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Laboratory guidelines for monitoring of antimicrobial drugs.

Few drugs used to treat infectious diseases meet the criteria established for therapeutic drug monitoring (TDM) [1] (1). Currently, the exceptions include, at least in some cases, the aminoglycosides, chloramphenicol, and vancomycin (2-12). For the aminoglycosides and chloramphenicol, monitoring serum concentrations may be used to (a) guide and monitor dosing changes, (b) evaluate efficacy or potential toxicity, or (c) assess antibiotic penetration into other body fluids. For vancomycin, the necessity and appropriateness of monitoring are less obvious and even controversial (8-11). The purpose of this article is to review the published data on effective TDM of these antimicrobial drugs.

The Aminoglycosides

The aminoglycoside antibiotics are used for the treatment of infections of susceptible strains of gram-negative microorganisms that are resistant to less toxic antibiotics.

Organisms commonly susceptible to these drugs include Klebsiella species, Enterobacter species, Serratia species, Citrobacter species, Escherichia coh, Proteus species, Acinetobacter species, and Pseudomonas aeruginosa (12-16). Monotherapy is usually reserved for the treatment of less serious infections (12-15), for example, uncomplicated urinary tract infections, and only when other antibiotics are not appropriate. Combination therapy with a (3-lactam antibiotic or a quinolone may be needed for the treatment of more serious gram-negative infections. Combination therapy with a [beta]-lactam permits the use of aminoglycosides in the treatment of infections caused by particular gram-positive organisms (12-15), such as Staphylococcus aureus, enterococci, or S. viridans endocarditis. Because of the incidence of toxicity and the relationship between toxicity and serum concentration and because of the dosing protocols utilized, monitoring of these drugs can be useful.

The mechanisms of action of aminoglycosides are readily found in many texts and will not be addressed here, with the exception of the postantibiotic effect. By definition, postantibiotic effect is the period of continued growth suppression after cessation of exposure of the bacteria to an active antibiotic (17-19). This in vitro effect occurs because concentrations at the tissue site are adequate to maintain killing although serum concentrations fall below the minimum inhibitory concentrations (MIC) of the organism being treated. This property has been used in the design of dosing regimens such as pulse dosing, in which the concentration-dependent killing properties of aminoglycosides are theoretically optimized, whereas the potential for tissue accumulation and subsequent toxicity associated with excessive trough concentrations are reduced (20-23).

Nephrotoxicity and ototoxicity are the most frequently reported adverse or toxic reactions associated with aminoglycoside therapy. Nephrotoxicity occurs in 5-10% of patients, with the risk of occurrence reported to depend on the specific aminoglycoside used (24-30), the trough serum concentration attained, and the definition of toxicity (12). Other reported risk factors include the total dose administered, length of therapy, age, dehydration or volume depletion, hypotension, concurrent liver disease, metabolic acidosis, hypokalemia, hypomagnesemia, high serum concentrations, and co-administration of other potentially nephrotoxic drugs (12,15,24-30). Aminoglycoside nephrotoxicity involves the proximal tubules, which are capable of regeneration; therefore, this adverse effect maybe reversible over time (28-29). Ototoxicity occurs in 0.5-3% of patients, but some studies suggest the incidence may be as high as 25% (24,26,31-34). The ototoxic effect on the neuroepithelial cells of the inner ear may produce cochlear damage, vestibular impairment, or both (24, 26, 31-32). Unlike the renal tubules, these cells cannot regenerate; therefore, these conditions are irreversible. Other adverse reactions, such as neuromuscular blockade, nausea, headache, and hypersensitivity, are reported at lower rates (12, 24, 34-35).

Dosing regimens for aminoglycosides can be classified as conventional or pulse. Most laboratory scientists are familiar with conventional dosing regimens in which the aminoglycoside is administered in divided doses every 8-12 h. Within this classification, many variations have been developed, in which either the dose or the dosing interval is adjusted with respect to renal function (35-38). Published therapeutic ranges, such as those seen in Table 1, are based on conventional dosing regimens and should be applied when using these types of dosing schedules.

Pulse dosing, which is gaining acceptance for use in some patients, involves administering the drug in a single dose per dosing interval (20-23,39). Because the interval may exceed 24 h, the term "pulse dosing" is preferred over the terms "once-daily aminoglycoside" or "single daily dosing". In these protocols, the dosing interval is based on drug clearance and generally falls between 24 and 48 h. The rationale behind this type of regimen includes achieving optimum concentration-dependent bactericidal activity to maximize efficacy, avoiding firstexposure adaptive resistance, and optimal utilization of postantibiotic effect (17,19,20-22, 39-42). In pulse dosing, serum concentrations are expected to fall below the MIC of the organism for a sustained period of time and may reach a concentration of zero before administration of the next dose. This theoretically minimizes the risk of accumulation and subsequent nephrotoxicity (43). Unfortunately, meta-analyses have demonstrated that, although the incidence of nephrotoxicity has not increased when pulse-dosing protocols are used, it has not been reduced (42, 44-48). Pulse-dosing protocols reportedly lead to cost and administrative savings, but achievement of these goals has not been realized universally (20-22, 39,44-48). Additionally, the protocols have not been validated in, nor recommended for, all patient populations.

