Antimicrobial Stewardship Program Perspective: IV-To-PO Switch Therapy

ANTIMICROBIAL STEWARDSHIP

Antimicrobial Stewardship Program Perspective: IV-to-PO Switch Therapy

CHESTON B. CUNHA, MD, FACP

INTRODUCTION tissue levels are the same PO as IV, outcomes are the same. In the past, initial antibiotic therapy was via the intrave- This most easily applies to IV and PO formulations of the nous (IV) route. Over the years, there has been increased same antibiotics, e.g., 100 mg of doxycycline IV/PO, 500 confidence and experience with oral (PO) antibiotic ther- mg levofloxacin IV/PO or 400 mg of moxifloxacin IV/PO. apy. The preferred antibiotics used for PO therapy are those Since serum/tissue time curves are the same, why not use with excellent GI absorption, i.e., high bioavailability (> PO antibiotic therapy whenever possible if outcomes are the 90% absorption).1,2 Given the pharmacokinetic (PK) and same?7,8 There are only two clinical scenarios where IV ther- pharmacodynamic (PD) properties of selected oral antibiot- apy may be preferred to PO therapy. Obviously, even when ics, there has been widespread acceptance of “transitional using antibiotics with high bioavailability (> 90%) effective- antibiotic therapy,” now known as IV-to-PO switch therapy. ness may be less if GI absorption is decreased. The other Early experience with this therapy demonstrated that some clinical situation is that of the “septic patient” who may or most antibiotic therapy in hospital could be transitioned succumb within an hour of initiating treatment. In this set- to PO following initial IV therapy.3,4 It became clear that ting, initial IV therapy is preferred.9-11 After clinical response patients treated with IV-to-PO therapy for common infec- to the initial IV antibiotic, its PO equivalent may then be tious diseases, e.g., community acquired pneumonia (CAP) used to complete/therapy. had comparable outcomes/cure rates to patients treated with entirely IV courses of antibiotics. Therefore, it became evi- IV-TO-PO SWITCH THERAPY dent that a key element of antibiotic stewardship programs USING THE SAME ANTIBIOTIC CLASS (ASP) is to support IV-to-PO switch therapy.4-6 Currently, The easiest IV-to-PO antibiotic switch therapy for various IV-to-PO switch therapy is a key component of ASP hospital infections is using antibiotics with both IV and PO formu- IV-to-PO switch initiatives. (Table 1) lation.12-16 Highly bioavailable PO antibiotics are clinically The basis of the interchangeability of IV and equivalent equivalent to their IV formulations. Commonly used anti- PO antibiotics is obvious, i.e., if, at any given dose, serum/ biotics with dose equivalent PO and IV formulations are presented with their respective bioavailabilities in tabular Table 1. Clinical and Pharmacoeconomic Advantages form. (Table 2) Since PO = IV, antibiotic regimens that begin of Oral Antibiotic Therapy

Advantages Comments Table 2. Bioavailability of Oral Antimicrobials Oral Lower antibiotic acquisition Avoid if markedly impaired Bioavailability Antimicrobials Antibiotic cost (at same dose) gastrointestinal absorption therapy Excellent Amoxicillin TMP Linezolid No IV antibiotic If therapeutic effect is (> 90%) Cephalexin TMP-SMX Tedizolid administration costs needed in < 1 h (patient Cefprozil Doxycycline Isavuconazole ($10/dose) in shock), begin therapy Cefadroxil Minocycline Voriconazole intravenously (IV) and Clindamycin Fluconazole Rifampin later switch to oral (PO) Quinolones Metronidazole Isoniazid to complete therapy Chloramphenicol Cycloserine Pyrazinamide Rapid gastrointestinal Good Cefixime Valacyclovir Ethambutol absorption (~ 1 h even in (60 – 90%) Cefpodoxime Famciclovir 5-Flucytosine critical ill patients) Ceftibuten Valganciclovir Posaconazole Eliminates phlebitis and IV Cefuroxime Macrolides Itraconazole line related infections Cefaclor (solution) Nitrofurantoin Nitazoxanide Decreases length of stay (with food) (LOS) Poor Vancomycin Cefdinir Nitazoxanide Patients pleased with earlier (< 60%) Acyclovir Cefditoren (without food) discharge Fosfomycin

