A 28 y/o female patient with a history of iron deficiency anemia presents to the clinic. She has a fever of 101F, productive cough/rusty sputum, and describes a single shaking chill. Her labs show a leukocytosis and a left shift but otherwise unremarkable. A gram stain of her sputum shows gram (+) cocci. She’s on oral iron for her iron deficiency and calcium carbonate for prevention of osteoporosis but nothing else. There’s no other significant medical or family history.

After a brief history and physical, the intern admits the patient with a diagnosis of community acquired pneumonia (most likely Strep pneumoniae). The intern starts the patient on levofloxacin 500mg po every day for 10 days. After 4 days of therapy, she is still running a fever.

The team is perplexed with her slow progress, esp since she’s on an antibiotic effective against the identified pathogen. Is there anything we can do to improve her medication regimen?

**THANKS to MAJ (Dr.) Nick Conger and Dr Annabel Schumaker for
their help with this Pearl**

The interaction of fluoroquinolones and divalent or trivalent cations is well known. A recent local MUE showed about one third of the fluoroquinolone patients taking concurrent divalent or trivalent cations within 1 hour of their oral flouroquinolone dose.

A study by Radandt and associates tried to quantify the effects of this interaction. They are (when administered within 1 hour of each other):

        Iron with Cipro: 25-50% reduction in FQ AUC and Cssmax

        Iron with Ofloxacin (Levo) 25-50% reduction in FQ AUC

        and Cssmax

Bigger interactions with: Aluminum (>75% for Cipro, 25-50% for Oflox), Calcium (25-50% for Cipro), Sucralfate (51-75% for Cipro). Zinc (25-50% for Cipro) The authors state, “Iron replacement therapy should be regarded as a possible contraindication for the treatment of serious infections with flouroquinolones. The mechanism of this interaction appears to be the formation of insoluble complexes or the chelation of drug and polyvalent cation; the interaction seems to be unrelated to changes on pH induced by antacids...supported by the lack of data showing impaired absorption of FQ’s co administered with histamine type 2 receptor antagonists.

Although the specific component of multivitamin responsible for the reduction of FQ absorption has not been identified, zinc is suspected.” Another article by Stein and colleagues in Clinics in Infectious Diseases (1996) states, “The absorption of quinolone antibiotics is significantly decreased by concomitant administration of compounds that contain multivalent metal cations such as aluminum, magnesium, zinc, iron, and calcium. This effect appears to be due to the formation of insoluble drug-cationic chelate complexes in the gastrointestinal tract.

It has been recommended that FQ’s be given at least 2 hours prior to administration of these compounds.”

Neither of these papers stated or hypothesized if a cation/FQ combination lead to a treatment failure. The significant decreases in AUC (area under the curve) may translate into decreased absorption from oral administration, lower systemic levels, and potentially, treatment failures. Our local MUE did not evaluate treatment failure either. The best recommendation is to space the dosing of these agents by at least 2 hours.

Iron is usually an easy one to spot but other medications or combinations containing divalent and/or trivalent cations include:

Antacids - calcium carbonate (Tums®), aluminum/magnesium combinations (Mylanta®, Maalox®), etc.

Multivitamins with minerals (iron, calcium, magnesium, zinc, etc)

Dairy products

Sucralfate [Carafate®] contains aluminum and has been used as a phosphate binder in dialysis patients.

REFERENCES:

*    Flor S, Guay DRP, Opsahl JA, Tack K, Matzke GR.  Effects of magnesium-aluminum hydroxide and calcium carbonate antacids on bioavailability of ofloxacin.  Antimicrob Agents Chemother 1990;34:2436-8.

*    Tanaka M, Kurata T, Fujisawa C, et al.  Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide.  Antimicrob Agents Chemother 1993; 37:2173-8

*    Radandt JM, Marchbanks CR, Dudley MN.  Interactions of flouroquinolones and other drugs:    mechanisms, variability, clinical significance, and management.  CID 1992; 14:272-84.

*    Stein GE.  Pharmacokinetics and pharmacodynamics of newer flouroquinolones.  CID 1996;23(Supp1):S19-S24