatment options. When a given antibiotic is available in both injectable and oral forms, the same agent may be used for both stages of treatment. On the other hand, if an antibiotic is available in parenteral but not in oral formulation, another drug of the same class or of a comparable spectrum may be substituted during the latter treatment stage. A few examples of the nnltny combinations reported in the literature are shown in Table I. Thus, there have been studies in which cefotaxime intravenous has been followed by cefuroxime axetiP or cefixime,“:’ as well as trials using ciprofloxacin,” co-amoxiclav,“?12 or cefuroxime l1 -all of which are available in both intravenous and oral forms. In other reported instances, antibiotics of different classes but covering the same spectrum are chosen, e.g., ceftazidime followed by ciprofloxacin to cover P~eudor~~~~ns infection.“’ Furthermore, the principles of sequential therapy are sufficiently flexible to manage differentially patients requiring lesser or greater degrees of acute intervention.]” A “stepped care” approach may be appropriate for patients with mild to moderately severe infections, who will receive parenteral antibiotics for f -3 days before being switched to an oral form of the same or comparable drug. For more severely infected patients, acute combination therapy, administered parenterally for 3 days, may be the first stage of treatment, followed by the described parenteral and oral phases of the steppedcare approach.”

RATIONALEFOR SEQUENTIALTHERAPY Clinical signs of a patient’s response to antibiot,ic therapy may be evident early in treatment, often within 24-48 hours. Indeed, if no such response is seen, a decision to alter or intensif\r treatment may be required. Correspondingly, from a microbiologic perspective, pathogens are likely to be present in greatest numbers during the early stages of infection; t,herefore, it could be beneficial to introduce therapy that would eradicate as many organisms as possible as early as possible. Both clinical and microbiologic evidence supports initial use of intravenous antibiotic therapy to ensure relatively rapid delivery of high concentrations of (Irug to the infection site. Moreover, acutely iii, febrile, or elderly patients may be unable to take December

Diierent Antibitic fV/PO

Same Antibiotic IV/PO Cefuroxlmeicefuroxime axetil

Cefotaximeicefuroxime axetll

Cephradlne

Cefotaxrme/cefixrme

Clprofloxaclo

Ampiul~n/sulbactwn/cwmax~clav

Co-amoxlclav

Ceftazldrme/crprotloxacrn

Doxycyclroe

Ceftriaxone-cephalexcn

Erythromycln EAetranldazole

food, which constitutes another argument in favor of initial injectable treatment.’ After a Z-3-day period of intravenous antibiotic therapy, most patients can be switched to oral treatment. By this time, the concentration of pathogens should be significantly reduced; the patient most likely is stabilized and quite possibly ambulatory and able to eat. With the switch to oral therapy, it may be appropriate and preferable for the patient to continue recovery at home. Indeed, it may be argued that the risk of nosocomial infection is reduced if the hospital stay is minimized. From the patient point of view, there are obvious advantages in terms of quality of life and return to normal activities; the benefits of reduced hospital stay may be especially evident in children.‘“*‘”

WHENTO SWITCHTO ORALTHERAPY One of the key decisions in sequential therapy is when to make the change to oral treatment. The decision is typically based on clinical parameters, and the switch is almost invariably made within 72 hours. In the published literature, 48 hours appears to be the preferred timing for changing from intravenous to oral treatment.“,” The following clinical criteria help assess the readiness of a patient for the switch to oral therapy: l There should be no clinical indication for continuing intravenous treatment. l The patient must be able to take oral medication, and so normal gastrointestinal absorption is required; patients with diarrhea would most likely be excluded. l The patient should be afebrile or at least almost so. l Other signs and symptoms of infection should be improved or resolved. Laboratory measurements may help support clinical observations’“? In patients with pneumonia, for example, white blood cell (WBC) count and C-reactive protein measures may be useful indieatorq. (Table II).“’

