Sequential antibiotic therapy for cost containment in the hospital setting: why not?

Journal of Hospital Infection (2001) 48: 249–257 doi:10.1053/jhin.2001.1006, available online at http://www.idealibrary.com on

REVIEW

Sequential antibiotic therapy for cost containment in the hospital setting: why not? M. Lelekis* and I. M. Gould† *Special Infections Unit,The General Hospital of Athens “G. Gennimatas” and †Medical Microbiology, Royal Infirmary, Aberdeen

Summary: Antibiotic cost represents a significant part of hospital budgets all over the world. Restriction policies, however and other similar programmes intervening in antimicrobial prescribing have not always been successful in lowering antibiotic expenditure. Timely switch or sequential therapy from initial intravenous to subsequent equivalent oral treatment has been implemented in many institutions for the same purpose. Using strict criteria for optimum patient selection, switch therapy has been proven both effective as antimicrobial treatment and cost saving. As healthcare resources remain lower than needed, cost-saving policies become very desirable. Thus, switch therapy is expected to be more widely used, since it is a cost containing policy which does not compromise treatment outcome. © 2001 The Hospital Infection Society

Keywords: Switch therapy; effective; cost saving.

Introduction In the era of rising healthcare costs and limited healthcare resources, antibiotic cost represents a significant part of hospital budgets. Despite the efforts, however, that have been made to lower antibiotic expenditure, the experience of the last decades shows that this is a very difficult goal to achieve. Thus, in a survey some years ago,1 maintenance of an antibiotic formulary did not result in cost savings in most responding US and Canadian institutions, while even in hospitals where aggressive programmes to monitor and intervene in antimicrobial prescribing have been implemented, there are data to suggest that these efforts were not always successful.1,2 A policy that has been used for antibiotic cost saving in the hospital setting is ‘sequential’ antibiotic therapy.3,4 This term is used to describe the conversion of parenteral (i.v.) antibiotic treatment to oral with the same medication. Another relative Author for correspondence: Dr I. M. Gould, Department of Microbiology, Aberdeen Royal Infirmary, Forester Hill, Aberdeen AB9 2ZB, UK. E-mail: [email protected]

0195-6701/01/040249;09 $35.00/0

term is ‘switch’ therapy, which generally refers to replacing parenteral therapy with oral therapy of the same therapeutic class. In fact, these two terms are often used interchangeably, because they are both based on the principle that the alternative oral therapy has comparable therapeutic efficacy. Another term that has been used for the same policy is ‘stepdown’ therapy. This term however implies conversion to treatment, which is not therapeutically equivalent and should best be avoided.4

Principles of oral switch In the ideal case, the patient is initially administered i.v. antibiotic treatment and early enough, after improvement is noted, the treatment is converted to oral. Provided that the selection of the initial i.v. therapy is appropriate, it is reasonable to consider that the best option for subsequent oral treatment is the oral formulation of the same drug. If such a formulation does not exist and the pathogen is still unknown, the oral treatment should cover the same spectrum as the i.v. treatment.5–7

© 2001 The Hospital Infection Society

250

M. Lelekis and I. M. Gould

However when switching to oral treatment alternatives fall into four groups:7

Table I Absorption (%) of the oral formulation for drugs existing in both formulations

(1) Oral formulation is the same drug and has 950% oral absorption (2) Oral formulation is a different drug and has 950% oral absorption (3) Oral formulation is the same drug but has unreliable (:50%) absorption (4) Oral formulation is a different drug and has :50% absorption.

Antibiotic

It is obvious that option No 1 is the best and option No 4 the worst. There is debate about ranking of the intermediate alternatives. Thus some investigators give priority to drugs with good gastrointestinal absorption and would prefer a different but equivalent antibiotic with this property to an unreliably absorbed oral formulation of the same antibiotic. This is the case for one hospital, which has already included switch therapy in their overall antibiotic policies.7 In one of their studies, out of 24 bacteraemic patients switched to oral therapy, 10 (41.7%) were switched to a different drug class (nine from i.v. ␤-lactam or ␤-lactam with aminoglycoside combinations to oral ciprofloxacin and one from i.v. vancomycin to oral clindamycin). The reasons for preferring ciprofloxacin to an oral ␤-lactam included more reliable absorption (in comparison with cefuroxime axetil) and more reliable activity against Gram-negative bacteria before the results of susceptibility testing were known (in comparison with co-amoxiclav).7 In any case, if positive culture results are available, they may help in rationalizing the treatment. Nowadays there are many antibiotics, with both oral and i.v. formulation that can be used for sequential therapy. These antibiotics include aminopenicillins with or without a ␤-lactamase inhibitor, clindamycin, macrolides, imidazoles, oxazolidinones, fluoroquinolones, cephalosporins etc. In Table I are examples of gastrointestinal absorption for some of these drugs. In addition, there are some other antibiotics with interesting pharmacokinetic and/or antibacterial profiles that can be useful when switching to oral treatment. Some of them are presented in Table II. Rationale for oral switch and benefits of oral treatment The rationale for sequential antibiotic therapy is that intravenous treatment is much more costly

