Beyond IV to PO switch therapy: Oral antimicrobial therapy

Issue: October 2015

ByBurke A. Cunha, MD, MACP

Traditionally, initial antimicrobial therapy for immediately life-threatening infections was administered intravenously. IV therapy has a rapid onset and delivers therapeutic blood/tissue levels in less than half an hour. Early in the antibiotic era, since the number of oral antibiotics available was limited and pharmacokinetic principles were just being applied to oral antibiotics, the notion that IV therapy was “more effective” than oral therapy became established. IV antibiotic therapy was preferred to oral therapy not only for critically ill patients but became the standard approach even for nonacute infections.

New antibiotics aside, the next advance in antimicrobial therapy was the introduction of IV to oral (PO) switch therapy. Those with a background in pharmacokinetics led the way forward for noninfectious disease physicians to follow. Patients in extremis with immediately life-threatening infections should, of course, initially be started on IV therapy, but after clinical defervescence, these patients may be switched to an equivalent oral antibiotic. If gastrointestinal (GI) absorption was adequate, and the patient was not critically ill, then oral antibiotic therapy was shown to be an equally effective alternative to equivalent IV therapy. Over time it became apparent that if an oral antibiotic has the same blood/tissue concentrations as its IV counterpart, then the therapeutic response with oral antibiotic therapy expectedly is the same as its IV counterpart. Currently, there are many oral antibiotics with good bioavailability that provide peak blood/tissue levels within 1 hour. Several antibiotics are available in IV and PO formulations, eg, doxycycline, minocycline, trimethoprim-sulfamethoxazole, levofloxacin, moxifloxacin and linezolid. Aside from the antibiotics mentioned, oral antivirals and oral antifungals with good bioavailability are useful in providing the same blood/tissue concentrations as their IV formulations, eg, voriconazole, fluconazole. Since acyclovir has poor bioavailability, Valtrex (valacyclovir, Glaxo-SmithKline) 1 g to 2 g PO every 6 hours to 8 hours provides equally effective treatment as IV acyclovir for herpes simplex virus/varicella-zoster virus.

Early in the IV to PO switch era, physicians would ask, “Which patients qualify for IV to PO switch therapy?” Over time, as clinicians became more comfortable with the many benefits of IV to PO switch therapy, the question was changed to: “Which patients should not be considered for IV to PO switch therapy?” Essentially, all noncritically ill patients with good GI absorption would benefit from oral vs. IV antibiotic therapy. The several advantages of IV to PO switch therapy are obvious. Pharmacoeconomically, early IV to PO switch therapy permits earlier discharge of the patient, decreasing patient length of stay (LOS). Decreased LOS not only improves patient satisfaction, but it also decreases exposure to nosocomial infections. Furthermore, oral antimicrobial therapy eliminates phlebitis and IV line sepsis, which have important legal and economic implications, not to mention medical complications. The estimated cost of phlebitis in the United States is $7,500 per episode, and for IV line sepsis, $15,000 per episode. These complications also increase LOS, which has to be factored into the economic impact on the health care system. Furthermore, PO therapy offers considerable economic savings over equivalent IV therapy. At the same dose, an IV antibiotic is more expensive than its oral equivalent, eg, levofloxacin — the only exception being linezolid, which costs relatively more orally than intravenously. Not only is the pharmacy acquisition cost of an oral antibiotic less at the same dosage than the IV formulation, but with oral antibiotics there is no additional cost of IV administration, which must be borne by the institution. The average cost of administering an IV antibiotic in the U.S. is approximately $10 per dose. Obviously, antibiotics that have a short half-life (t ½), eg, IV ampicillin (t ½ = 0.8 hours) should optimally be given every 4 hours. Therefore, the cost to the institution of administering IV ampicillin ($10 x 6 doses/day = $60) may exceed the pharmacy acquisition cost of ampicillin.

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It is clear that there are multiple benefits of oral antimicrobial therapy. The only question is why IV to PO switch therapy is not used more universally. The hesitation to use IV to PO switch therapy rests on preconceptions of IV antibiotics’ superiority or lack of pharmacokinetic (PK) background. Further successful experience should result in more widespread use of IV to PO switch therapy.