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TABLEII ClinicalCriteria for Parenteralto Oral Switch a No clinrcal indicabon for contrnuing IV therapy 4 No abnormal GIabswphon * Temperature returning to normal B Signs and symptoms related to mfecbon rmprovrng or resolved e WC and differential counts returning to normal * Cfeactve protein returning to normal

The utility of these decision-making concepts is demonstrated in two recent clinical studies. In a pediatric pneumonia study involving 87 children (mean age, 20.0 & 12.7 months), Shalit et al’” used WBC and temperature, along with chest radiographic findings, as clinical markers. They found that these parameters supported the change to oral antibiotic therapy at about 48 hours. All the children were febrile initially and had significantly elevated WBC. By day 2 of intravenous antibiotic therapy, >90% of patients had returned to normal temperatures, and mean WBC had fallen dramatically among those tested. The mean time to resolution of fever was 1.6 days, with an overall range of l-6 days. This range highlights the point that not all patients are necessarily candidates for the switch to oral therapy. In this study, patients were continued on intravenous treatment if the clinical response was not satisfactory. Chest radiography was performed initially and at follow-up but was

not considered sufficiently sensitive to serve as a determinant of when to switch to oral therapy. Overall, the findings of this study supported resolution of fever and lowered WBC as useful quantitative markers, at least in pediatric pneumonia. Another, larger study involved 627 adult patients with acute exacerbations of chronic bronchitis (data on file; Glaxo). The protocol called for initial intravenous treatment with cefuroxime, ‘750 mg two or three times daily, to be changed within 48-72 hours to oral treatment with cefuroxime axetil, 500 mg twice daily for 5-7 days. Clinical assessments were performed at pretreatment baseline, at changeover to oral treatment, at completion of oral treatment, and at 14-28 days following completion of treatment, The investigators sought both quantitative and qualitative markers to define the appropriate point for changeover to oral therapy. Cough, dyspnea, peak expiratory flow rate (PEFR), sputum quality, and temperature were among the parameters evaluated. Most patients were found to have improvement in PEFR measurements within the first 48 hours. Patients who had a low baseline PEFR (~250 L/min) showed the greatest improvement, with 45% of those with low baseline measurements demonstrating ~20% improvement with intravenous treatment. Mean PEFR for all patients improved from around 200 L/min at the pretreatment assessment to 250 L/min at the point of switch to oral therapy and to 283 L/min after completion of treat-

TABLEIll SequentialTherapy: Studieswith p-LactamAntibiotics Study Vogel etal.

1991r6

Active Ingredient Cefuroxime axetil

Strlle and Vogel, 1993l’

126

Brambilla et al, 1991”

Indication

Dose

Therapeutic success1%)

dnfections of Me airways *Urogendal infections *Skin/soft bssue lnfectrons

Zx5OOmg

Pneumonra

Zx5CQmg

98

93

tower resprratory tract rnfections

2 :< 500 mg

93

246

tower resprratory tract Infections

Zx500mg

91

154

Kohl, 1991’8

92

100 97

Shalrt et al, 1991r5

78

Pneumonia

Regnrer et ai, 1989a

47

Serious urinary tract rnfections

Zx200mg

74

tower respiratory tract infections

1 x 400mg

97

30 mg.kg

97

Vogel, 1993”

Cefrxime

100

Mbonda et al, 1992*’

Amprcillin Sulbactam

41

Amoxrcrllrn Clavulanrc acid

48

tower resprratoiy tract infectrons

3x625mg

94

33

tower resprratoiy tract infections

3 i: 625m.g

94

Vetgnenagne et ai, 198P Khafoba et al, 199022

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n

*lnfectrons 01the arrways #Urinary tract rnfectrons *Skin/soft trssue rnfecbons

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loo80-

Figure

1. Cirnrcal

response

therapy

with rntravenous

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axetrl,

cefotaxrme mostly

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in 305

at the trme of Intravenous

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40-

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Cured

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As-

Unchanged

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I

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ECCMID.“)

ment, and this improvement was maintained through the final follow-up assessment. Thus, PEFR measurement may provide a useful objective indicator of the efficiency of therapy in these patients. Marked improvements in dyspnea and cough were also seen at the time of switch to oral therapy, with approximately 86% of patients showing signs of resolution of these symptoms. As anticipated, temperature was a less useful marker with this population, compared with the pediatric pneumonia patients, as ‘5% of the patients in this study were afebrile at baseline.