Absorption (%) of oral formulation

Levofloxacin Ofloxacin Ciprofloxacin Metronidazole Clindamycin Cotrimoxazole Ampicillin Amoxicillin Ampicillin-sulbactam Co-amoxiclav Flucloxacillin Cefuroxime Clarithromycin Erythromycin Trimethoprim

9958 85–959 70–85*8 9958 75–908 9958 408 50–7010 98011 ⬇6011 96010 40–50** 8 52–5512 50–808 99013

*Absorption must be taken into consideration when converting from i.v. to oral (i.e. ciprofloxacin 400-mg i.v. q 12 h should be converted to 500-mg p.o. q 12 h); **Absorption increases when administered with food. Table II

Oral antibiotics useful for switch therapy

Antibiotic Cephradine Cefaclor Cefpodoxime proxetil Cefetamet pivoxyl Ceftibuten Cefixime Azithromycin Doxycycline

Bioavailability (%) 99014 99015 40–65*14,16 ⬇50*16 ⬇6516 20–5014,16 408 80–9517

*Absorption increases when administered with food.

than oral, has significant adverse reactions and is not always superior to oral treatment in terms of efficacy.8 Indeed the main obstacle limiting its implementation is the notion that i.v. antibiotics are better than oral ones.18 Another misconception is that all infections need parenteral treatment. Better understanding of antibiotics’ properties such as pharmacokinetics and pharmacodynamics has shown that antibiotic potency is not dependent solely on the route of administration. For antibiotics like ␤-lactams, studies have shown that the best predictor, in terms of bactericidal activity and clinical efficacy, is the time during which drug concentration is greater than the MIC (T9MIC). This time should be at least 25–30% and 25–40% of the dosing interval for penicillins and cephalosporins

Sequential antibiotic therapy for cost containment in hospital setting: why not?

respectively, depending on the bacterial species causing the infection, in order to achieve bacteriostatic effect, which in the absence of leukopenia is usually sufficient for a favourable clinical result.19 Higher peak concentrations, easily achieved by i.v. administration, do not give greater clinical benefit for most infections, as they do not provide significantly more bacterial killing. The knowledge of this principle of ‘time over the MIC’ allows the clinician to select appropriate oral dosage and administration frequencing, in order to have effective oral treatment. In contrast to the time over the MIC principle, quinolones exhibit concentration-dependent killing. Forrest and co-workers20 found that the ratio of the 24-h area under the curve (AUC) to the MIC (AUIC) was the best parameter in determining efficacy in patients treated with i.v. ciprofloxacin. A ratio of 125 or greater was associated with clinical and bacteriological response rates greater than 80%. Values below 125 resulted in less than 50% efficacy in both clinical and bacteriological response. A value of 125 meant that the average concentration over 24 h should be slightly above five times the MIC. These values are virtually equivalent when comparing the 24-h AUIC ratios for standard i.v. and oral doses of ciprofloxacin and ofloxacin.21,22 Thus, it may be concluded that if an antibiotic is given orally in an appropriate manner, has good gastrointestinal absorption and provides blood and tissue levels equivalent to those attained by i.v. administration, then no difference in terms of therapeutic efficacy should be expected.8,23 Compared with oral treatment, cost and more significant adverse reactions are well-known disadvantages of intravenous treatment.8,24,25 There are many studies showing that the total cost of intravenous treatment with an antibiotic, including acquisition and administration cost, is much higher than that of the oral treatment with the same or equivalent antibiotic.7,26–30 Furthermore, phlebitis which appears in almost 70% of intravenous courses and infections due to i.v. lines very often prolong patient hospitalization and increase indirectly the total cost of treatment as well as causing patient major discomfort.24,25 On the other hand, oral treatment is more convenient to both patients and personnel, easy to administer and very well accepted by the patient since there is no need to be confined to his bed or even hospital.8 In the last PHLS survey, i.v. catheters were the most common source of hospital-acquired bacteraemia accounting for 38% of all such cases and for over 50% of bacteraemias

