Quinolones and False-Positive Urine Screening for Opiates by Immunoassay Technology

TOWARD OPTIMAL LABORATORY USE

Lindsey R. Baden, MD Context Millions of assays are performed each year to monitor for substance abuse Gary Horowitz, MD in various settings. When common medications cross-react with frequently used test- Helen Jacoby, MD ing assays, false-positive results can lead to invalid conclusions. Objective To evaluate cross-reactivity of quinolone antimicrobials in common opi- George M. Eliopoulos, MD ate screening assays and to assess the in vivo implications of this phenomenon. Design, Setting, and Participants The reactivity of 13 quinolones (levofloxa- N RESPONSE TO PUBLIC CONCERNS cin, ofloxacin, pefloxacin, enoxacin, moxifloxacin, gatifloxacin, trovafloxacin, spar- regarding use of illicit drugs, ran- floxacin, lomefloxacin, ciprofloxacin, clinafloxacin, norfloxacin, and nalidixic acid) dom drug testing has become a com- was tested in 5 commercial opiate screening assays from September 1998 to March mon practice for employees in the 1999. In 6 healthy volunteers, we confirmed the cross-reactivity of levofloxacin or workplace,I for individuals incarcerated ofloxacin with these opiate screening assays. or under suspicion by the criminal jus- Main Outcome Measure Opiate assay activity (threshold for positive result, 300 tice system, and in other circum- ng/mL of morphine). 1 stances. This practice has been sanc- Results Nine of the quinolones caused assay results above the threshold for a positive tioned by legislation and affirmed by result in at least 1 of the assays. Four of the assay systems caused false-positive results court decisions, including the US for at least 1 quinolone. Eleven of the 13 compounds caused some opiate activity by at Supreme Court.2-6 In general, samples are least 1 assay system. At least 1 compound caused opiate assay activity in all 5 assay sys- usually subjected to screening by rela- tems. Levofloxacin, ofloxacin, and pefloxacin were most likely to lead to a false- tively inexpensive, rapid, and reliable positive opiate result. Positive results were obtained in urine from all 6 volunteers. immunoassays, with samples testing Conclusion Greater attention to the cross-reactivity of quinolones with immunoas- positive requiring confirmation by an says for opiates is needed to minimize the potential for invalid test interpretation. alternative method. When such strict pro- JAMA. 2001;286:3115-3119 www.jama.com tocols are followed, false-positive screening test results do not cause problems. methods (as would be required in le- Meatherall and Dai9 reported in 1997 It is now widely appreciated that im- gal settings) when there is a question that ofloxacin could result in a false- munoassays are extremely reliable and about the validity of screening results. positive test result for opiates by the have relatively few false-positive re- For this reason, information concern- EMIT [enzyme multiplied immunoas- sults. As a result, at least for some ap- ing therapeutic use of possible cross- say technique] II assay (Syva, San Jose, plications, it has been advocated that reacting prescription medications Calif). However, this fact does not ap- confirmation is not necessary.7,8 Thus, should assist authorities in testing and pear to be widely known among clini- as testing expands beyond the strictly ultimately help the individual who is cians. We encountered a patient in controlled legal arenas, there is a pos- being tested. whom a false-positive urine screening sibility that positive results will be acted Author Affiliations: Departments of Medicine (Drs a speaker and consultant for Bayer and Ortho McNeil on in the absence of confirmatory test- Baden, Jacoby, and Eliopoulos) and Pathology (Dr Pharmaceuticals, and a consultant for Merck, Warner- ing. Such is the case in most hospital Horowitz), Beth Israel Deaconess Medical Center, Har- Lambert/Parke-Davis, and Abbott Laboratories. vard Medical School, Boston, Mass. Corresponding Author and Reprints: Lindsey R. Baden, laboratories, and thus it becomes im- Financial Disclosures: Dr Baden has received fellow- MD, Division of Infectious Diseases, Brigham and portant for clinicians to know that false- ship support from Pfizer and is participating in a multi- Women’s Hospital, 15 Francis St, PBB-A400, Boston, center clinical trial with Merck. Dr Eliopoulos has served MA 02115 (e-mail: [email protected]). positive test results do occur and to re- as a consultant and speaker and has received research Toward Optimal Laboratory Use Section Editor: quest confirmatory testing by alternative contract funding from Aventis Pharmaceuticals, has been David H. Mark, MD, MPH, Contributing Editor.

