Escalating resistance to Streptococcus pneumoniae is a global problem. Streptococcal resistance to antibiotics has increased not only among penicillins and cephalosporins but also among macrolides, tetracyclines, and sulphonamides. In contrast, rates of resistance to the newer generation fluoroquinolones remain rare.

Cross-resistance between penicillin-resistant isolates and other antimicrobials has also been widely reported. In fact, isolates that demonstrate high-level resistance to penicillin are virtually 100% resistant to all first- and second-generation cephalosporins, and approximately 25% are also resistant to the third-generation cephalosporin cefotaxime. In addition, a majority of penicillin-resistant pneumococcal isolates are also resistant to macrolides, tetracyclines or sulphonamides.

Cross-resistance is also demonstrated by azithromycin, and as penicillin resistance increases, the rate of azithromycin resistance rapidly increases to almost 80%. In sharp contrast, no cross-resistance has been demonstrated with levofloxacin.

Factors that facilitate the development of penicillin resistance include previous antibiotic administration, usage in children under the age of five, day care centers, and a limited number of well-defined serotypes. Importantly once the resistant clone has developed it will always increase rapidly over time. This is highlighted by data showing increases in penicillin resistance in a single decade. In Japan, the rate rose from 1% to almost 30%, and the rate also escalated dramatically from 6% to over 40% in Spain.

In the United States there has been a dramatic increase in penicillin-resistant Streptococcus pneumoniae in the last decade. In 1979 through 1987 there was only 0.02% high-grade penicillin resistance in the United States, contrasted to the current rate of 18%, and 35% if intermediate levels of resistance are included.

At the same time there has been a dramatic increase in macrolide resistance. A recent review article has shown rapid increases in macrolide resistance in Barcelona, Spain, and Italy. This has also happened elsewhere, with macrolide resistance undetectable in Hong Kong in 1983, rising to over 40% by 1997. Recent data from Hong Kong now puts this figure at about 79%.

In the Unites States the rate of macrolide resistance was virtually undetectable prior to 1990, but this has steadily increased and 22% of pneumococci in the US were macrolide resistant in 1997 to 1998, with current rates increasing to 28% to 30%.

The most recent data from the US shows this trend of increasing resistance is continuing. The penicillin resistance among the pneumococcus was 14.7% in 1998, increasing to 18.4% in 2002. Azithromycin resistance has increased from 22.7% to 27.5%, while the trimethoprim-sulphamethoxazole rates have remained stable.

Resistance to ceftriaxone and cefotaxime, the most active of the β-lactam antibiotics, remains low with a small increase in high-level resistance to 1.7%. Correspondingly, levofloxacin has retained excellent activity with resistance less than 1%.

To clarify the clinical significance of resistance, a retrospective study of nearly 6,000 patients with bacteremic pneumococcal infections was performed. While the total mortality rate was 12%, death after four days increased 6 to7 fold if the pathogen was highly resistant to penicillin. This was also true for cefotaxime.

The clinical impact of resistance is still not clear, however, with contrasting results recently reported. A large international study of more than 800 patients reported a mortality rate in pneumococcal bacteremia of 17%. Multivariate analysis identified the risk factors for mortality as advanced age, severity of illness and immunosuppression, but not penicillin resistance.

While debate continues on the clinical impact associated with resistance, it is now well recognized that; due to the escalating incidence of resistance to penicillins, macrolides and cephalosporins; there is an expanded role for newer-generation fluoroquinolones. In contrast to β-lactams and macrolides, resistance to fluoroquinolones is heterogeneous and relatively low frequency of resistance. Emergence of resistance can occur however if these excellent compounds are overused, and judicious use is advocated.