251

of known source.31 At this point, it is worth noting that there is a worldwide misuse of intravenous cannulae. In fact in many cases putting an i.v. cannula has become part of the admission procedure. The existence of i.v. access is believed to promote the unnecessary i.v. use of medications including antibiotics.32,33 In conclusion, there are three main benefits associated with the use of sequential treatment: economic benefits, patient benefits and benefits to the healthcare provider.26 Development and implementation of switch therapy There are several factors which can influence the development of programs promoting sequential therapy (Table III). A parameter that facilitates the implementation of cost-saving policies such as sequential therapy is the shift of the primary method of reimbursement for hospitalization expenses, from a ‘fee for service’ environment, to a prospective payment. In fact this is now the case for most states in USA and other countries of the world as well.4 In the first way of payment, reimbursement is based on charges submitted by the treatment facility and there is little incentive to minimize costs associated with patient care. Furthermore intravenous therapy was often used to ‘justify’ hospitalization to third-party payers. In the second way of ‘managed care’, reimbursement is based on diagnosis, often at a fixed or pre-negotiated price. In this case, cost saving including early patient discharge is highly desirable.4 Table III Factors influencing the development of programmes promoting timely sequential antimicrobial therapy in the USA4 Positive influences Publication of consensus statements regarding antimicrobial prescribing Increases in antimicrobial expenditures despite formulary management Success of similar programs in the published literature Availability of clinical trials supporting favourable clinical outcomes Growth of pharmacoeconomics Computer technology Availability of potent antimicrobial agents with favourable oral bioavailability Growth of clinical pharmacy practice Negative influences Lack of data regarding bioavailability of select oral antibacterials in hospitalized patients Lack of efficacy data in selected patient populations (e.g. paediatrics)

252

M. Lelekis and I. M. Gould

In hospitals where sequential antimicrobial therapy programmes are particularly successful, they are usually developed jointly by the infectious disease and pharmacy departments working in conjuction with the Pharmacy and Therapeutics Committee. The introduction of such a programme is sometimes a difficult task and requires the existence of an appropriate infrastructure.26 This infrastructure can be established with the collaborative efforts of members of the pharmacy, microbiology, infectious disease, nursing and administration department. Sometimes there is resistance to change on the part of medical staff; a perceived increase in workload by those involved in the sequential antimicrobial therapy programme and reluctance due to medical or legal concerns. These problems can be solved by using the above-mentioned infrastructure and by educating personnel.26 In fact, face-to-face meetings and education seems to have the greatest effect on influencing antibiotic prescribing behaviour, whereas group meetings have the smallest impact.34 Non-confrontational educational methods are the best received but

are often transient in benefit. Therefore most successful programmes use a combination of strategies.4 In practice, the promotion of switch therapy can be achieved by different ways. A simple as well as inexpensive way is the use of sequential antimicrobial therapy reminders which are highly visible printed forms with the necessary information on them.26 This was the case for the Vancouver Hospital and Health Sciences Centre which implemented a successful switch therapy programme involving first clindamycin and metronidazole and subsequently fluconazole, cefuroxime and ciprofloxacin.35 However, the complete model of the implementation of such a strategy is illustrated in Figure 1 which represents the implementation pathway for switch therapy in Dundee Teaching Hospitals.34 Following the establishment of a policy such as switch therapy, formal audit should be carried out at regular intervals with the results disseminated to all concerned. An audit in six hospitals of four NHS trusts in Tayside revealed that i.v. to oral switch occurred at the appropriate time in 82% of

Switch Therapy (ST) Implementation

Outcome - clinical - economic

Development of Multidisciplinary Group

Guidelines

Pharmacist

Clinical decision makers

Verbal 'stickers' 'fliers'

Automatic stop order

Support of hospital: leadership

Figure 1

Flow chart for implementation.

Antibiotic prescription chart

Sequential antibiotic therapy for cost containment in hospital setting: why not?

