Pilot Randomised Controlled Trial of Penicillin Versus Flucloxacillin for Definitive Treatment of Invasive Penicillin Susceptible Staphylococcus Aureus

Background and rationale:

Resistance to penicillin was discovered in Staphylococcus aureus in the mid-1940s, soon after the introduction of penicillin as a therapeutic agent into clinical practice. The emergence of penicillin resistant S. aureus (PRSA) was widely encountered in hospitals thereafter, with some reports finding rates of PRSA rising from 14% to 38% in less than 1 year. Two mechanisms are known that result in resistance to penicillin in staphylococci. The most common, and earliest described, was by the production of a serine β-lactamase, known as penicillinase (PC1), which hydrolyses the β-lactam ring resulting in the production of penicilloic acid. A second mechanism leads to resistance to penicillin and other beta-lactam agents by production of penicillin-binding protein, PBP2a, encoded by mecA. Following the emergence of PRSA, a new class of anti-staphylococcal penicillins were developed that were resistant to hydrolysis of the beta-lactam ring by penicillinase. The isoxazolyl-penicillins, semi-synthetic penicillin derivatives that are stable during exposure to penicillinase, are now the most commonly used agents for the treatment of S. aureus infections.

Despite widespread resistance to penicillin amongst S. aureus, a significant proportion of invasive isolates remain susceptible. Although penicillin and isoxazolyl-penicillins have been used in clinical practice for more than 50 years, the optimal therapy for patients with invasive penicillin susceptible S. aureus (PSSA) remains controversial. Methicillin susceptible S. aureus (MSSA) bloodstream infections are commonly sub-divided into categories based upon the presence of penicillinase, the absence of which defines PSSA strains. Many clinicians advocate treating both MSSA and PSSA the same, irrespective of whether penicillinase is detected or not. One group who strongly supports this view is the American Heart Association, which has published recently updated guidelines on infective endocarditis. This recommendation is based upon literature suggesting that detection of penicillinase is not reliable in some clinical laboratories. Multiple publications have demonstrated that the previous widely used phenotypic method of penicillinase detection, by nitrocefin hydrolysis, lacks adequate sensitivity for detecting penicillinase. Yet, treatment failure with penicillin due to inability to detect penicillinase has not been previously described in the medical literature to our knowledge. Regardless, many laboratories have now changed methods to the penicillin disc test, where isolates harbouring penicillinase may be detected by interrogation of the edge of the disc, with a sharp edge confirming the presence of penicillinase and a tapered edge indicating an absence. This method is now employed in most Pathology services and is the method approved by international governance organisations.

Other experts argue for potential superiority with penicillin due to a lower MIC distribution when compared with other beta-lactam agents active against S. aureus, combined with the ability to obtain high levels of free non-protein-bound plasma drug concentrations.

To date there is only one previous study that has directly compared the outcome between a semi-synthetic penicillin derivative (dicloxacillin) and penicillin for PSSA infections. In this retrospective study, no statistically significant difference was observed between penicillin and dicloxacillin based on a mortality outcome. Although this study does not support improved outcome with penicillin compared with dicloxacillin, it should be noted that significantly more patients treated with penicillin had a higher Pitt bacteraemia score and deep-seated infection such as endocarditis or osteomyelitis. Data from the ANZCOSS study, a prospective observational study of SAB within Australia between 2007 - 2016, demonstrated a possible 30-day crude mortality benefit for patients treated with benzylpenicillin compared to flucloxacillin or dicloxacillin (unpublished data). Patients in this cohort were treated 2:1 with flucloxacillin over benzylpenicillin, however, benzylpenicillin treatment was proportionally higher in patients with endocarditis or other deep-seated infections. In a multivariate logistic regression model, Flucloxacillin therapy was associated with a non-statistically significant increase in the odds ratio for 30-day mortality (OR 1.55, 95% CI 0.99 - 2.47).