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test for opiates during therapy with le- [cloned enzyme donor immunoassay] With approval from the Committee vofloxacin nearly resulted in his ejec- reagents (Microgenics, Concord, on Human Studies and informed con- tion from a drug-treatment center. As Calif), which were run on Hitachi sent from the participants, in 1999, 6 a result, we examined systematically the 912 analyzer (Roche Diagnostics), (4) healthy volunteers were given a single propensity of various quinolones to Roche Abuscreen OnLine reagents oral dose of antibiotic (3 received 500 cause false-positive reactions for opi- (Roche Diagnostics), which were run mg of levofloxacin and 3 received 400 ates using 5 major commercially avail- on the Dimension XL analyzer (Dade mg of ofloxacin) and urine samples were able screening assays. Behring, Newark, Del), and (5) Beck- collected at approximately 6-hour in- man opiate reagents, which were run tervals for the following 48 hours. These METHODS on the Synchron CX analyzer (Beck- samples were analyzed for opiates by the Thirteen quinolones (levofloxacin, man Instruments, Brea, Calif). EMIT II 717 system. Select samples were ofloxacin, pefloxacin, enoxacin, moxi- For those samples that tested posi- run on the other 4 assay systems. floxacin, gatifloxacin, trovafloxacin me- tive in a given assay at the lowest con- sylate, sparfloxacin, lomefloxacin, centration (600 µg/mL), further dilu- RESULTS ciprofloxacin hydrochloride, clinafloxa- tions were performed to determine the Assay Cross-Reactivity cin, norfloxacin, and nalidixic acid) approximate lowest concentration that The results of the screening assays for were either provided by the manufac- would test positive. Controls with mor- the 13 quinolones tested in vitro are turer or purchased from a biologic com- phine concentrations of 0, 225, 300, and shown in TABLE 1. A concentration of pany. All antibiotics were made soluble 375 ng/mL were run simultaneously on 300 ng/mL of morphine was set as the as per standard techniques10 to a con- each assay. All assays were run in ac- positive threshold, as previously sug- centration of 5000 µg/mL to ensure we cordance with the manufacturers’ rec- gested by the Department of Health and exceeded possible in vivo urinary lev- ommendations. Specifically, the thresh- Human Services and widely used by els and dilutions to concentrations of old for a positive result was set at 300 clinical laboratories.11-14 By conven- approximately 1700 µg/mL and 600 ng/mL of morphine, and samples with tion, a value of 250 ng/mL would be con- µg/mL were made. error messages not amenable to trouble- sidered a negative value for opiates, al- These samples were then analyzed shooting protocols were not run on di- though substantial opiate activity above by 5 different commercial immunoas- lution (as recommended by manufac- baseline (0 ng/mL) is present. The fol- says: (1) EMIT II reagents, which turers). A more detailed investigation lowing quinolones cross-reacted to cause were run on Hitachi 717 analyzer of the dose-response curves for ofloxa- a positive test result for opiates at con- (Roche Diagnostics, Indianapolis, cin and levofloxacin was performed centrations assayed: levofloxacin and Ind), (2) AxSYM fluorescence polar- with the EMIT II 717 system, span- ofloxacin (using Abbott AxSYM, ization immunoassay (Abbott Labora- ning the range of concentrations from CEDIA, EMIT II, and Roche OnLine as- tories, Abbott Park, Ill), (3) CEDIA 5000 µg/mL to 0.005 µg/mL. says), pefloxacin (using CEDIA, EMIT

Table 1. Expected Urinary Concentration of Quinolones and the Concentration Required for Immunoassay Activity* Quinolone Concentration Causing Assay Positivity for Opiates, µg/mL