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with an IV antibiotic may be switched to its PO equiva- preferable. Instead, the ratio of the MIC to achievable serum lent at any time during therapy, i.e., usually after clinical levels (drug serum levels can be found in chapter 11 of refer- response/defervesce or after 72 hours.17-20 ence 2) of different antibiotics must be compared. All other things being equal, the drug with a serum level of 20 mcg/ml and an MIC of 1 (20:1) is more active than one with an MIC GIVEN ANY DOSE, IV-TO-PO SWITCH of 0.5 mcg/ml and a peak serum level of 1.5 mcg/ml (3:1). USING ANTIBIOTICS FROM Another key concept to be aware of is the difference DIFFERENT ANTIBIOTIC CLASSES between in vitro susceptibility and in vivo effectiveness. IV-to-PO switch therapy using the same antibiotic, e.g., For example, TMP-SMX is in vitro susceptible to GAS and IV-to-PO levofloxacin is straightforward. However, if there MSSA/MRSA. Clinical experience has shown that TMP- is no oral formulation of a particular antibiotic, the ASP SMX is suboptimal against GAS and MRSA, but is excel- infectious disease (ID) clinician can advise which PO antibi- lent clinically against MSSA. Doxycycline is commonly otic will provide equivalent therapy. Often, a different class reported as MRSA susceptible. However, with MRSA soft of antibiotic is used at a different dose. For example, if ini- tissue abscesses, doxycycline frequently fails clinically. In tial IV therapy for an uncomplicated methicillin sensitive S. spite of susceptibility, its use creates its own inactivation/ aureus (MSSA) skin abscess is with cefazolin, then IV to PO resistance. For these reasons, minocycline is preferable to switch is best accomplished with cephalexin. Spectrum and doxycycline for MRSA.23-25 (Table 3) activity of both are comparable, but differ in PK/PD aspects. Comparing the peak serum levels after cefazolin IV dose of Table 3. Antibiotic-Organism Combinations for Which In Vitro 1 gram peak serum levels are ~185 mcg/ml. This is clearly Susceptibility Testing Does Not Predict In Vivo Effectiveness far in excess above the minimal inhibiting concentration Antibiotic “Susceptible” Organism (MIC) for MSSA, i.e., usually < 1 mcg/ml. Therefore, as long as serum levels exceed the MIC of MSSA, with an equally Penicillin H. influenzae, Yersinia pestis, active drug against MSSA, e.g., cephalexin (serum levels of VSE* 18 mcg/ml), PO therapy should be more than adequate (if TMP-SMX Klebsiella, VSE, Bartonella the skin abscess is not yet encapsulated requiring incision Polymyxin B Proteus, Salmonella and drainage in addition to antibiotic therapy). Other oral (2nd and 3rd generation) cephalosporins are less active than Imipenem Stenotrophomonas maltophilia cephalexin against MSSA, and for this reason (not PK/PD Vancomycin Erysipelothrix rhusiopathiae related), it is preferable to use cephalexin.2,21,22 Gentamicin Mycobacterium tuberculosis The same principle pertains in treating cellulitis due to group A streptococci (GAS) with initial ceftriaxone IV ther- Aminoglycosides Streptococci, Salmonella, Shigella apy. Since there is no PO formulation of ceftriaxone, an anti- Clindamycin Fusobacteria, Clostridia, Listeria biotic with a comparable anti-GAS spectrum and activity Macrolides P. multocida may be used. The MIC for GAS is lower than with MSSA, i.e., ~0.1 mcg/ml. Once again, cephalexin is preferred since 1st, 2nd generation cephalosporins Salmonella, Shigella, Bartonella a 1-gram (PO) dose results in peak serum levels of 18 mcg/ 3rd, 4th generation cephalosporins Listeria, Bartonella, MRSA† ml, more than sufficient to effectively treat GAS cellulitis. Quinolones MRSA†