368 patients and 528 prescriptions reviewed. In the remaining 18% a delay in oral switch by a median of 1 day was recorded and this was attributed to a reluctance by junior staff to change to oral treatment before the next consultant ward round or at a weekend.32 A key element in the audit of switch therapy is accurate and complete clinical case records. However audits at Dundee Teaching Hospitals showed that the indication for antibiotic use was recorded only in 30–60% of case notes. The situation improved after the dissemination of these results to Clinical Directors.7 Which patients After the publication of Quintiliani et al.30 that laid the foundations for the scientific approach to switch therapy and formalized the whole process, a great deal of experience has been accumulated. In this extensive international experience it was clearly shown that appropriate patient selection and monitoring is the cornerstone for the success of such a policy.36–42 Not all patients with infectious diseases are suitable for sequential antibiotic treatment. Furthermore the potential cost for the management of possible treatment failure is much greater than the money saved with sequential treatment.7 In general, the following patients are not considered candidates for such treatment:8 1. Patients on nil by mouth (risk of aspiration, need for complete bowel rest, gastrointestinal obstruction, pre- or post-operative fast) 2. Patients with an unreliable response to oral medication (severe nausea/vomiting, continuous nasogastric suction, malabsorption syndrome, motility disorder of the gastrointestinal tract, unresponsive to previous oral therapy, short bowel syndrome) 3. Patients whose disease state or infection does not permit conversion (e.g. high-risk neutropenia, meningitis, endocarditis etc) The programme to promote timely sequential antimicrobial therapy at Duke University Medical Center (Durnham, NC, USA) has been conducted by clinical pharmacists serving the various patients care units throughout the hospital. All patients receiving parenteral antimicrobial therapy are reviewed for eligibility.4 The criteria for patient selection were developed after multidisciplinary collaboration (Pharmacy, Infectious Diseases, Infection Control, Microbiology, Surgery, Paediatrics and Obstetrics and Gynaecology). These criteria are shown in Table IV.4

253

Table IV Criteria used to consider patients eligible to receive oral antimicrobial therapy at Duke University Medical Center. All criteria must be satisfied (1) Infectious indications requiring parenteral antibacterial or antiviral antibiotics are absent.These indications include: empiric or targeted antibacterial therapy for fever in patients with neutropaenia or who are significantly immunocompromized, meningitis, osteomyelitis, endocarditis, septic shock, or disseminated viral illness such as herpes virus infection (2) Infection for which the antibiotic is prescribed, is not presently considered serious or life-threatening according to physician’s assessments (3) Signs and/or symptoms of infection are improved or have resolved according to physician’s assessments (4) Patient is afebrile (Tmax-37.9°C) or has had consistent improvement in fever over a 24-h period (5) White blood cells are normalizing (if repeated measurements are available) (6) Gastrointestinal absorption of drugs is likely to be normal (absence of vomiting or abnormal GI anatomy) (7) The patient is able to receive enteral therapy (orally or through gastric feeding tubes) as evidenced by concomitant enteral medications or nutrition

The criteria used for patient selection in different studies are not the same. In a recent study by Sevinç et al.41 the criteria were that the patient should satisfy all of the following:







At least 48–72 h of previous i.v. treatment. The patient should be haemodynamically stable, his condition should be improving with a trend towards normalization of the body temperature and the peripheral leukocyte count. Availability of an oral antibiotic which could provide adequate levels in the site of infection. Patient able to take oral medication with functioning gastrointestinal tract and no signs of malabsorption.

Using these criteria, patients with meningitis, intracranial abscesses, endocarditis, mediastinitis and other equally severe infections were excluded from sequential therapy. A significant saving of money was achieved with this policy, without relapse of the infection in the two-month period following treatment. Costs In many studies like this one and using similar criteria for patient selection, switch therapy has been proven both effective and cost saving.4,26,37,42–44 Furthermore, since oral treatment allows early

254

patient discharge, another advantage of sequential therapy is the ability for shortening hospital stay.45–49 In terms of estimating cost containment with sequential therapy, the trials performed have used different approaches. Using the simple and inexpensive way of sequential treatment reminders, the Vancouver General Hospital achieved cumulative cost savings of US$31 920 concerning metronidazole and US$53 880 concerning clindamycin from 1988–1991, taking into consideration only the acquisition, preparation and delivery cost for the antibiotic.35 In other more sophisticated trials, the cost containment reported included the savings from the shortened hospital stay too. In a prospective, controlled, randomized study in 50 patients with Gram-negative bacteraemia, sequential treatment with i.v. oral ciprofloxacin compared to i.v. treatment alone resulted in overall considerable savings (US$46 000–78 000).49 In a double-blind randomized clinical trial in patients with intra-abdominal infections50 sequential i.v. to oral treatment with ciprofloxacin plus metronidazole was cost-effective compared with full i.v. course with the same antibiotics or imipenem-cilastatin. In patients unable to receive oral treatment, no difference in mean cost was found between i.v. imipenem or i.v. ciprofloxacin plus metronidazole. The mean cost of a patient on sequential therapy was estimated to be US$7678 and on full i.v. treatment US$8774 (P:0.029). In a study of switch therapy in children with severe lower respiratory tract infections in N. Ireland, the overall savings per patient on switch therapy was estimated to be £1296 (antimicrobial costs £26.40; laboratory costs £8.60; hospital bed costs £1261).51 Concerning cost containment from early discharge, there are some issues that remain to be clarified. While it is obvious that early discharge has a beneficial impact on hospital cost and it may shorten hospital waiting lists, further studies are needed to measure its overall impact on the hospital, the community services, the patient or their carers and relatives.52 Finally, it is encouraging that a recent survey showed that this policy is accepted by the patients as well.47 Given all these favourable characteristics there are hospitals that have already included this strategy in their antibiotic policies.2,4,7 Potential limitations of antimicrobial switch therapy There is a concern that sequential therapy could encourage the administration of follow-up oral