In Vivo Peak Urinary Concentration Abbott Quinolone With Standard Dosing, µg/mL† AxSYM CEDIA EMIT II Roche Synchron Levofloxacin 1000 1700-5000 60-200 140 200-600 S Ofloxacin 400 1700-5000 60-200 140 200-600 S Pefloxacin 40 S 60-200 600-1700 200-600 N Enoxacin 8 S 1700-5000 600-1700 S N Gatifloxacin 300-400 S S 600-1700 S N Lomefloxacin 300 N S S 1700-5000 N Moxifloxacin 69 N S S 1700-5000 N Sparfloxacin 12 N S S S N Ciprofloxacin 400 N S S 1700-5000 N Clinafloxacin 147 N S S N N Norfloxacin 400 N S S 1700-5000 N Trovafloxacin 12 N N N N N Nalidixic acid 1000 N N N N N *Expected urinary concentrations of quinolones and concentrations triggering a positive result for the different assays are demonstrated. Levofloxacin and ofloxacin would be expected to trigger a positive opiate assay by the EMIT II, CEDIA, and Roche OnLine assays. Several of the quinolones cause demonstrable assay activity, but below the threshold concentration for assay positivity. S indicates signal detected at maximum concentration tested, but below the threshold value, may contibute in an additive fashion with other cross-reacting compounds; N, no signal detected at maximum concentration tested. See the “Methods” section for details about the assays. †Data obtained from several sources.15-25

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II, and Roche OnLine assays), enoxa- Figure 1. EMIT II Immunoassay Activity Due to Levofloxacin cin (using CEDIA and EMIT II assays), gatifloxacin (using EMIT II assay), and 60 Levofloxacin Run 1 lomefloxacin, moxifloxacin, ciprofloxa- Levofloxacin Run 2 cin, and norfloxacin (using Roche OnLine assay). Sparfloxacin, clinafloxa- 40 cin, trovafloxacin, and nalidixic acid did not cross-react to cause a positive test 20 result with any of the assays. To prop- erly interpret the clinical relevance of 0

these observations, the urinary concen- Signal trations of these quinolones15-25 must be considered. Based on these in vitro data –20 and given the anticipated urinary concentrations, pharmacodynamics, and –40 dosing interval, the quinolones most

likely to cause a false-positive urinary test –60 5 result for opiates are levofloxacin and 625 312 160 80 40 20 10 2.5 1.25 0.75 0.33 0.16 0.08 0.04 0.02 0.01 5000 2500 1250 0.0050.0025 ofloxacin (using CEDIA, EMIT II, and Concentration, µg/mL Roche OnLine assays) and pefloxacin Opiate assay activity as a function of levofloxacin concentration by the EMIT II system is demonstrated. The (using CEDIA). threshold value for assay positivity (300 ng/mL, represented by zero on the y-axis) is approximately 110 µg/mL These screening assays for opiates are of levofloxacin. Assay activity corresponding to a morphine concentration of 225 and 375 ng/mL are –15 and qualitative (threshold) tests and should 15 units on the y-axis, respectively. not be used quantitatively. However, it is important to consider low-concen- Figure 2. Urine Opiate Activity Due to a Single Dose of Levofloxacin or Ofloxacin tration opiate cross-reactivity (below in Volunteers the threshold) as this may, in certain settings, facilitate reaching assay thresh- Levofloxacin 1 Levofloxacin 2 old—thus, a false-positive test result. Levofloxacin 3 Detailed analysis of 2-fold serial dilu- Ofloxacin 1 Ofloxacin 2 tions of levofloxacin (FIGURE 1) and Ofloxacin 3 ofloxacin (using EMIT II assay) dem- onstrates dose-responsive assay activ- 375 ity between concentrations of 5 µg/mL

to 1250 µg/mL, with the assay thresh- 300 old being achieved at approximately 110 µg/mL. The following quinolones 225 have some opiate activity but below the assay threshold; thus, they have the potential to act in an additive manner to ng/mL Morphine Activity,

trigger a positive opiate assay: levo- 0 floxacin and ofloxacin (Synchron assay); pefloxacin (Abbott AxSYM as- 0 10 20 30 40 50 say); enoxacin (Roche OnLine and Time, h