EFFICACYOFSEQUENTIALTHERAPY The clinical efficacy of sequential therapy has been demonstratetl in a large number of studies. However, many of these studies concentrated on cost issues and did not involve large numbers of

patients. This discussion will focus on data from the largest of these studies, which had sufficient enrollment to provide statistical validation of efficacy and safety findings. /3-I,actam antibiotics have been among the most. widely used oral antibiotics in sequential therapy trials; Table III indicates the range of studies involving these agents. In most cases, a second- or third-generation cephalosporin was used as the initial intravenous component. Clinical efficacy is generally quite good, with a therapeutic success rate of XfO% in all but one of the studies. Miller and Hancock” recently reported findings from a comparative study conducted in the United Kingdom, in which 305 hospitalized patients (two thirds had respiratory infections) were randomized to receive either a full cour’~e of intravenous cefotaxime 1 g three times daily or sequential treatment with cefuroxime 750 mg intravenouslcefu-

Pneumonia

Figure

2. Post-treatment

clrnrcal

response

sequenhal therapy wrth Intravenous roxime followed by cefuroxime axebl, pared

wrth amoxicillrn

patrents

(n = 512)

pneumonra

or acute

bronchrhs.

From

Deteriorated

plus clavulanic

to cefucom-

acid,

hosprtalized

wtth erther

exacerbahons

of chronic

Eur J Clin Mrcrobrol

Bronchitis

in I

Cured/ improved

Failure I

Infect

Unevaluable

CXMKAE

Cured/ improved 0

Failure

Unevaluable

AmoxlCA

DIS.“)

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Response

before IV/oral switch

Response 1001

1001

m CXM tid (n = 322)

0

CXM bid (n = 305)

roxime axetil500 mg orally twice daily. An interim clinical assessment based on resolution of fever and bacteremia performed just before the switch t.o oral therapy (after an average of 3 days), found very similar responses at this point (Figure 1). Responses to the two regimens remained quite close at the post-treatment assessment. In another large comparative study of sequential therapy options, Brambilla et al” randomized 512 patients hospitalized with pneumonia or acute exacerbations of bronchitis either to amoxicillin plus clavulanic acid (1.2 g three times daily intravenous, followed by 625 mg twice daily orally) or to intravenous cefuroxime (750 mg three times daily) followed by cefuroxime axet.il (500 mg three times daily). The switch to oral drug occurred after 48-72 hours of intravenous therapy, and oral treatment continued for 5 days. Again, the post-treatment clinical response was very similar in both treatment groups (Figure 2). Bacterial clearance rates among patients with positive pretreatment sputum samples and drug-related adverse events were also comparable. Finally, as noted earlier, a recent multicenter study compared two and three times daily regimens of intravenous cefuroxime, followed after 48-72 hours by cefuroxime axetil, in >600 bronchitis patients (data on file; Glaxo). Most patients in both groups (94%) showed improvement at the point of change to oral therapy, and there was no difference in clinical response between groups at the point of change or at post-treatment assessment (Figure 3). These findings demonstrate that twice daily dosing of intravenous cefuroxime is comparable in efficacy to three times daily dosing and preferable from a cost standpoint.

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Figure 3. Cknrcal responses at the trme of Intravenous to oral switch (48-72 hours) and foilowrng completion of treatment In 627 European bronchitis patients receiving mtravenous cefuroxime, 750 mg either twice daily or three times daily, followed by oral cefuroxime axetil for 5-7 days (data on file; Glaxo).