INDICATIONS FOR MONITORING

For the aminoglycosides, monitoring includes tests of renal function in addition to serum drug concentrations. There is some controversy over the need to monitor serum drug concentrations in patients with adequate renal function. For example, studies conducted in the mid-1980s in this institution questioned the cost-effectiveness of serum concentrations in children (defined as >3 months to 18 years) with adequate renal function (49). For this group, creatinine or creatinine clearance is still necessary to establish renal function and to determine whether additional monitoring in the form of serum concentrations is needed. In addition, other clinical parameters discussed throughout this section are considered in the decision to, or to not, monitor this group of children. For premature infants and neonates up to 3 months of age, renal function is changing and serum monitoring is recommended. For adults, a combination of monitoring (renal function and serum concentrations) is performed to guide and monitor dosing regimens and to evaluate efficacy and potential toxicity (4, 33, 37). The level of monitoring needed will depend on the patient's clinical status and the dosing protocol used.

Regardless of the aminoglycoside dosing regimen used, a baseline serum creatinine has been recommended before initiating therapy to assess existing renal function (15,20-22,39,41,50-52). Measurements are repeated in 1- to 3-day intervals, as required by the dosing protocol or as needed to assess nephrotoxicity (15, 20-22, 39, 41, 5052). Creatinine clearance is considered useful, but if a timed urine sample is unobtainable, creatinine clearance may be estimated using one of the calculations or nomograms available (53-55).

For those patients receiving the drug via conventional dosing and for whom monitoring is indicated, drug monitoring should begin after steady-state is achieved (usually after the 3rd or 4th dose), with the monitoring of at least one peak and trough concentration recommended (5-6,15,24,34-37,56-57). Samples for peak concentrations are collected 60-90 min after intramuscular injection and 30-60 min after intravenous (i.v.) infusion. Samples for trough concentrations are collected within 30 min of the next dose. The serum trough concentration should be repeated at 3- to 4-day intervals or sooner, if warranted by the clinical status of the patient (5-6,15,37,57). For example, monitoring is recommended when the dose is changed or if the patient exhibits symptoms of toxicity, has co-existing processes known to alter aminoglycoside excretion, or is concomitantly receiving drugs known to potentiate toxicity (5-6, 34-37, 58-62).

[FIGURE 1 OMITTED]

When the pulse-dosing method for aminoglycoside treatment is used, several studies recommend including a baseline creatinine concentration before initiation of therapy and monitoring creatinine every 1 to 3 days (2022, 39, 41). Because every dose is essentially a "first" dose, steady-state concentrations are not achieved, and monitoring can begin after the first dose. Monitoring strategies vary with dosing regimens, but in general, a random but timed sample is collected 8-12 h after completion of the aminoglycoside infusion (20-22, 39, 41). The resulting concentrations are applied to existing nomograms, such as the one seen in Fig. 1, to determine the subsequent dosing interval. These should be repeated at 3- to 7-day intervals (20-22, 39, 41), or more frequently as warranted. At least one study has suggested a need to monitor two serum concentrations at least one half-life apart to identify patients with atypical clearance (63).

Occasionally, aminoglycoside concentrations have been measured in other body fluids, such as cerebrospinal fluid (CSF), to assess the degree of antibiotic penetration into the space or to assure adequate intrathecal dosing (64-66).

ANALYTICAL ISSUES

Serum or EDTA-treated plasma (Table 2) is the recommended specimen for aminoglycoside testing. Heparin in the concentrations used in phlebotomy has been shown to interfere with some methods by inactivating the aminoglycoside and is not recommended (67) unless suitability is verified by the manufacturer or laboratory. Samples should be separated and, if not tested within 2 h, stored at 0-5 [degrees]C (68). Most investigations regarding collection tubes and serum separator devices show little or no absorption of aminoglycosides by gel barriers, serum separator devices, or plastic (69-72); however, a recent letter does report evidence of the adsorption of these drugs to the gel barriers (73). It is unclear from the data given if this observation is caused by absorption or drug interaction (67-68).

We could find no references regarding the collection, processing, and storage of other specimens, including CSF. In the treatment of meningitis, the aminoglycoside is often combined with other antibiotics known to inactivate aminoglycosides (64,66-68). Given the low concentrations expected, these samples should be tested immediately or stored frozen.