Abbott AxSYM assays); gatifloxacin Urine opiate assay results by the EMIT II system for 3 healthy volunteers who received a single dose of levo- (Abbott AxSYM, CEDIA, and Roche floxacin (500 mg) or ofloxacin (400 mg). For both antibiotics, the assay became positive as soon as 2 hours OnLine assays); sparfloxacin (CEDIA, after dosing and remained positive for approximately 20 to 25 hours. Significant assay activity was maintained for 30 to 40 hours postdosing, though below the threshold value for opiate positivity. EMIT II, and Roche OnLine assays); and lomefloxacin, moxifloxacin, clinafloxacin, ciprofloxacin, and norfloxa- Volunteer Studies (single dose of 400 mg) revealed a simi- cin (CEDIA and EMIT II assays) (Table A single dose of 500 mg of levofloxa- lar pattern. Detectable opiate activity in 1). At the concentration levels tested, cin caused a false-positive test result us- the urine was seen for more than 30 trovafloxacin and nalidixic acid dem- ing the EMIT II assay within 2 hours hours with both antimicrobials. onstrated no detectable opiate cross- for as long as 22 hours in all 3 healthy Selected urine samples from these reactivity by any of the assays. volunteers (FIGURE 2). Ofloxacin subjects were run on the other 4 as-

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port the 300 ng/mL as our cutoff for as- Table 2. Duration of Urine Opiate Activity in Volunteers After a Single Dose of Levofloxacin or Ofloxacin* say positivity. Urine Concentration Causing Assay Positivity for Opiates, µg/mL Why certain quinolones react with some opiate screening assays is un- Time, h Abbott AxSYM CEDIA EMIT II Roche Synchron clear, as there is no obvious structural 0 N NNN Nsimilarity between morphine and this Ն Ն Ն Ն 7S375 375 375 225 class of drugs nor is there an obvious Ն Ն Ն 20 S 375 300 225 S structural relationship between the qui- Ն Ն 24 S 300 225 S S nolones that cross-react. These data are *Duration of opiate activity by 5 different immunoassay technologies after a single dose of levofloxacin (500 mg) or ofloxacin (400 mg). The given opiate assay would be considered positive for values of 300 ng/mL or greater. S in- of particular importance given the wide- dicates signal detected at maximum concentration tested but less than 225 ng/mL control, may contribute in an additive fashion with other cross-reacting compounds; N, no signal detected at maximum concentration tested. spread use of these agents, such as for the treatment of community-acquired pneumonia, nosocomial-acquired says and were found to cause assay posi- son receives a positive opiate test result pneumonia, sexually transmitted dis- tivity above the 375 ng/mL level by the in the setting of recent quinolone use. eases, multidrug-resistant tuberculo- CEDIA assay and positivity persisted What all of these assays have in com- sis, and the prophylaxis for possible an- above the 300 ng/mL concentration for mon is that an antibody directed against thrax exposure.15,36-45 As many of these over 24 hours (TABLE 2). The Roche opiate epitopes is exposed to labeled infections occur in patients who might OnLine assay found positivity above drug in the reagent system and free drug be susceptible to substance abuse, the 375 ng/mL, with persistent (slight) as- in the sample. With higher concentra- potential for misinterpretation of test- say activity at 24 hours. The Synchron tions of drug in the sample, less of the ing is self-evident. In addition, the care assay had activity above the 225 ng/mL labeled drug in the reagent system binds of patients in clinical situations may be level at 7 hours after dosing, with per- to the antibody. Depending on the spe- misguided by a positive urine test for sistent activity detected at 24 hours. The cific assay, the signal detected (turbid- opiates, such as inappropriately halt- Abbott AxSYM assay demonstrated ity, enzyme activity, fluorescence po- ing the evaluation of a change in men- some opiate reactivity; however, this larization, etc) is changed by the tal status. was below the 225 ng/mL concentra- concentration of free drug in the sample It is important to realize that the tion and persisted for over 24 hours. in a predictable, although typically not screening assays are designed to be posi- proportional manner. When the sig- tive when the urine concentration of COMMENT nal exceeds that of an arbitrary stan- morphine is 300 ng/mL or greater. Few compounds have been identified dard (typically, for opiates, 300 ng/mL These are qualitative not quantitative that cross-react with the common opi- of morphine), the assay is considered tests. Different immunoreactive com- ate screening assays26 and include rif- positive (ie, contains an opiate with a pounds can have an additive effect on ampin (described for the kinetic inter- concentration whose reactivity ex- reaching the threshold for a given as- action of microparticles in solution ceeds that of 300 ng/mL of morphine). say. For example, if a given quinolone method), ofloxacin (described for the Until recently, the recommended cut- would lead to 225 ng/mL and a poppy EMIT method),9 and poppy seeds (de- off for opiate assay positivity (by the De- seed muffin to 100 ng/mL of immuno- scribed not for cross-reactivity, but partment of Health and Human Ser- reactivity, consumption of either prod- detection of minute amounts of vices) was 300 ng/mL of morphine.11-14 uct alone would not induce a positive opiates).27-34 We have shown that sev- To minimize the unnecessary gas chro- urine opiate test result. However, if both eral quinolones have the potential to yield motography/mass spectrometry effort were consumed simultaneously, the test false-positive test results by a number of and expense due to poppy-seed food threshold might be achieved. Thus, a commonly used opiate screening assay products, the opiate screening thresh- compound that induces signal activity systems currently used in the United old was raised from 300 ng/mL to 2000 by a given immunoassay technology, al- States. It is important to note that sev- ng/mL of morphine in December 1998. beit below assay threshold, could ad- eral of the quinolones are metabolized This cutoff, however, has been re- ditively contribute to a positive urine in vivo and the metabolites (eg, norfloxa- ported to have only a 70% sensitivity screening test result when other cofac- cin as a metabolite of pefloxacin) may be for detecting opiates.11 In part, due to tors are present. excreted into the urine.15,35 We did not this sensitivity concern and for pur- When a screening test for drugs fre- assess the potential contributions of other poses of clinical rather than forensic quently abused returns positive, it metabolites in this study. Because of the testing, most clinical laboratories con- is essential to obtain appropriate enormous ramifications for an unrecog- tinue to use the 300-ng/mL threshold confirmatory testing, such as gas chro- nized false-positive test result, the re- for assay positivity. Given the clinical matography, mass spectrometry, or sults of our study strongly support the implications of quinolone cross- high-performance liquid chromatog- use of confirmatory testing when a per- reactivity with opiate testing, we re- raphy.32,46,47 Quinolones are not misin-

