Clarithromycin resistance

Preexisting antimicrobial resistance is an increasing cause of treatment failure and is estimated to account for up to 70% of all treatment failures. Geography is the most important factor in HP resistance. Metronidazole-resistant strains are more prevalent in Asia (85%) than North America (30%).15 Primary resistance to amoxicillin and tetracycline remains low in both the United States and Europe. Clarithromycin resistance rates are estimated to be approximately 10% in the United States. Another confounding factor when evaluating potential antibiotic resistance is that culture and sensitivity studies are not routinely performed with HP infection. 

Resistance of H. pylori to clarithromycin appears to have increased in proportion to clarithromycin nse. Clarithromycin resistance arises throngh mntations that lead to base changes in 23S ribosomal RNA snbnnits. A rapid PCR hybridization assay with a sensitivity of 97% for the detection of clarithromycin resistance of strains of H. pylori has been described (71). Resistance to clarithromycin has a serious impact on the efficiency of eradicating regimens that include clarithromycin (72-74). The reported incidences of primary resistance of H. pylori to clarithromycin are 6.1% in the USA, 8% in Austria, 8.7% in Bulgaria, 9.5% in Japan, 10% in Spain, 11% in France, 13% in Nigeria, and 23% in Italy (75-82). 

Petersen AM, Schradieck W, Krogfelt KA. Helicobacter py/or -resistens over for clarithromycin. [Resistance of Helicobacter pylori to clarithomycin.] Ugeskr Laeger 1998 160(23) 3412-13. 

Ducons JA, Santolaria S, Guirao R, Ferrero M, Montoro M, GomoUon F. Impact of clarithromycin resistance on the effectiveness of a regimen for Helicobacter pylori a prospective study of 1-week lansoprazole, amoxycillin and clarithromycin in active peptic ulcer. Aliment Pharmacol Ther 1999 13(6) 775-80. 

Osato MS, Reddy R, Graham DY. Metronidazole and clarithromycin resistance amongst Helicobacter pylori isolates from a large metropolitan hospital in the United States. Int J Antimicrob Agents 1999 12(4) 341-7. 

Miki I, Aoyama N, Sakai T, Shirasaka D, Wambura CM, Maekawa S, et al. Impact of clarithromycin resistance and CYP2C19 genetic polymorphism on treatment efficacy of Helicobacter pylori infection with lansoprazole- or rabeprazole-based triple therapy in Japan. Eur J Gastroenterol Hepatol 2003 15 27-33. 

In addition to the base methylation, transitional mutations (A2142G and A2143G) near the peptidyltransferase region in domain V of the RNA from clarithromycin-resistant Helicobacter pylori have clinically been found to give... 

In those patients for whom prior eradication therapy has been unsuccessful or in individuals who exhibit antimicrobial resistance, quadruple therapy may be contemplated. Diagnosis of clarithromycin resistance can be done by sequencing the specific region of the 23S RNA where a point mutation results in prevention of drug binding. 

Clarithromycin resistance in most countries in the order of 1 to 12% prevalence is not yet a major issue, but causes more problems, as only 1 out of 2 patients with H. /rptorz-resistant strains would respond to the PPI triple therapy (OAC). Combinations of PPI with metronidazole (independent of the dose in the range from 800 to 1600 mg) and amoxicillin were con-sistantly 10% less effective than PPI-MC or PPI-AC [125]. Another important point emerging from all the studies is that clarithromycin with metronidazole as a partner in the PPI triple regimens requires only a dose of 2 X 250 mg, whereas in combination with amoxicillin regimens the required dose of clarithromycin is 2 x 500 mg. 

Erythromycin- sulfisoxazole 50 mg/kg per day of erythromycin component in 3 4 doses Nausea, vomiting, abdominal pain, diarrhea, rash SS Many drug interactions (like clarithromycin), contraindicated in children under 2 months increasing pneumococcal resistance... 

Pilotto A, Franceschi M, Rassu M, Furlan F, Scagnelli M In vitro activity of rifabutin against strains of Helicobacter pylori resistant to metronidazole and clarithromycin. Am J Gastroenterol 2000 95 833-834. 

In uncomplicated exacerbations, recommended therapy includes a mac-rolide (azithromycin, clarithromycin), second- or third-generation cephalosporin, or doxycycline. Trimethoprim-sulfamethoxazole should not be used because of increasing pneumococcal resistance. Amoxicillin and first-generation cephalosporins are not recommended because of /1-lactamase susceptibility. Erythromycin is not recommended because of insufficient activity against H. influenzae. 

The treatment of HP has become increasingly difficult due to the frequency of antibiotic resistance and recurrence after successful treatment. In Peru, the recurrence rate of the infection is as high as 73% even after successful eradication. In this instance, recurrence is not attributed to antibiotic resistance but to re-infection of patients. In the United States, resistant HP is also of concern. The Helicobacter pylori Antimicrobial Resistance Monitoring Program (HARP) is a multicenter US network that tracks HP patterns of resistance. In 2004, HARP reported that 34% of 347 HP isolates tested were resistant to one or more antibiotics commonly used to treat HP infections.In the US, most antibiotic resistance is associated with metronidazole and clarithromycin, both standard treatment options for HP. Thus, antibiotic resistance and high re-infection rates strongly argue for the development of new therapeutic modalities to prevent and treat HP infections worldwide. 

Zaidi SE, Yoshida 1, Butt F, Yusuf MA, Usmanghani K, Kadowaki M, Sugiyama T. (2009) Potent bactericidal constituents from Mallotus philippinensis against clarithromycin and metronidazole resistant strains of Japanese and Pakistani Helicobacter pylori. Biol Pharm Bull 32 631-636. 

Dual therapy - 30 mg lansoprazole plus 1 g amoxicillin both taken 3 times/day for 14 days for patients intolerant or resistant to clarithromycin. 

There are a number of factors that limit the effectiveness of regimens designed to eradicate H. pylori. The first, antibiotic resistance, is seen with metronidazole and clarithromycin but has not been reported with bismuth, amoxicillin, or tetracycline. Second, mild adverse effects (eg, diarrhea, metallic taste, black stools) do occur in approximately 30% to 50% of patients. Therefore, shorter treatment periods in this group of patients may be better tolerated. 

C. Microbial resistance is generally more common to clarithromycin and metronidazole than to amoxicillin. Therefore amoxicillin should be used in initial treatment (except where the patient is sensitive to it), plus one of the others. Metronidazole should be avoided if there has been prior patient use of the drug as the organism may be resistant to it. 

Clarithromycin is derived from erythromycin by addition of a methyl group and has improved acid stability and oral absorption compared with erythromycin. Its mechanism of action is the same as that of erythromycin. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin is more active against Mycobacterium avium complex (see Chapter 47). Clarithromycin also has activity against M leprae and Toxoplasma gondii. Erythromycin-resistant streptococci and staphylococci are also resistant to clarithromycin. 

When meningitis with penicillin-resistant pneumococcus is suspected, empiric therapy with this regimen is recommended. 4Erythromycin, clarithromycin, or azithromycin (an azalide) may be used. 

---