M. Lelekis and I. M. Gould

treatment to patients who actually do not require any antibiotic therapy at all.7 This is further supported by the lack of consensus on the optimum duration of antimicrobial therapy for most infections. In a study by Schein et al.53 on the duration of antimicrobial therapy after emergency abdominal surgery, no treatment extended beyond 5 days even in cases of diffuse, established purulent peritonitis of various aetiologies. This paper highlights two important points. The first is that a high proportion of infections resolve with only a few days of i.v. treatment and the second is that it may be reasonable to stop antimicrobial therapy even if the patient is still febrile, provided that there is another identifiable cause for fever. Therefore careful patient monitoring and selection is a good way to avoid inappropriate sequential treatment prescription. Other potential limitations of switch therapy include potential poor compliance with oral treatment at home, which could lead to either treatment failure or sub-optimal dosing and emergence of resistance of the pathogen.54 Furthermore, it must always be kept in mind that even for drugs with excellent bioavailability, there are conditions which may compromize oral absorption. Drug interaction is a well-documented such condition. For example, with the use of calcium or magnesium-containing antacids or sucralphate, the uptake of quinolones or clindamycin will be disturbed, if there is not an adequate interval between intake.55 In a kinetic study by Cohn et al.,56 nine patients received 750 mg of ciprofloxacin, via nasogastric tube twice daily for 48 h after major abdominal surgery. Despite the fact that after the fourth dose, absorption was significantly better than after the first one, still 3/9 patients had peak concentrations :1 mg/L (range 0.19–0.74) and AUCs:10 mg/h/L (range 1.4–6.1). This study clearly shows that major surgery impairs absorption of ciprofloxacin and calls for further studies to clarify this issue. Another large (691 patients), randomized, double-blind, placebo-controlled study gives an indirect answer (it is a clinical study) to the question of oral absorption of antibiotics under sepsis conditions.57 In this study, patients with intra-abdominal sepsis were given either i.v. imipenem or i.v. ciprofloxacin with metronidazole throughout or i.v. ciprofloxacin with metronidazole followed by oral therapy with the same drugs when oral feeding was resumed. All evaluable patients underwent operative or percutaneous intervention. Of the 155 patients who were switched to oral treatment, 46 received oral ciprofloxacin and metronidazole and

Sequential antibiotic therapy for cost containment in hospital setting: why not?

109 an oral placebo while continuing on i.v. therapy. A total of 12 patients failed to respond to treatment, two (4.3%) of the 46 ciprofloxacin patients versus 10 (9.2%) of the 109 patients who continued on i.v. treatment. Despite these favourable results, kinetic studies are more appropriate for evaluation of oral drug absorption under sepsis conditions. In such a study, absorption of ciprofloxacin was examined after oral administration in nine leukaemic patients with chemotherapy-induced leukopenia and evidence of sepsis.58 Overall, poor absorption of the drug was observed which could be attributed to several factors (sepsis, chemotherapy-induced damage to small bowel intestinal mucosa and concurrent use of antacids in some patients). Again this study addresses the need for further kinetic studies. The issue of successful administration of antibiotics through a nasogastric tube was examined in a study of the absorption and pharmacokinetics of a clarithromycin suspension administered via nasogastric tube to seriously ill patients in an intensive care unit (ICU).59 Because of the satisfactory results obtained, the authors consider clarithromycin suspension suitable for sequential therapy in patients in the ICU. However further studies using different antibiotics are needed to give a definite answer to this issue. Another concern related to the use of oral antibiotics in general is the potential increased ecological hazzard. Unless the antibiotic has significant entero–hepatic circulation, like cefotaxime, or intestinal excretion like ciprofloxacin, then oral rather than i.v. administration of the antibiotic will lead to increased intra-luminal gut antibiotic concentrations with consequent, if temporary increase in ecological damage to the patients protective bowel flora.60 Presumably this will also increase the chances of selecting resistant strains, although we are not aware of any comparative studies of oral versus i.v. administration in this area. Furthermore, with poorly absorbed agents this problem is likely to be exacerbated and this may partly also explain the greater propensity for C. difficile infection after certain oral ␤-lactam drugs, which, on average, are more poorly absorbed than other group of antibiotics (Tables I and II). In this context, it may be advantageous to have agents that are unstable in faeces and which degrade to harmless molecules with no antibacterial properties. One such agent is cefaclor which, in addition to unusually good bioavailability for an oral ␤-lactam antibiotic (Table II) is also chemically unstable.61