Immunoassays have become the methods of choice because of the ease of use, the increase in automated techniques, and rapid turnaround time. Reviews of the 1994-1996 College of American Pathologists (CAP) proficiency surveys shows fluorescence polarization and enzyme immunoassays to be most commonly used among subscribers. Procedures using methods such as RIA, HPLC, and gas chromatography have been described, but these methods offer little advantage over current immunoassays. The drugs are excreted unchanged; therefore, specificity in terms of metabolite cross-reactivity is not a concern. However, structural similarities exist between the aminoglycosides such that cross-reactivity within the group is possible. Although simultaneous administration of two (or more) aminoglycosides is unusual, laboratory scientists should be aware of this possibility (74-76).

When the model proposed by Fraser (77) for determining precision goals for TDM is used, an analytical CV of 20% is acceptable for aminoglycoside assays. The CLIA and CAP proficiency fixed criteria are [+ or -] 25% of a target mean for gentamicin and tobramycin, and [+ or -] 3 SD or 10%, whichever is greater, for amikacin (78). For gentamicin and tobramycin, this means the day-to-day imprecision (CV) should be [less than or equal to] 8%. With most commercially available assays and automated systems, this precision can be achieved for peak or toxic concentrations, but it may not be achieved at the lower concentrations encountered in serum trough or alternative specimens (63-65). Because serum trough concentrations are used in some protocols to calculate dose modifications, we simulated the impact of increasing imprecision at the low end of the assay on the calculated elimination rate constant, the calculated true peak concentration, and the subsequently predicted peak and trough concentrations of the newly calculated dose. As seen in Table 3, a CV of 20-30% leads to predicted peak and trough concentrations that may lead to inappropriate dosage modifications and the potential for decreased efficacy and/or increased toxicity. Therefore, we recommend that assays have a CV <10% at 0.5-1.0 mg/L (0.5-1.0 [micro]g/mL). To determine imprecision, we recommend that laboratories include a precision profile as part of their method evaluation protocol and repeat it periodically. Additionally, assays should be capable of measuring below 1.0 mg/L (1.0 [micro]g/mL). Reported values of <1 mg/L (<1[micro]g/mL) are not useful in pharmacokinetic calculations and offer little more than assurance that the serum concentration is not toxic. Laboratories receiving CSF specimens, or any other specimen, must validate the performance of the assay using similar samples. Only one study to date documents the performance of these assays with CSF (65). Both CAP and CLIA require such validation studies (78).

PRACTICE ISSUES

Many of the clinically related practice issues regarding the appropriateness of drug utilization, dosing protocols, and efficacy are beyond the realm of the laboratory. One should be aware of the physiological and pathological changes that alter aminoglycoside disposition and thus affect monitoring parameters. These include age, renal function, nutritional status, the presence of ascites or fever, or if the patient has cystic fibrosis or requires dialysis (6, 27, 33-34,40, 47,57-58, 79-84).

Recognizing and identifying drug interactions and the effects of a drug on other laboratory tests is an important aspect of a TDM service. We refer the reader to the compilation by Young (85) for drug-test interactions. The list of drug interactions for aminoglycosides is not as extensive as for some drugs: the absorption of digoxin, penicillin V, and methotrexate is decreased when co-administered with an oral aminoglycoside; the action of some neuromuscular blocking agents may be prolonged; and increased renal excretion of aminoglycosides occurs with indomethacin. One interaction, however, does warrant more discussion because of the potential impact on the laboratory result. Inactivation of aminoglycosides by (3-lactam antibiotics both in vivo and in vitro is well documented (67-68) but often forgotten. The rate at which the reaction proceeds varies with the aminoglycoside and (3-lactam involved and the concentration of each, as well as the time, temperature, and pH. Aminoglycoside solutions are not pre-mixed with these other drugs before administration but may be administered sequentially. As a result, both drugs may be present in specimens collected for monitoring, and the inactivation process may occur. All specimens, therefore, should be tested immediately or stored at 0-5[degrees]C (68) to prevent an artifactual decrease in the measured concentration.

As mentioned earlier, continued assessment of renal function is necessary, given the risk of nephrotoxicity. By tradition, changes in serum creatinine are used to define and monitor nephrotoxicity. Unfortunately, there are numerous variations in the degree of change in creatinine concentration achieved before nephrotoxicity is considered to occur (12, 21, 27-30, 41, 45, 57). Additionally, some investigators have questioned the appropriateness of relying on creatinine measurements as a monitor of aminoglycoside-induced nephrotoxicity (12,27-30,86-89). In some of these studies, an increase in the serum trough concentration preceded the increase in creatinine by several days. Because the mechanism of nephrotoxicity involves proximal tubule injury, the first signs of this toxicity are proteinuria, cylindruria, and a reduction in concentrating ability (12, 57, 86-90). The increase in creatinine follows later (86-90). This is the rational behind the manufacturers' recommendations that a urinalysis with specific gravity and a microscopic examination be performed (50-52) early in the course of drug therapy. Several alternative analytes are proposed as better indicators of injury, as well as the degree of injury, to the proximal tubules in both humans and in animal models under experimental conditions. These analytes include urinary [[beta].sub.2] microglobulin, al-microglobulin, lysosomal enzymes, and phospholipids (12,57,86-89). We recognize that serum creatinine has long been used to assess aminoglycoside nephrotoxicity, but these investigations raise valid questions regarding the practice. Although the alternative analytes do permit earlier detection of toxicity, they are not specific to proximal tubular dysfunction. We suggest that this is an area warranting additional investigation.