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terpreted as opiates by these methods. stances in which resources are lim- intellectual content: Baden, Horowitz, Jacoby, Eliopoulos. Confirmatory testing should not be ited, the significant cost of additional Administrative, technical, or material support: Baden, done by another immunoassay tech- testing will remain a formidable ob- Horowitz, Eliopoulos. Study supervision: Baden, Horowitz, Eliopoulos. nique for the reasons demonstrated in stacle to accurate test interpretation. Previous Presentations: This work was presented in this analysis. Confirmatory testing does These data demonstrate the need for part at the 36th Annual Meeting of the Infectious Dis- eases Society of America, Denver, Colo, November 12- not always resolve the issue of sub- vigilance in identifying unintended con- 15, 1998. stance abuse as consumption of poppy sequences of new therapies. Acknowledgment: We acknowledge the following individuals and institutions for performing assays on and seeds or medicinally prescribed Author Contributions: Study concept and design: providing raw data from their respective analytical sys- opiates have been reported as inno- Baden, Horowitz, Jacoby, Eliopoulos. tems: Barbarajean Magnani, MD, PhD, Boston Medi- Acquisition of data: Baden, Horowitz, Eliopoulos. cal Center, Boston, Mass; George A. Fischer, PhD, cent explanations for positive opiate Analysis and interpretation of data: Baden, Horo- Brigham and Women’s Hospital, Boston; Nader Ri- screening test results.29,31,46 The major witz, Eliopoulos. fai, PhD, and Terence Law, Children’s Hospital Medi- Drafting of the manuscript: Baden, Horowitz, cal Center, Boston; and Gifford Lum, MD, Gerri Mo- limitations to obtaining confirmatory Jacoby, Eliopoulos. ses, and Barry Mushlin, West Roxbury Veterans Affairs testing are time and money. In circum- Critical revision of the manuscript for important Hospital, West Roxbury, Mass.

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