255

An additional advantage of unstable molecules concerns increasing worries about environmental pollution with biologically stable antibiotics as a vehicle for selection of antibiotic resistance in sewage systems where many antibiotics are detectable in relatively large concentrations.62,63 Administration of large doses to compensate for poor absorption adds further to this potential ecological disaster. Conclusion As money for healthcare will continue to be less than needed, cost-saving policies will be given top priority. Thus, in the future more hospitals are expected to implement sequential antimicrobial therapy, a policy that is both realistic and effective for hospital cost saving without compromizing clinical outcome. Acknowledgements The members of the Antibiotic Team, Royal Infirmary, Aberdeen, for their continued commitment to good-quality antibiotic prescribing. References 1. Rifenberg RP, Paladino JA, Hanson SC, Tuttle JA, Schentag JJ. Benchmark analysis of strategies hospitals use to control antimicrobial expenditures. Am J Health-System Pharm 1996; 53: 2054–2062. 2. Gould IM, Jappy B. Trends in hospital antibiotic prescribing after 9 years of stewardship. J Antimicrob Chemother 2000; 45: 913–917. 3. Guay DRP. Sequential antimicrobial therapy. A realistic approach to cost containment. Pharmaco Economics 1993; 3: 341–344. 4. Drew RH. Programs promoting timely sequential antimicrobial therapy: an American perspective. J Infect 1998; 37(suppl 1): 3–9. 5. Jewesson PJ. Cost-effectiveness and value of an IV switch. Pharmacoeconomics 1994; 5(suppl 2): 20–26. 6. Jewesson PJ. Pharmaceutical, pharmacokinetic and other consideration for IV to oral stepdown therapy. Can J Infect Dis 1995; 6: 11A–16A. 7. Davey P, Nathwani D. Sequential antibiotic therapy: the right patient, the right time and the right outcome. J Infect 1998; 37(suppl 1): 37–44. 8. Wetzstein GA. Intravenous to oral (IV: PO) antiinfective conversion therapy. Cancer Control J 2000; 7: 170–176. 9. Brown EM, Reeves DS. Quinolones. In: O’ Grady F, Lambert HP, Finch RG, Greenwood D, Eds. Antibiotic and Chemotherapy: Anti-infective agents and their use in therapy, 7th edn. Edinburgh: Churchill Livingstone 1997; 419–452. 10. Sutherland R. ␤-Lactams: penicillins. In: O’Grady F, Lambert HP, Finch RG, Greenwood D, Eds.

256

11.

12. 13.

14.

15. 16.

17. 18. 19. 20.

21.

22.

23.

24. 25. 26.

27.

