As CRO is widely used in the United States to treat numerous invasive bacterial infections, several authors took interest in the initial FDA safety warning (10, 22, 23). Since recent changes have been implemented in the United States on the basis of data from in vitro studies, vigilant safety monitoring and clinical analysis can provide the best guidance for the use of these agents. Hence, we reviewed the available medical literature for reports of CRO-calcium precipitation in adults and analyzed the FDA MedWatch Adverse Event Reporting System (AERS) databases for adverse drug interactions reported with CRO treatment in association with calcium. For comparison, we also searched AERS for interactions reported between ceftazidime (CAZ) and calcium.

Others have also recently analyzed the AERS database and focused specifically on the neonatal population (8). A total of seven cases were identified among the individuals in this cohort, six of which resulted in death. The neonates were 3 weeks of age or younger in five of these six cases; age was not recorded in the sixth report. Many of the neonates received doses of CRO higher than those recommended in the package insert, and some of the neonates received the drug via intravenous push administration, which is not recommended due to the increased initial serum concentrations that result. Additionally, none of the seven cases occurred in the United States (8). This analysis supports the FDA warning that CRO not be used by neonates (≤28 days of age) if they are receiving (or are expected to receive) calcium-containing intravenous products.

The history of the events leading to the multiple warnings is complex and can be difficult to follow. The 2007 warning issued by the FDA emanated from a report generated by the French National Commission of Pharmacovigilance on 31 January 2006 (1) which detailed fatal outcomes in neonates as a result of CRO-calcium precipitates in the lungs and kidneys. The investigation was conducted between 2002 and 2004 by the Regional Center of Pharmacovigilance (Paris, France) and combined international laboratory data with regional French data (Table ​(Table4)4) (1). Ten of 77 regional files and 21 of 247 international files were selected for in-depth reviews. Within the 10 regional files, one calcium-CRO interaction resulting in death occurred in a premature infant in 2002. In 2004, one “favorable outcome” occurred. This outcome was not further defined, but one can speculate that the patient survived. Additionally, there was suspicion of one CRO-acetaminophen and calcium gluconate interaction (outcome undefined), one error of administration, and seven cases of lithiasis in six total patients (two renal events in infants and one in a child, two biliary events in children, and one case of mixed lithiases). Within the chosen international reports, newborn reactions included one case of renal lithiasis, one case of biliary lithiasis, and two suspected cases of undetermined lithiasis. In the 2- to 18-year-old segment, there were 13 cases of biliary lithiasis, 2 case of renal lithiasis, and 2 cases of mixed lithiases. After the completion of this initial inquiry, the investigators reviewed 178 additional international cases dating from 1996 to 2001 in children less than 2 years of age. These data revealed 7 cases of calcium-CRO interactions, 13 cases of biliary lithiasis, and 7 cases of renal lithiasis (14 of these cases occurred in infants less than 1 year old, and 8 of these cases were less than 6 months), as well as 2 deaths due to unknown causes. Of all the lithiases reviewed by the commission, approximately 75% of the total cases occurred in children less than 18 years of age (1). The FDA later stated that it had uncovered three additional fatalities in neonates and concluded that it was necessary to institute a modification to the labeling of CRO (28). While the exact sources were unclear, the FDA cited a total of nine cases, including eight deaths. In five cases, embolic events appeared to lead to patient demise, with crystalline structures being identified in three of the cases. In one of these cases, crystalline emboli were found in both the lungs and the kidneys. The remaining three cases died as a result of unclear causes (18).

Internationally, the events triggered heterogeneity in guidance. The AFSSAPS and the WHO issued warnings asking providers to refrain from using CRO and calcium simultaneously in infants, although neither agency has offered formal recommendations regarding their usage in adults. In a November 2006 release, the AFSSAPS indicated that CRO was contraindicated in premature infants up to 41 weeks of age and in term neonates less than age 28 days with hyperbilirubinemia or concomitant calcium use. Likewise, the latest WHO recommendations mirror the French recommendations (2) (Table ​(Table5).5). Thus, the majority of recommendations are now focused on neonates.

The lack of documented clinical events in adults is supported by the results of in vitro experiments and calculations. An in vitro study completed by Roche and the FDA in 2009 evaluated the recovery of CRO (i.e., the purported precipitation) in pooled human plasma according to various concentrations of calcium and CRO (7). Purported precipitation occurred at lower calcium concentrations for isomorphic CRO concentrations in neonatal plasma than in adult plasma (precipitation likely at ≥16 mg/dl and ≥24 mg/dl, respectively). Such results indicate that there may be differences in the level of protein binding which exacerbate precipitation. One can also consider the likelihood of precipitation on the basis of the known serum concentrations of CRO and calcium (Table ​(Table6).6). To estimate calcium serum concentrations conservatively, a well-stirred model, as well as zero-order infusion and no distribution (the total volume is equal to the intravascular volume), was assumed for calcium. Dose calculations for calcium were based on mg/kg dosing (16) and average weights for age stratifications for each age group (20). Free calcium concentrations were used for the calculations (27). The maximal expected CRO concentrations were obtained from values in the literature (17, 24, 26). Calculation of the saturation index was based on the product of the maximal expected serum CRO concentration obtained at steady state (post-distributive phase) and maximal free calcium concentration (the supraphysiologic concentration plus the bolus dose concentration) divided by the solubility product constant (27). Analysis of these age-stratified saturation indices reveals that neonates have a saturation index twofold greater than that for adults (Table ​(Table6).6). The calculations showing a higher saturation index for neonates as a result of higher calcium concentrations coupled with the in vitro findings that precipitation occurs at calcium concentrations ≥16 mg/dl for neonates and ≥24 mg/dl for nonneonates suggests that neonates are at the highest risk for precipitation. The findings empirically support the presence of CRO-calcium precipitation when conditions are favorable for this outcome and, hence, support the current FDA contraindication of CRO and calcium in patients less than 28 days old (24, 28). Additionally, these data support the retraction of the 2007 FDA warning (that all age groups not receive CRO and calcium-containing products within 48 h of one another) (28). One should also consider that certain variables can make precipitation more favorable. Pathophysiology, such as dehydration, may disproportionately increase drug and calcium concentrations and may place neonates at increased risk for precipitation compared to the risk for adults when they are given CRO and calcium in combination.