One area rarely discussed with respect to aminoglycoside dosing or monitoring is chronicity. We mention some recent studies because this is an area gaining interest. Because the aminoglycosides are excreted predominantly by glomerular filtration, the diurnal variation of the glomerular filtration rate reportedly leads to higher morning peak serum concentrations compared with those obtained in the evening (91-93). The amplitude of the glomerular filtration rate diurnal variation decreases with aging and possibly with fever (94-95). One recent study evaluating the time of aminoglycoside administration using a pulse-dosing protocol reportedly found an increase in nephrotoxicity when patients received the dose between 2400 and 0730 (96). Although the study requires additional confirmation, the authors raise important concerns.

REPORTING ISSUES

Stat turnaround times are rarely required. Measured concentrations and time of collection are used to calculate a "true" peak and trough to guide additional dosing. Therefore, recording the actual collection time is important. Targeted therapeutic ranges used in conventional dosing vary with the severity of disease (Table 1). Critical values should be verified and the physician notified. Conventional therapeutic ranges should not be applied in pulse-dosing protocols. Instead, nomograms such as the one for gentamicin and tobramycin developed by Nicolau et al. (20) (Fig. 1) are used to interpret the result and determine the next dose and interval. Serum trough concentrations are used to assess suspected toxicity (12, 21, 39). Any drug present should be considered suggestive of toxicity. A comment such as, "Toxic trough concentration-consider modifying dosing interval" is useful.

Reported CSF concentrations vary from 10% to 50% of the serum concentrations. Targeted therapeutic ranges are not established (64-65), but concentrations should be above the MIC of the organism.

The integration of laboratory and hospital information systems would make monitoring more efficient and effective. Coordination of laboratory data (microbiological susceptibility, renal function testing, and drug concentrations) with pharmacy/nursing data (dose, route, time, and other drugs) and medical data is critical.

Chloramphenicol

Chloramphenicol is a broad spectrum antibiotic with activity against both gram-positive and gram-negative anaerobic and aerobic bacteria. The use of chloramphenicol (7, 97-109) should be reserved for serious infections where less toxic antibiotics are contraindicated or organisms are resistant. This antibiotic is used to treat cholera (Vibrio cholerae), typhoid, infections of Bacteroides fragilis, tetracycline-resistant or contraindicated rickettsial infections, and meningitis caused by ampicillin-resistant Hemophilus influenzae, or when ampicillin or a third-generation cephalosporin cannot be used. The drug is also used in some cystic fibrosis protocols.

Three forms of chloramphenicol are used: chloramphenicol base, chloramphenicol palmitate, and chloramphenicol succinate. Both the palmitate and succinate prodrugs undergo hydrolysis by pancreatic (palmitate) and hepatic (succinate) enzymes for conversion to the active chloramphenicol. As will be seen, this information is important when determining the appropriate time of sample collection and in evaluating the concentrations of some patients.

Serum chloramphenicol concentrations are monitored to guide dosing and to avoid dose-related toxicity (7, 97107). The immature hepatic enzyme system of newborn infants, especially premature infants, is unable to adequately conjugate chloramphenicol. Renal tubular and glomerular filtration rates are also immature. As a result, chloramphenicol may accumulate, leading to a potentially fatal toxic reaction known as the "gray baby syndrome" (97,99-101). Serum concentrations in excess of 40 mg/L (40 [micro]g/mL) have been associated with the occurrence of this syndrome (97, 99-101).

Myelosuppression, one of the more common adverse reactions, is thought to be related to an inhibition of ferrochetalase by the drug and leads to anemia, reticulocytopenia, leukopenia, and thrombocytopenia. The condition is most commonly seen with sustained serum concentrations of 25 mg/L (25 [micro]g/mL) or greater (9798,102). Myelosuppression is reversible when the drug is discontinued.

The occurrence of aplastic anemia during chloramphenicol therapy is rare: 1 case in 24 000 to 40 000. It is not related to dose or serum concentration. Aplastic anemia is more common in patients who have received either lengthy or multiple courses of the drug. The pathogenesis of the toxic reaction is unknown (97-98,102-104). A relationship between the occurrence of aplastic anemia and the use of topical ocular chloramphenicol remains controversial (103-104).