CONCLUSION Patients recovering from lower respiratory and other infections find oral medication preferable to intravenous formulations. By switching to oral therapy as early as possible (according to clinical indications), local side effects such as phlebitis may be avoided, and patients may regain mobility more rapidly, which may in turn reduce the risks of nosocomial infection and thrombosis, as well as improve general well-being. From an economic perspective, the cost of parenteral antibiotics (including storage) is usually greater than that of oral antibiotics. More importantly, oral therapy requires less hospital staff time and, generally, a shorter hospital stay than parenteral therapy. In addition, the switch to oral therapy means reduced utilization of infusion equipment, resulting in less waste for disposal and further cost savings.‘““” The findings from numerous clinical studies demonstrate convincingly that sequential antibiotic therapy offers significant benefits to hospitalized patients and provides equivalent efficacy, compared with a full course of intravenous treatment.““-m”i Nevertheless, the decision to switch from intravenous to oral therapy is not predetermined and must reflect the careful clinical observations and judgment of the physician.

REFERENCES 1. Col NF, O’Connor RW. Estrmating worldwrde current antibtotic usage: report of Task Force. Rev Infect DIS 1987; 9 (Suppl3): S232-43. 2. Davey PG, Malek MM, Parker SE. Pharmacoeconomrcs of antibacterral treatment. PharmacoEconomrcs 1992; I: 409-37. 3. Townsend TR, Shaprro M, Rosner 8, Kass EH. Use of antirnrcrobial drugs in general hosprtals. Descrrotron of population and definition of methods. J Infect Dis 1979: 139: 688-97

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SYMPOSIUM ON RESPIRATORYTRACT INFECTIONS/VOGEL 4. Conly J, Low DE. intravenous to oral antrbtotrc stepdown therapy: rmproving the qualrty of care and reducrng costs. Can J Infect DIS 1995; 6 (Suppl A): 3A-5A. 5. Vogel F. A gurde to the treatment of lower resprratory tract mfections. Drugs 1995; 50: 62-72. 6. Miller A, Hancock F. Sequential therapy for srgnrfrcant infectron: a comparison of the efficacy, safety profrle and cost of rntravenous cefuroxrme followed by oral cefuroxrme axetil versus cefotaxime. (Abstr. 664.) 7th ECCMID. Vrenna, Austria, 1995. 7. Ducrorx JP, Martin F, Laurans G, Darchrs JP, Chrche D, Barllet J. Efficacy and tolerability of cefuroxrme IM followed by cefuroxrme axettl by mouth in the treatment of lung Infections acquired rn the communrty. (Abstr 278K18.1 1 lth RICA1 Paris, 5-6 December 1991. 8. Regnrer B. Etude comparattve du c&me en relais oral de la ceftrraxone rntraverneuse versus ceftnaxone seule dans le trartement des infections urmarres hautes severes. Presse Med 1989; 18: 1617-21. 9. Peyramond D. Leclerc P. Treatment of chronrc obstructrve pulmonary drsease iCOPD)-compartson of cefuroxrme (IM/PO) and ceftriaxone (IM) followed by cefixime PO. (Abstr. 324:94.1 5th International Congress for lnfecttous Diseases, Nairobi, Kenya, 1992. 10. Khan FA. Baser R. Sequential rntravenous-oral admrnrstratron of ciprofloxacrn vs ceftazrdrme in serious bactenal respiratory tract rnfectrons. Chest 1989; 96: 52% 37. 11. Brambrlla C, Kastanakis S, Knight S, Cunningham K. Cefotaxrme and cefuroxrme axetil versus amoxicrllrn plus clavulanrc acid in the treatment of lower respiratory tract infections. Eur J Clin Mrcrobiol Infect Dis 1992. 11: 118-24. 12. Kastanakrs S. A comparative study of amoxrcrllrn + clavulanrc acrd (IV then oral) versus IV cefuroxime followed by cefuroxrme axetil In the treatment of lower resprratory tract infections. (Abstr. 1817.1 17th lnternahonal Congress of Chemotherapy, 1991, Berlrn, Germany. 13. Jewesson PJ. Pharmaceutrcal, pharmacokrnetlc and other considerations for Intravenous to oral stepdown therapy. Can J Infect DIS 1995; 6 (Suppl A): 1 lA-6A 14. McCracken GH. New era for orally administered antibrotics: use of sequentral parenteral-oral antrbiotrc therapy for serrous infectious drseases of infants and chrldren. Pedratr infect Dis J 1987; 6: 951-3. 15. Shalrt I, Dagan R, Engelhard D, Ephros M, Cunnrngham K. Cefuroxrme efficacy rn pneumonra: sequentral short-course Iv/oral suspension therapy. Isr J Med Set 1994: 30: 684-9.