It has been well-shown in the treatment of community-acquired pneumonia (CAP) that early IV to PO switch therapy, ie, 3 days of initial IV therapy followed by 11 days of oral therapy was equivalent in efficacy and outcomes to 2 weeks of IV therapy. This should beg the question, “If 11 out of 14 days of oral therapy is as efficacious as 14 days of IV therapy, why wouldn’t 14 days of entirely oral therapy result in the same clinical effectiveness?” In medicine, preconceived ideas persist, and established habits die hard. Some physicians are reluctant to utilize oral therapy more extensively since their infectious disease background may not be in antimicrobial therapy or PK, and their reluctance to treat entirely with oral antibiotics is understandable.

Lack of understanding of PK principles often results in undue reluctance to treat orally. Leaders in the field of antimicrobial therapy are always ahead of the curve and keep pushing the envelope in using oral antibiotic therapy to treat serious systemic infections. For years, oral antibiotic therapy has been used successfully to treat serious systemic infections, eg, endocarditis, osteomyelitis, CAP. Just as it was early in the IV to PO switch era, as more confidence is gained in treating entirely with oral antibiotic therapy, it will become the norm rather than the exception. In this era of limited health care resources, oral antimicrobial therapy provides a powerful antibiotic stewardship tool to effectively treat patients in the most cost-effective manner, eliminating IV-related complications. Some oral antibiotics are being “revisited” as useful treatments against multidrug-resistant organisms, eg, oral minocycline has excellent activity against Acinetobacter baumannii and MRSA. The myriad uses of oral doxycycline for a wide variety of infectious diseases — including Q fever endocarditis, plague and neuroborreliosis — continues to be expanded.

Case reports should encourage others to extend their experience with oral antimicrobial therapy. As experience is reported, confidence is gained, and eventually large studies will demonstrate that oral antibiotic therapy is equivalent to IV therapy for many serious systemic infectious diseases. The clinician using oral therapy must understand the PK basis of oral therapy, and be sure that the oral antibiotic is equivalent to IV therapy in terms of spectrum/activity and blood/tissue levels. One should not be discouraged if oral therapy occasionally fails, as occasionally does IV therapy, for nondrug-related reasons, including undrained abscesses and device-associated infections. Published reviews, while still limited, should provide further encouragement to practicing clinicians that oral therapy is not only noninferior to IV therapy, but more importantly, oral therapy provides several key advantages. PharmDs and ID clinicians should lead the way in demonstrating to non-ID practitioners that oral antimicrobial therapy is equivalent to IV therapy. IV to PO switch therapy is the “low hanging fruit” of antibiotic stewardship programs, and antibiotic therapy entirely via the oral route is a natural extension of this concept. Effective blood/tissue levels are more important than mode of antibiotic administration. The widespread utilization of oral antibiotic therapy is hampered only by preconceived notions and lack of understanding of PK principles.

Suggested readings:
Al-Omari A, et al. Oral antibiotic therapy for the treatment of infective endocarditis: a systematic review. BMC Infect Dis. 2014;doi:10.1186/1471-2334-14-140.
Cunha BA. Oral antibiotic therapy of serious systemic infections. Med Clin North Am. 2006;90:1197-1222.
Cunha BA, et al. Haemophilus parainfluenzae aortic prosthetic valve endocarditis (PVE) successfully treated with oral levofloxacin. Heart Lung. 2015;doi:10.1016/j.hrtlng.2015.04.006.
Cunha CB, et al. Antimicrobial stewardship programs (ASPs): the devil is in the details. Virulence. 2013;doi:10.4161/viru.23856.
Escudero D, et al. Sequential drug therapy. Switching from the intravenous to the oral route. A good strategy for reducing catheter-related bacteremia? Med Intensiva. 2014;doi:10.1016/j.medin.2013.09.004.
Jones M, et al. Parenteral to oral conversion of fluoroquinolones: low-hanging fruit for antimicrobial stewardship programs? Infect Control Hosp Epidemiol. 2012;doi:10.1086/664767.
Quintiliani R, et al. Transitional antibiotic therapy. Infect Dis Clin Pract. 1994;3:161-167.
Ramirez JA, et al. Arch Intern Med. 2001;161:848-850.
Siegel RE, et al. A prospective randomized study of inpatient intravenous antibiotics for community-acquired pneumonia: the optimal duration of therapy. Chest. 1996;doi:10.1378/chest.110.4.965.

For more information
Burke A. Cunha, MD, MACP, is an Infectious Disease News Editorial Board member, chief of the infectious disease division at Winthrop-University Hospital, Mineola, N.Y., and professor of medicine at SUNY School of Medicine, Stony Brook, N.Y.

Disclosure: Cunha reports no relevant financial disclosures.