INDICATIONS FOR MONITORING

Before chloramphenicol therapy is initiated, specimens for culture and drug sensitivity, a baseline complete blood count with differential, platelet count, renal, and hepatic profiles should be obtained (7, 97-98,101, 105-107). The complete blood count should be repeated in 2- to 3-day intervals and the drug discontinued if the complete blood count drops below 2.5 X [10.sup.12] cells/L (107). The renal and hepatic profiles should be repeated 1-3 days later and then at least weekly (7, 97-98,105-107). Because efficacy and adverse effects are associated with a maximal serum concentration, peak concentrations of chloramphenicol are used for monitoring (Table 1) (7,105-106). The first sample should be obtained at steady-state. Samples should be drawn 60 min after administration of an oral chloramphenicol capsule, 1.5-3 h after administration of an oral chloramphenicol palmitate suspension, and 0.51.5 h after the completion of an i.v. infusion of chloramphenicol succinate. Repeat measurements should be performed if the dose is altered, if renal or hepatic function changes, or if changes in the hemopoietic profile are noted.

Occasional monitoring of chloramphenicol concentrations in CSF is reported when treating meningitis (105,108-110). The drug, pro-drugs, and metabolites are found in urine; however, although these concentrations are measured in urine in animals, there are no data to suggest usefulness in humans.

ANALYTICAL ISSUES

A number of nonspecific methods for the measurement of chloramphenicol have been described, including colorimetric and microbiological methods. We recommend that nonspecific methods be avoided. The most commonly used methods for routine monitoring are based on immunoassay and HPLC. The immunoassays do not differentiate between the biologically active and inactive forms but offer ease of use and rapid turnaround times. The advantage of the chromatographic methods is the ability to separate and differentiate between the pro-drugs, chloramphenicol, and metabolites. Although such monitoring may not be necessary in all patients, it is useful in identifying patients with decreased metabolic or clearance capacity. The drug is not part of widely used proficiency surveys, so an in-house proficiency program must be developed by those laboratories performing the test (78).

Serum or plasma (EDTA or citrate) are acceptable samples. Gel barrier or serum separator tubes can be used. Data suggest that samples should be protected from light and either analyzed immediately or stored frozen. Chloramphenicol ophthalmic solutions are reported to degrade if not protected from light (111-113). Unlike other light sensitive analytes, apparently no studies have been done to determine if a similar process occurs when the drug is in human sera (112). Samples from patients receiving chloramphenicol succinate have been reported to undergo in vitro hydrolysis (106), but similar studies apparently have not been done for chloramphenicol palmitate (114). Freezing samples or using EDTA for collection inhibits in vitro hydrolysis and is recommended to assure sample integrity.

Approximately 10% of chloramphenicol base given as an oral dose is excreted unchanged by the kidneys via both glomerular filtration and tubular secretion. Most of the chloramphenicol is conjugated in the liver with glucuronic acid to form the primary metabolite, chloramphenicol glucuronide. This inactive metabolite is rapidly excreted. Additional metabolites identified in human blood and/or urine include chloramphenicol glycol alcohol, chloramphenicol aldehyde, chloramphenicol oxamic acid, chloramphenicol amine, and chloramphenicol base (97,115-118). The roles of these metabolites are under investigation. Under experimental conditions, the nitro moiety has been shown to undergo reduction to yield reactive nitroso and hydroxylamine intermediates (97, 106, 115-119). Some investigators have suggested that these intermediates play a role in aplastic anemia, whereas others argue that the intermediates are degraded before reaching the bone marrow (97-98,116,120-121).

Those laboratories performing analyses on CSF must verify assay performance using similar specimens (78). The assay used must have sufficient sensitivity to monitor concentrations in the range of 1-6 mg/L (1-6 [micro]g/mL) (106,110).

PRACTICE ISSUES

Multiple drug interactions are possible because of the competitive inhibition by chloramphenicol on cytochrome P450 enzymes. The potential for drug interactions should be considered when chloramphenicol is co-administered with another drug metabolized by this enzyme system (85). Diuretics increase the renal excretion of chloramphenicol.

Patients with hepatic dysfunction metabolize chloramphenicol at a slower rate and may require more frequent monitoring because toxicity is a concern in such patients (7,105,121). Decreased clearance of the parent drug and metabolites is reported in patients with decreased renal function. Increased pro-drug and decreased active drug concentrations, i.e., decreased bioavailability, may be seen in patients with pancreatic diseases such as cystic fibrosis when enzyme replacement is inadequate (114).

REPORTING ISSUES

The therapeutic range for chloramphenicol is 10-20 mg/ L (10-20 [micro]tg/mL; Table 1). Samples below the recommended therapeutic range, i.e., <10 mg/L (10 [micro]g/mL), should be flagged as such when reported. Reported concentrations for CSF typically fall in the 1-6 mg/ L (1-6 [micro]g/mL) range (109-110) and should be targeted to fall above the MIC of the organism.