M. Lelekis and I. M. Gould

Antibiotic and Chemotherapy: Anti-infective agents and their use in therapy, 7th edn. Edinburgh: Churchill Livingstone 1997; 256–305. Bush K. Other beta-lactams. In: O’ Grady F, Lambert HP, Finch RG, Greenwood D, Eds. Antibiotic and Chemotherapy Anti-infective agents and their use in therapy, 7th edn. Edinburgh: Churchill Livingstone 1997; 306–327. Rodvold KA. Clinical pharmacokinetics of clarithromycin. Clin Pharmacokinet 1999; 37: 385–398. Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections. Drugs 1982; 23: 405–430. Wise R. ␤-lactams: cephalosporins. In: O’ Grady F, Lambert HP, Finch RG, Greenwood D, Eds. Antibiotic and Chemotherapy. Anti-infective agents and their use in therapy, 7th edn. Edinburgh: Churchill Livingstone 1997; 202–255. Meyers BR. Cefaclor revisited. Clin Ther 2000: 22: 154–166. Fassbender M, Lode H, Schaberg T, Borner K, Koeppe P. Pharmacokinetics of new oral cephalosporins including a new carbacephem. Clin Infect Dis 1993; 16: 646–653. Cunha BA, Sibley CM, Ristuccia AM. Doxycycline. Ther Drug Monit 1982; 4 : 115–135. Cunha BA. Intravenous to oral antibiotics switch therapy: a cost-effective approach. Postgrad Med 1997; 101: 111–123. Turnidge JD. The pharmacodynamics of ␤-lactams. Clin Infect Dis 1998; 27: 10–22. Forrest A, Nix DE, Ballow CH et al. Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993; 37: 1073–1081. Lettieri JT, Rogge MC, Kaiser L et al. Pharmacokinetic profiles of ciprofloxacin after single intravenous and oral doses. Antimicrob Agents Chemother 1992; 36: 993–996. Yuk JH, Nightingale CH, Quintiliani R et al. Bioavailability and pharmacokinetics of ofloxacin in healthy volunteers. Antimicrob Agents Chemother 1991; 35: 384–386. Hitt CM, Nightingale CH, Quintiliani R, Nicolau DP. Streamlining antimicrobial therapy for lower respiratory tract infections. Clin Infect Dis 1997; 24 (suppl 2): S231–S237. Raad II, Bodey GP. Infectious complications of indwelling vascular catheters. Clin Infect Dis 1992; 15: 197–208. Arnow PM, Quimosing EM, Beach M. Consequences of intravascular catheter sepsis. Clin Infect Dis 1993; 16: 778–784. Mandell LA, Bergeron MG, Gribble MJ et al. Sequential antibiotic therapy; effective cost management and patient care. Can J Infect Dis 1995; 6: 306–315. Powers T, Bingham DH. Clinical and economic effect of ciprofloxacin as an alternative to injectable

28. 29. 30.

31. 32. 33. 34. 35.

36. 37. 38.

39. 40.

41.

42. 43.

44. 45.

antimicrobial therapy. Am J Pub Health 1990; 47: 1781–1784. Kerr JR, Barr JG, Smyth ETM, O’ Hare J. Technique for calculation of the true costs of antibiotic therapy. Eur J Clin Microbiol Infect Dis 1992; 11: 823–827. Kerr JR, Barr JG, Smyth ETM. Computerized calculation of the true costs of antibiotic therapy. Eur J Clin Microbiol Infect Dis 1993; 12: 622–625. Quintiliani R, Cooper BW, Briceland LL, Nightingale CH. Economic impact of streamlining antibiotic administration. Am J Med 1987; 82(suppl 4A): 391. Anonymous. Surveillance of hospital-acquired bacteraemia in English hospitals 1997–1999. London: Public Health Laboratory Service 2000. Nathwani D, Davey P. Strategies to rationalize sepsis management- a review of 4 years’ experience in Dundee. J Infect 1998; 37(suppl 1): 10–17. Smith T, Pritchard-Howarth M, King D. Are intravenous cannulae still being misused? BJCP 1996; 50: 466–467. Nathwani D. Sequential switch therapy for lower respiratory tract infections. A European Perspective. Chest 1998; 113(suppl): 211S–218S. Frighetto L, Nickoloff D, Martinusen SM, Mamdani FS, Jewesson PJ. Intravenous-to-oral stepdown program: four years of experience in a large teaching hospital. Ann Pharmacother 1992; 26: 1447–1451. Okpara AU, Maswoswe JJ, Stewart K. Criteria based antimicrobial IV to oral conversion programs. Formulary 1995; 30: 343–348. Vogel F. Sequential therapy in the hospital management of lower respiratory infections. Am J Med 1995; 99(suppl 6B): 14S–19S. Paladino JA, Sperry HE, Backes JM et al. Clinical and economic evaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics. Am J Med 1991; 91: 462–470. Ramirez JA. Switch therapy in community-acquired pneumonia. Diagn Microbiol Infect Dis 1995; 22: 219–223. Weingarten SR, Riedinger MS, Varis G et al. Identification of low risk hospitalized patients with pneumonia. Implications for early conversion to oral antimicrobial therapy. Chest 1994; 105: 1109–1115. Sevinç F, Prins JM, Koopmans RP et al. Early switch from intravenous to oral antibiotics: guidelines and implementation in a large teaching hospital. J Antimicrob Chemother 1999; 43: 601–606. MacGregor RR, Graziani AL. Oral administration of antibiotics: a reasonable alternative to the parenteral route. Clin Infect Dis 1997; 24: 457–467. Hamilton-Miller JMT. Switch therapy: the theory and practice of early change from parenteral to nonparenteral antibiotic administration. Clin Microbiol Infect 1996; 2: 12–19. Conley J, Low DE. Intravenous to oral antibiotic stepdown therapy: improving the quality of care and reducing costs. Can J Infect Dis 1995; 5: 62–72. Louis TJ. Intravenous to oral stepdown antibiotic therapy: another cost-effective strategy in an era of