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16. Vogel F, Reetz K-P Muller TH. Oral follow-up therapy wrth cefuroxrme axebl rn the treatment of bacterral Infections in the clonic. lnfekt Klin 1991; 4: 3-14. 17. Strlle W, Kranz-Jansen M, Maass A-8, Vogel F. Sequential therapy of communrty acquired pneumonia: intravenous cefuroxrme versus intravenous cefuroxrme followed by cefuroxrme axetil in the treatment of prrmary pneumonrae. (Abstr. 1376.1 17th International Congress of Chemotherapy IICC), Stockholm, Sweden: 1993. 18. Kohl KF, Kohler CO. A multicentre clrntcal trral to compare antrbrobc regrme In patients with LRTl’s: cefuroxrme IV followed by cefuroxrme axetrl vs cefotaxrme IV. IAbstr. 1821.1 17th lnternatronal Congress of Chemotherapy, 23-28 June 1991, Berlin. 19. Vogel F. Parenteral cephalosponns for the treatment of lower resptratory tract rnfectrons. Clrnrcal experience wrth cefuroxrme. Infection 1993; 21 (SuppI Il. S2834 20. Mbonda E, Drease F, Genbelle F. Evaluation of the efficacy and safety of parenteral sulbactam/ampicilltn followed by oral sultamrcillrn for paedratrrc rnfectrons. Acta Ther 1992; 18: 301-6. 21. Vergnenegne A, Brambilla C, Sergnalet C, Bonnal C, Chrche D. Comparatrve study of cefuroxrme IV and oral with amoxrcillrn/clavulanate iv and oral rn the treatment of lower respiratory tract infection rn adults. (Abstr.1 Reunron lnterdrsciplrnarre de Chemotherapre anti-lnfectieuse, Pans, France 1991. 22. Khajotia R, Drlrcek M, Vetter N. A comparative study of ofloxacrn and amoxrcillrn/ clavulanate in hospttalrzed patients with lower resprratory tract infections. Aust J Antimrcrob Chemother 1990; 26 (SuppI D): 83-91. 23. Fisher FJ. The environment and sequentrai therapy w&h anbbrotrcs. Krankenhauspharmazre 1991; 12: 327-31. 24. Tanner DJ. Cost contarnment of reconstituted antibrotrcs: personnel and supply costs associated with preparahon, dispensrng and administrahon. Rev Infect DIS

1984; 6: S924-37. 25. LOUIS TJ. Intravenous to oral stepdown antrbiotrc therapy: another cost-effective strategy in an era of shrrnkrng health care dollars. Can J Infect DIS 1994; 5 (Suppl C): 4X-5oc 26. Nelson JD. Options for outpatient management of serious infections, Pediatr Infect Dis J 1992; 11: 175-8. 27. Raz R, Atar S, Schaeffer S. Rerchman N, Flatau E. The economic Impact of cefuroxime axeb following cefuroxrme intravenously in treatment of pahents wrth respiratory tract rnfecbon. (Abstr. 219.) 8th Mediterranean Congress of Chemotherapy, 24.-29 May 1992, Athens, Greece: 1992.

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