Serum concentrations >25 mg/L (25 [micro]g/mL; Table 1) should be treated as critical values, verified, and called to the physician. Although some references recommend higher concentrations, 30-50 mg/L (30-50 [micro]g/mL), as the set points for toxic ranges, laboratories using these higher ranges should keep in mind that toxic reactions have occurred when serum concentrations were >25 mg/L (25 [micro]g/mL).

Vancomycin

Vancomycin, a glycopeptide antibiotic, has a narrow spectrum of activity, with action primarily against grampositive cocci and bacilli. The drug is bacteriostatic against most enterococci and exhibits synergy when combined with an aminoglycoside. Vancomycin has been used widely in treating many susceptible infections, but the emergence of vancomycin-resistant enterococci has lead to recommendations restricting its use (8,122-124). Current recommendations for vancomycin therapy include the treatment of serious infections of (3-lactam- or metronidazole-resistant organisms or when the use of other antibiotics is contraindicated (124). Vancomycin may be used prophylactically in some situations in which the patient is at risk for endocarditis or when methicillinresistant Staphylococcus aureus or Staphylococcus epidermidis is a risk (124). Restricting the use of this drug has not been without controversy, nor has restricted use been easy to accomplish in many institutions.

The primary route of administration is i.v. infusion given slowly. Orally administered vancomycin is poorly absorbed from the gastrointestinal tract and is associated with vancomycin-resistant enterococci; therefore, this route of administration is reserved for treating serious or life-threatening gastrointestinal infections, such as Clostridium difficile colitis or S. aureus colitis (124). Because penetration of vancomycin into the CSF is unpredictable, intrathecal or intraventricular administration may be necessary to attain adequate CSF concentrations when treating central nervous system infections (125-128).

For many of the drugs discussed in this symposium, there are clear relationships between the drug and reported toxic reactions. Unfortunately, this is not the case with vancomycin. The major toxic reactions reported for this drug include "red-man syndrome," nephrotoxicity, and ototoxicity. Thrombophlebitis, fever, rash, and neutropenia occur at lower rates.

Red-man syndrome, also known as "red-neck syndrome," is reported to occur in up to 47% of patients (129-132) receiving vancomycin. The reaction is characterized by an erythematous flushing of the face, neck, and upper extremities; it does not appear to have a relationship to serum concentrations. Although it is thought to be related to histamine release in response to a too-rapid infusion (130-131), there are reports of the reaction after an appropriately slow infusion rate (132).

Nephrotoxicity is reported in 5-7% of patients when vancomycin is used alone. The data are less clear when the drug is used in combination with an aminoglycoside. Some studies find an increase of nephrotoxicity (up to 35% of patients), whereas others report no change when it is used in combination with an aminoglycoside (129,133143). Studies of vancomycin in animal models, both alone and in combination with aminoglycosides, have not clarified this issue (140-142). The original preparations of vancomycin contained impurities now thought to have played a role in the early cases of nephrotoxicity (10, 129,136), although a clear relationship between the two has not been proven. There is some evidence that nephrotoxicity occurs more frequently when trough serum concentrations exceed 10 mg/L (10 [micro]g/mL) (129,133-142).

The frequency of ototoxicity varies from <2% to 5.5% (129,138,143-144). Ototoxicity is more commonly reported in patients with decreased renal function when serum concentrations are persistently increased above 80 mg/L (80 [micro]tg/mL) (129,138, 143). Temporary tinnitus has been associated with serum concentrations of 40 mg/L (40 [micro]g/mL) (143). Controversy exists as to whether the risk of ototoxicity increases (129,143) when the drug is co-administered with another ototoxic or nephrotoxic drug. As is the case with nephrotoxicity, animal studies of ototoxicity conflict (145-146).

INDICATIONS FOR MONITORING

The criteria for monitoring vancomycin serum concentrations are not as evident as for the previously discussed drugs. The practice of routinely monitoring peak and trough serum concentrations as monitors of efficacy and toxicity originated when guidelines for aminoglycoside monitoring were applied to vancomycin. Currently, several controversies exist, including whether vancomycin be monitored for any patient; if monitoring is necessary, which specimen to monitor; and the appropriate serum concentrations to target.

The debate regarding the need to monitor arose as retrospective studies suggested that the incidences of nephrotoxicity and ototoxicity were relatively low with current preparations of the drug and as it became evident that a clear relationship between toxicity and serum drug concentrations was lacking (10-11, 147-151).