†In spite of apparent in vitro susceptibility of antibiotics against MRSA, only ANTIBIOTIC SPECTRUM AND vancomycin, minocycline, quinupristin/dalfopristin, linezolid, tedizolid, daptomycin, ceftaroline fosamil, telavancin, dalbavancin, oritavancin, and tigecycline are ACTIVITY CONSIDERATIONS effective in vivo. Before initiating PO therapy, practitioners must be sure that *Effective penicillin therapy for systemic enterococcal infections due to VSE different class antibiotics (IV ~ PO) have the same spectrum requires an amino-glycoside, e.g., gentamicin. and a high degree of activity against the target pathogen. The Adapted from: Cunha CB. Overview if Antimicrobial Therapy. In: Cunha CB, PO drug equivalent need not achieve the serum level of the Cunha BA (Eds). Antibiotic Essentials (15th Ed). Jay Pee Medical Publishers, IV antibiotic, but serum levels should exceed the MIC of the New Delhi, 2017. pp 6 Effective in vivo antimicrobials for these organisms pathogen.2,4 can be found on pp 218-255 of this reference. The most difficult concept for non-infectious disease practitioners to comprehend is that antibiotic susceptibility ADVANTAGES OF ANTIBIOTIC PO THERAPY: is not the same as activity. Comparing the relative activ- BEYOND IV-TO-PO SWITCH ity of two different antibiotics, that are susceptible against Practitioners are slow to change practice habits. 2,4 Clinical the same organism, it is often believed in error, that the logic and reasoning should be considered while gaining the antibiotic with the lower MIC is more active and therefore confidence that comes from successful experience. Such is

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Table 4. Oral Antibiotic Therapy of Selected Infectious Diseases using PO therapy whenever possible. Risk of C. difficile is antibiotic specific and there is no difference in risk whether Acute infections Subacute/chronic infections the IV or PO route is selected. However, many PO options, Anthrax Q fever e.g. doxycycline, are C. difficile protective. In short, entirely Plague Brucellosis PO antibiotic therapy for nearly all outpatient and inpatient infections (non-septic) is clinically equivalent and preferred Tularemia Leptospirosis for the above reasons to IV therapy.2-6 Rocky Mountain spotted fever Nocardia As experience increases, confidence in entirely PO anti- (RMSF) biotic therapy will become as established and accepted as Typhoid fever Actinomycosis the PO component of IV-to-PO switch therapy. In ASPs, oral Legionnaire’s disease Meliodosis therapy is to the natural extension of antibiotic IV-to-PO switch therapy. Diphtheria Bartonellosis Vibrio vulnifcus Lung abscesses†

Cholera Liver abscesses† References 1. Cunha CB. In: Principles of Antimicrobial Stewardship. 2017; Clostridium difficile Intraabdominal abscesses† pp. 1-8. 2. Cunha CB, Cunha BA. (Ed.) Antibiotic Essentials 15th Ed. Jay Pneumocystitis (jiroveci) Pelvis abscesses† Pee Med Pub New Delhi 2017. carinii pneumonia (PCP) 3. Sensakovic JE, Smith LG. Oral antibiotic treatment of infec- Malaria Renal abscesses† tious diseases. Med Clin N Amer 2001;85:115-23. 4. Cunha BA. Intravenous to oral antibiotic switch therapy. Drugs Lyme disease Sinusitis Today 2001; 37:311-19. (neuroborreliosis, myocarditis) 5. Cunha BA. Oral Antibiotic Therapy of Serious Systematic Infec- Febrile neutropenia Pyelonephritis tions. Med Clin N Am. 1197-1222, 2006. 6. Quintiliani R, Nightingale CH. Transitional antibiotic therapy. Nosocomial pneumonia Prostatitis Infect Dis Clin Practice 1994;3(Suppl):161-7. 7. Nightingale CH, Grant EM, Quintiliani R. Pharmacodynamics Acute bacterial endocarditis in Complicated skin/soft tissue and pharmacokinetics of levofloxacin. Chemotherapy. 2000; IVDAs (MRSA) infections (cSSSI) 46:6-14. Osteomyelitis 8. Siegel RE, Halpern NA, Almenoff PL, et al. A prospective ran- domized study of inpatient intravenous antibiotics for com- Pulmonary and extrapulmonary TB munity-acquired pneumonia: the optimal duration of therapy. Chest 1996;110:963-71. † may also require abscess drainage 9. Altemeier WA, Culbertson WR, Coith RI. The intestinal absorption of oral antibiotics in traumatic shock: an experimental the case with entirely PO antibiotic therapy, i.e., if IV-to-PO study. Surg Gynecol Obstet 1951;92:707-11. switch is good (and it is), PO only is even better!5,6 (Table 4) 10. Power BM, Forbes AM, van Heerden PV, et al. Pharmacokinet- Antibiotic PO only therapy is the next step beyond ics of drugs used in critically ill adults. Clin Pharmacokinet 1998;34:25-56. IV-to-PO switch therapy. If with CAP, after initial 3 days of 11. Rebuck JA, Fish DN, Abraham E. Pharmacokinetics of intrave- IV therapy and the next 11 days (total therapy IV/PO = 14 nous and oral levofloxacin in critically ill adults in a medical days) PO only therapy is not inferior to 14 days of IV therapy. intensive care unit. Pharmacotherapy 2002;22:1216-25. Excluding immediate life threatening infection, it is not a 12. Cunha BA. Oral or intravenous-to-oral antibiotic switch therapy for treating patients with community acquired pneumonia. Am great leap of faith to treat for the full course entirely with a J med 2001;111:412-13. PO antibiotic. Antibiotic PO therapy, using antibiotics with 13. Ramirez JA, Bordon J. Early switch from intravenous to oral an- high bioavailability > 90%, e.g., levofloxacin, moxifloxacin, tibiotics in hospitalized patients with bacteremic community doxycycline for PO therapy should be used as often as pos- acquired Streptococcus pneumoniae pneumonia. Arch Intern Med 2001;161:848-50. sible for CAP. Entirely PO therapy results in shorter LOS 14. Cunha BA. Doxycycline for community acquired pneumonia. and earlier discharge. The patient goes home earlier and is Clin Infect Dis 2003;37:870. not burdened by home IV therapy and eliminates IV asso- 15. Torres A, Muir JF, Corris P, et al. Effectiveness of oral moxi- ciated phlebitis or IV line infections. Furthermore, as with floxacin in standard first line therapy in community acquired pneumonia in community acquired pneumonia. Eur Respir J IV-to-PO therapy, the cost of PO antibiotic therapy is mark- 2003;21:135-43. edly less than for equivalent IV therapy. Antibiotic cost is 16. Cunha BA. Oral antibiotics to treat MRSA infections. J Hosp always much lower PO (except with linezolid) than IV (at Infect 2005;60:88-90. the same dose). There are no IV administration costs (which 17. Cunha BA. Empiric therapy of community-acquired pneumonia: guidelines for the perplexed? Chest 2004;125:1913-19. may exceed the cost of the IV antibiotic) with PO therapy. 18. Cunha BA. Empiric oral monotherapy for hospitalized patients While certain PO medications may result in GI upset, this is with community acquired pneumonia: an idea whose time has usually manageable and should not dissuade providers from come. Eur J Clin Microbiol Inf Dis 2004;23:78-81.

