MRSA Fluoroquinolones – An Interesting Bunch Playing a High-Stakes Game

antiMRSA 1 copy

Fluoroquinolones (FQ) of the ofloxacin/ciprofloxacin generation were mainly active against Gram-negative bacteria, distinguishing themselves as cidal IV/PO drugs with high potency against most lactose- and non-lactose fermenters.  They were excellent against problem pathogens like P. aeruginosa, had excellent efficacy against Salmonellae, the Gonococcus and other Neisseriae, and you could count on them for coverage of atypicals like Chlamydia (now: Chlamydophila), Mycoplasma, Legionella and some more exotic bugs (e.g., Vibrio cholerae).  There were so few holes in the spectrum that it was easier to recite the organisms not covered.  Among the latter, MRSA was always a big wide gaping hole, pretty much from Day 1 on.

Well, not exactly: The activity of ciprofloxacin against MSSA and MRSA was not bad when you review the MIC ranges in several early publications (0.25-0.5 mg/L)[1].  The rapid development of resistance in a relatively short period of time (with MIC > 64 mg/L), sometimes occurring in patients while on therapy, soon became a universal problem.  Clearly, these older FQ did not do well at all in MSSA or MRSA infections.  With the advent of the ‘respiratory quinolones’, like levofloxacin, moxifloxacin and gatifloxacin, the situation has not improved: while these drugs had demonstrably better activity against S. pneumoniae, none of them can be relied on for S. aureus infections.[2] 

The development of high-level resistance in MRSA occurred fast – sometimes while patients were on therapy

More recent susceptibility studies for CA-MRSA show ciprofloxacin MIC90 >32, with 77% of isolates resistant by CLSI criteria. [3]  Almer found that all resistant isolates had mutations in both the gyrA (DNA gyrase) and the grlA (topoisomerase IV) genes resulting in aminoacid changes.  The ‘classical’ gyrA mutation (Ser84-Leu) was the most prevalent.  Similar findings apply to levofloxacin.

This spectrum gap is significant; FQ compounds with good MSSA and MRSA activity would fill a great need as only linezolid can currently provide IV and PO coverage for these pathogens.  In order to succeed, any new FQ has to show excellent activity against MRSA with various co-resistance patterns based on pathogenicity islands (mainly an issue in HA- MRSA), including ciprofloxacin-R strains.

Here my list of FQs in development that claim activity against MRSA (your feedback is appreciated):

MRSA FQ

FM= Frequency of Mutation

Given the history of rapid resistance development, it is not surprising that these purely MRSA compounds (they really have no other raison d’etre than reliably kill MRSA!) are being developed with much attention to bolster their MRSA claim.  All MRSA FQ in the table have better MICs and lower spontaneous mutation rates than ciprofloxacin; unfortunately neither parameter is particularly predictive of the question at hand: Can they counted on to provide reliable long-term anti-MRSA  activity?

Q: Can MRSA fluoroquinolones provide reliable long-term anti-MRSA activity?

The MPC is a newer concept; it was developed to assess at which concentration single step mutations no longer occur.  However, its clinical value has been challenged. [15]  It would be nice to predict resistance development based on microbiological data only, generated in the lab.  But we are not there yet.

To sum it up, clinical data proving that good MIC values translate into good clinical response rates without rapid development of resistance are still lacking.  Even for the most advanced project, Delafloxacin, too little is known to gauge whether its MRSA activity will hold up.

So, the jury is still out on which FQ is best against MRSA. But time will tell…


Abbreviations
PAE            post-antibiotic effect
MPC           mutation prevention concentration
FM              frequency of mutation
CLSI           Clinical Laboratory Standards Institute
CA-MRSA   community-acquired MRSA
HA-MRSA   hospital-acquired MRSA
FQ               fluoroquinolone

References:
[1] I Shalit, AAC 1989; 33: 593
[2] H Blumberg,  JID 1991;163:127
[3] L Almer. Diagnostic Microbiology Infectious Disease 43: 2225; 2002
[4] B Morrow. AAC  55: 5512, 2011
[5] J Remy.  J Antimicrob Chemother. 2012; 67:2814
[6] Goh ICAAC 2009, Abstract C1-1358
[7] T Lauderdale Antimicrob Agents Chemother. 2010 Mar;54(3):1338
[8] Expert Opin. Pharmacother. 16: 266; 2015
[9] C Tsai Abstract L-1748b, ICAAC 2014: Meeting the Threat of Antibiotic Resistance: In Vitro Activity, Clinical Efficacy and Safety of Nemonoxacin, a Novel Non-Fluorinated Quinolone with QIDP Status
[10] H Park. AAC 50: 2261, 2006
[11] M Huband.  AAC 59:  467; 2015
[12] S Bhagwat.  AAC; 53: 811; 2009
[13] S Bhagwat. AAC 50: 3568; 2006
[14] F Schmitz.  AAC 44: 3229, 2000
[15] G Allen. Internat J Antimicrobial Agents 24; 2004: 150

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