As a result, most clinicians currently agree that many patients, particularly adult patients with adequate renal function (9-11,148-154), do not need to be monitored routinely. However, we agree with Moellering (154) and others (9,148,151) that, until proven otherwise, monitoring is warranted for some patients: patients with impaired or rapidly changing renal function (148,150-151), especially those patients receiving combination therapy with an aminoglycoside or another nephrotoxic drug (9,148,151); patients undergoing renal dialysis (9,151, 155), to assure that adequate vancomycin concentrations are maintained; patients in whom the volume of distribution (9,148,151,156159) is altered, e.g., burn patients, i.v. drug abusers (156), neonatal and pediatric patients (79,158), pregnant patients, and patients with malignancies (157); patients receiving prolonged courses (160) of vancomycin (because clearance has been shown to decrease after 10 days); and patients receiving higher than usual doses (151).

Given that vancomycin exerts its bactericidal actions by inhibiting bacterial cell wall synthesis, a process that is relatively independent of concentration, drug concentrations exceeding four to five times the MIC are not necessary. Instead, maintaining drug concentrations above the MIC of the organism for the entire dosing interval, a situation best monitored using serum trough concentrations, is desired. Consequently, the value of peak serum concentrations in monitoring vancomycin has been questioned (10-11, 151, 153, 159). Because of the lack of correlation between efficacy or toxicity and the extreme interpatient variability regarding the time at which peaks occur with vancomycin (151,153, 159), we recommend that peak serum concentrations not be obtained for routine vancomycin therapy.

Therefore, for those patients for whom serum concentration monitoring is deemed necessary, we recommend the use of trough serum concentrations. Samples should be obtained once steady-state is achieved, within 30 min of the next dose. Although no firm recommendations have been established regarding subsequent serum concentration determinations, some authorities (151) have suggested that follow-up measurements be repeated in 1 to 2 weeks or more frequently, depending on the clinical status of the patient. For example, patients with poor therapeutic response, severe renal impairment or changing renal function, unusually high MICs, concurrent nephrotoxic drugs, long-term vancomycin therapy, or other risk factors for toxicity would require more frequent monitoring.

In addition, some have recommended that serum creatinine should be monitored before initiation of therapy and repeated at least weekly, depending on patient status and clinical judgment of the clinician (9,149). Occasionally, drug concentrations in other body fluids, such as CSF, peritoneal fluid, or dialysate, are monitored to assess penetration (125-128).

ANALYTICAL ISSUES

Immunoassay- and HPLC-based methods are used routinely. A review of the 1996 CAP proficiency reports suggests that fluorescence polarization immunoassaybased assays are the most frequently used methods. Some immunoassays, fluorescence polarization immunoassays more than enzyme immunoassays, exhibited considerable cross-reactivity (161-163) with vancomycin crystalline degradation products (CDPs). The formation of vancomycin CDPs occurs in patients with renal dysfunction when the drug is exposed to temperatures above 25 [degrees]C. The amount of product formed varies between and within patients. CDPs have no antimicrobial activity. Samples containing CDPs had higher vancomycin concentrations when tested using these immunoassays compared with HPLC methods. Current versions of commercial assays do not have this problem. Precision profiles should be performed, but the analytical sensitivity reported by available methods is adequate for monitoring trough serum concentrations. Assay performance should be validated if other specimens are tested (65, 78).

Either serum or EDTA-treated plasma is a suitable specimen (Table 2) for monitoring. Although heparinized samples are considered acceptable by most manufacturers, there are reports of vancomycin instability in the presence of heparin (164-165); therefore, these samples should be tested with caution or suitability verified. No data have been reported to suggest that vancomycin binds to gel barrier tubes or serum separator devices (69-72).

REPORTING ISSUES

Trough serum concentrations (Table 1) of 5-10 mg/L (5-10 [micro]g/mL) are considered acceptable serum concentrations for the treatment of most gram-positive organisms. Although Saunders (149) suggests that concentrations of 10-12 mg/L (10-12 [micro]g/mL) be considered early signs of drug accumulation and potential nephrotoxicity, a study by Zimmerman et al. (166) correlated serum concentrations with outcomes for patients with grampositive bacteremia and concluded that the trough range should be raised slightly. As discussed earlier, there are reports of nephrotoxicity in patients whose trough serum concentrations were <10 mg/L (10 [micro]g/mL). Until additional studies are conducted to clarify this issue, we recommend the use of this range. Results for samples below the trough range should be flagged as such when reported. Concentrations >40 mg/L (40 [micro]g/mL) have been associated with toxic or adverse reactions (Table 1). These samples should be verified and reported as critical values.

Because of concerns regarding the prevention of emerging vancomycin-resistant enterococci, more efficient coordination of laboratory information (microbiology and chemistry) with pharmacists and physicians is an area being addressed by many hospital pharmacy and therapeutics committees. Clearly the use and monitoring of vancomycin is an area requiring close watching and additional research.

We thank Kenneth H. Rand (Department of Pathology, Immunology, and Laboratory Medicine and Department of Medicine, Division of Infectious Diseases, University of Florida College of Medicine) and Lisa Haglund (Department of Medicine, Division of Infectious Diseases, University of Cincinnati College of Medicine) for their assistance in the preparation of the manuscript.