The findings of in vivo studies with animals should also be considered. Supplementary investigations with animals have provided evidence of precipitation of the calcium salt of CRO in the gallbladder bile of dogs and baboons; however, the likelihood of this occurrence in humans is thought to be lower since CRO in humans has a prolonged half-life compared to that in the animals studied, the calcium salt of CRO is more soluble in human bile, and the calcium concentrations in humans are reduced (24). While the likelihood of precipitation is lower for humans, the potential for manifestation is not zero and may be higher in certain scenarios. For example, the collecting tubules of organs that typically function in the clearance of xenobiotics may experience elevated drug concentrations. Thus, it is not surprising to observe biliary sludging or nephrolithiasis in patients who receive CRO and calcium, as high concentrations predispose individuals to these conditions (4, 18, 27). In the biliary tract, CRO concentrations are elevated due to biliary excretion (40% of total elimination); the concentrations of CRO can exceed the concentrations measured in serum by 20 to 150 times (6, 27). Additionally, when CRO is secreted into bile, a passive flow of calcium ions is induced (30). In both children and adults, precipitation events are most often transient and the incidence of lithiasis is <0.1% (15). Such events may be more common and predictable in individuals with high concentrations of CRO in the gallbladder due to fasting or dehydration, as is common in elderly individuals or individuals with impaired gallbladder emptying (14, 27).

While this phenomenon is predictable in the gallbladder, precipitation has occurred in the kidneys and lungs of neonates as embolic phenomena from the circulating blood supply (1, 10, 18, 28). These events might be explained by the possibility that neonates metabolize CRO differently than adults, since their biliary secretion pathway is poorly developed, resulting in elevated serum concentrations (25, 27). A lower total systemic clearance produces a 100 to 200% longer half-life in infants than in children and adults (25). Similar precipitation events could potentially occur in adults, as there are many clinical scenarios that result in simultaneously high concentrations of endogenous calcium and administered CRO, such as treatment for superimposed infections in dehydrated adult patients with elevated serum calcium concentrations. We suggest the use of caution when the use of sequential therapy is contemplated in these scenarios and agree with the labeling that suggests that intravenous therapy with CRO and calcium not be commenced simultaneously in any patient (9, 24). Thus, in vitro studies, a systematic analysis of an adverse event reporting database, and the lack of clinical observations of adverse events yielding similar results for CRO and CAZ agree that precipitation events leading to renal or pulmonary compromise are not likely for most adult patients.

To our knowledge, this study employs the most comprehensive clinical evaluation to date of a possible reaction between CRO and calcium in patients, although several important limitations exist. First, our study is restricted to reported data available from the public domain and MedWatch reports. While all medications prescribed in the United States are subject to MedWatch reporting, AERS data represent reports that are voluntary, sporadic, and often incomplete (5). Differences in the numbers of reports between drugs relate to utilization rates as well as many other notable limitations. To retain high sensitivity, we included all reports of CRO or CAZ in conjunction with calcium for any adverse drug event reported to MedWatch. Second, CAZ was used as a comparator of the associated but likely noncausal precipitation events. While these methods are nonspecific for the identification of embolic events, the “noise” created by this mechanism of study is high in the CAZ group, which signifies that most reactions observed are probably unrelated to the administration of the drugs in combination with calcium; this is further emphasized by the fact that older patients were identified in the CRO-treated group. Since neonates appear to be the only category of patients with an embolic event relationship to date, a study mechanism with low levels of noise should have identified CRO-treated patients as younger. Our model lost the ability to predict outcomes when we restricted the data to those patients whom we classified as probable or possible renal or pulmonary events, due to a combination of the small sample size and weak effects. Hence, either no difference or a very small difference exists between the two groups. Third, it is also possible that the reporters may not have considered including calcium products in their MedWatch reports. Fourth, AERS data do not provide sufficient information to calculate incidence rates due to the nature of passive, voluntary reporting to MedWatch and the lack of a denominator (utilization). Fifth, the methods used to categorize the likelihood of events attributed to the drug, while they are systematic, remain subjective. Specifically, our modified definition of “probable” cannot be interpreted literally, as it is only closer to causal in a spectrum ranging from unrelated-associated to causal. Finally, it is possible that clinicians might have recognized embolic phenomena with CRO and calcium but were unwilling to report them secondary to eventual favorable clinical outcomes or time constraints. It has been estimated that due to the voluntary, passive surveillance design of the MedWatch system, <10% of adverse events are reported to the FDA (21). The inability to distinguish rare from underreported events underscores the need for improved postmarketing surveillance.