Sequential antibiotic therapy for cost containment in hospital setting: why not?

46.

47. 48.

49.

50.

51.

52. 53. 54.

shrinking health care dollars. Can J Infect Dis 1994; 5: 45C–50C. Ehrenkranz NJ, Nerenberg DE, Shultz JM, Slater KC. Intervention to discontinue parenteral antimicrobial therapy in patients hospitalized with pulmonary infections: effect on shortening patient stay. Infect Control Hosp Epidemiol 1992; 13: 21–32. Ramirez JA, Vargas S, Ritter GW et al. Early switch from intravenous to oral antibiotics and early hospital discharge. Arch Intern Med 1999; 159: 2449–2454. Laing RBS, Mackenzie AR, Shaw H, Gould IM, Douglas JG. The effect of intravenous-to-oral switch guidelines on the use of parenteral antimicrobials in medical wards. J Antimicrob Chemother 1998; 42: 107–111. Amodio-Groton M, Madu A, Madu CN et al. Sequential parenteral and oral ciprofloxacin regimen versus parenteral therapy for bacteraemia: a pharmacoeconomic analysis. Ann Pharmacother 1996; 30: 596–602. Walters DJ, Solomkin JS, Paladino JA. Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intraabdominal infections. Pharmacoeconomics 1999; 16: 551–561. Al-Eidan FA, McElnay JC, Scott MG et al. Sequential antimicrobial therapy: treatment of severe lower respiratory tract infections in children. J Antimicrob Chemother 1999; 44: 709–715. Davey P. Cost effectiveness of quinolones in Hospitals and the community. Drugs 1999; 58(suppl 2): 71–77. Schein M, Assalia A, Bachus H. Minimal antibiotic therapy after emergency abdominal surgery. A prospective study. Br J Surg 1994; 81: 989–991. Nathwani D, Tillotson G, Davey P. Sequential antimicrobial therapy – the role of quinolones. J Antimicrob Chemother 1997; 39: 441–446.

257

55. Anonymous. Antibiotic drug interactions. Drug Interactions Update 1993; 13: 199–284. 56. Cohn SM, Cohn KA, Rafferty MJ et al. Enteric absorption of ciprofloxacin during the immediate postoperative period. J Antimicrob Chemother 1995; 36: 717–721. 57. Solomkin JS, Reinhart HH, Dellinger EP et al. Results of a randomized trial comparing sequential intravenous – oral treatment with ciprofloxacin plus metronidazole to imipenem/cilastatin for intraabdominal infections. Ann Surg 1996; 223: 303–315. 58. Neilly IJ, Dawson AA, Golder DA, Gould IM. Absorption of ciprofloxacin after oral administration to leukaemic patients with presumed septicaemia. Antiinfect Drugs Chemother 1995; 13: 215–218. 59. Fish DN, Abraham D. Pharmacokinetics of a clarithromycin suspension administered via nasogastric tube to seriously ill patients. Antimicrob Agents Chemother 1999; 43: 1277–1280. 60. Vollaard EJ, Clasener HA, van Griethuysen AJ et al. Influence of cefaclor, phenethicillin, co-trimoxazole and doxycycline on colonization resistance in healthy volunteers. J Antimicrob Chemother 1988; 22: 747–758. 61. Mackenzie FM, Milne KE, Gould IM. An investigation on the action of cefaclor on Streptococcus pneumoniae. Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 1999, p. 213. 62. Al-Ahmad A, Daschner FD, Kummerer K. Biodegradability of cefotiam, ciprofloxacin, meropenem, penicillin G and sulfamethoxazole and inhibition of wastewater bacteria. Arch Environ Contam Toxicol 1999; 37: 158–163. 63. Kummerer K, al-Ahmad A, Mersch-Sundermann V. Biodegradability of some antibiotics, elimination of the genotoxicity and affection of wastewater bacteria. Chemosphere 2000; 40: 701–710.