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19. Hoelken G, Talan D, Larsen LS, et al. Efficacy and safety of se- Author quential moxifloxacin for treatment of community-acquired Cheston B. Cunha, MD, FACP, Assistant Professor of Medicine, pneumonia associated with atypical pathogens. Eur J Clin Mi- crobiol Infect Dis 2004;23:772-775. Alpert Medical School of Brown University; Medical Director, 20. Marrie TJ, Lau CY, Wheeler SL, et al. A controlled trial of Antimicrobial Stewardship Program (Rhode Island Hospital and critical pathway for treatment of community-acquired pneu- Miriam Hospital), Providence, RI. monia. CAPITAL study investigators. Community-Acquired Pneumonia Intervention Trial Assessing Levofloxacin. JAMA Correspondence 2000;283:749-55. Cheston B. Cunha, MD, FACP 21. Kucers A, Crowe SM, Grayson MI, et al. (eds.) The use of antibi- Division of Infectious Disease th otics. 5 Ed Oxford: Butterworth-Heinemann; 1977. Rhode Island Hospital 22. Bryskier A (Ed.) Antimicrobial agents. Washington (DC); ASM 593 Eddy Street Press; 2005. Physicians Office Building Suite # 328 23. Cunha BA. Minocycline, often forgotten, but preferred to tri- methoprim-sulfamethoxazole or doxycycline for the treatment Providence, RI 02903 of community acquired methicillin-resistant Staphylococcus 401-444-4957 aureus skin and soft tissue infections. Int J Antimicrob Agents Fax 401-444-8179 42:497-499, 2013. [email protected] 24. Cunha BA. Minocycline versus doxycycline for methicillin-resistant Staphlococcus aureus (MRSA): in vitro susceptibility versus in vivo effectiveness. Int J Antimicrob Agents. 35:517- 518, 2010. 25. Cunha BA, Baron J, Cunha CB. Similarities and differences between doxycycline and minocycline: clinical and antimicrobial stewardship considerations. Eur J Clin Microbial Infect Dis 37: 15-20, 2018.

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