Received August 29, 1997; revision accepted February 27, 1998.

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CATHERINE A. HAMMETT-STABLER * and THOMAS JOHNS

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine; and College of Pharmacy, Gainesville, FL 32610.

* Address correspondence to this author at: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Box 100275, Gainesville, FL 32610. Fax 352-395-0585; e-mail stabler.pathology@mail.health.ufl.edu.

[2] Nonstandard abbreviations: TDM, therapeutic drug monitoring; MIC, minimum inhibitory concentration; i.v., intravenous; CSF, cerebrospinal fluid; CAP, College of American Pathologists; and CDP, crystalline degradation product.
Table 1. Therapeutic and toxic ranges.

Drug Therapeutic range, mg/L

 Peak

 Less severe Life-threatening
 infections infections
Aminoglycosides
 Gentamicin 5-8 8-12
 Tobramycin 5-8 8-12
 Amikacin 25-35 25-35
Chloramphenicol 10-20
Vancomycin

Drug Therapeutic range, mg/L

 Trough

 Less severe Life-threatening
 infections infections
Aminoglycosides
 Gentamicin <1 <2
 Tobramycin <1 <2
 Amikacin 1-4 4-8
Chloramphenicol
Vancomycin 5-10

Drug Toxic range, mg/L

 Peak Trough

Aminoglycosides
 Gentamicin >12 >2
 Tobramycin >12 >2
 Amikacin >35 >10
Chloramphenicol 25
Vancomycin 40

Table 2. Samples for therapeutic monitoring.

Drug Sample timing

Aminoglycosides Conventional dosing
 Gentamicin Peak:
 Tobramycin 60-90 min after i.m. (a) injection
 Amikacin 30-60 min after i.v. infusion
 Trough: within 30 min of next dose
 Pulse dosing
 Random timed, 8-12 h after dose
 Trough: within 30 min of next dose
Chloramphenicol Peak:
 Capsule: 60 min after dose
 Suspension: 1.5-3.9 h after dose
 i.v.: 0.5-1.5 h after infusion
Vancomycin Trough: within 30 min of next dose

Drug Sample type Sample stability

Aminoglycosides Serum; EDTA plasma 2 h room temperature;
 Gentamicin freeze
 Tobramycin
 Amikacin
Chloramphenicol Plasma (EDTA, citrate) Protect from light;
 freeze
Vancomycin Serum; EDTA plasma 2 h room temperature;
 freeze

Drug Metabolite monitoring

Aminoglycosides None
 Gentamicin
 Tobramycin
 Amikacin
Chloramphenicol Pro-drug occasionally
Vancomycin None

(a) i.m., intramuscular.

Table 3. Effect of imprecision (CV) on aminoglycoside dosing. (a)

 +10% -10%

Measured peak, mg/L 9 9
True peak, mg/L 9.8 9.7
Measured trough, mg/L 1.35 1.65
[K.sub.e] (b) 0.1725 0.1542
New dose, mg 120 every 18 h 120 every 18 h
Estimated peak, mg/L 7.6 8.2
Estimated trough, mg/L 0.34 0.51

 +20% -20%

Measured peak, mg/L 9 9
True peak, mg/L 9.8 9.68
Measured trough, mg/L 1.2 1.8
[K.sub.e] (b) 0.1832 0.1463
New dose, mg 120 every 18 h 120 every 18 h
Estimated peak, mg/L 6.73 8.3
Estimated trough, mg/L 0.24 0.6

 +30% -30%

Measured peak, mg/L 9 9
True peak, mg/L 9.9 9.64
Measured trough, mg/L 1.05 1.95
[K.sub.e] (b) 0.1953 0.139
New dose, mg 120 every 18 h 120 every 18 h
Estimated peak, mg/L 7.85 8.4
Estimated trough, mg/L 0.23 0.68

(a) The simulated patient was a 50-year-old woman; weight, 60 kg;
serum creatinine, 15.0 mg/L; CrCl, 50 mL/min; [V.sub.d], 15 L
(0.25/kg); started on gentamicin at a dose of 120 mg i.v. every
12 h. The measured peak concentration was 9.0 mg/L; the calculated
true peak concentration was 9.75 mg/L; the measured trough
concentration was 1.5 mg/L; Ke was 0.1629 h. From these data, a
new dose of 120 mg every 18 h was ordered to achieve a serum
trough concentration of <1.0 mg/L. The subsequent estimated peak
concentration was predicted to be 8.11 mg/L and the estimated
trough to be 0.5 mg/L.

(b) [K.sub.e], elimination rate constant; CrCl, creatinine
clearance; and [V.sub.d], volume of distribution.
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Title Annotation:NACB Symposium
Author:Hammett-Stabler, Catherine A.; Johns, Thomas
Publication:Clinical Chemistry
Date:May 1, 1998
Words:10112
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