$re = '/(me)(?!([^<]+)?>)/i';
$str = 'I have ever been prone to seek adventure and to investigate and experiment where <span class=\'me\'>wiser men</span> would have left well enough alone.';
$subst = "<span class='highlight'>$1</span>";
$result = preg_replace($re, $subst, $str);
echo "The result of the substitution is ".$result;
Please keep in mind that these code samples are automatically generated and are not guaranteed to work. If you find any syntax errors, feel free to submit a bug report. For a full regex reference for PHP, please visit: http://php.net/manual/en/ref.pcre.php