Moxifloxacin Hydrochloride (Page 6 of 11)

12.4 Microbiology

Mechanism of Action

The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair, and recombination.

Resistance

The mechanism of action for fluoroquinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. Resistance to fluoroquinolones occurs primarily by a mutation in topoisomerase II (DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or drug efflux. In vitro resistance to moxifloxacin develops slowly via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10–9 to < 1 x 10–11 for Gram-positive bacteria.

Cross Resistance

Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin. There is no known cross-resistance between moxifloxacin and other classes of antimicrobials.

Antimicrobial Activity

Moxifloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].

Gram-positive bacteria

Enterococcus faecalis

Staphylococcus aureus

Streptococcus anginosus

Streptococcus constellatus

Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] **)

Streptococcus pyogenes

**MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin resistant S. pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC) ≥2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.

Gram-negative bacteria

Enterobacter cloacae

Escherichia coli

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Proteus mirabilis

Yersinia pestis

Anaerobic bacteria

Bacteroides fragilis

Bacteroides thetaiotaomicron C

lostridium perfringens

Peptostreptococcus species

Other microorganisms

Chlamydophila pneumoniae

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for moxifloxacin against isolates of similar genus or organism group. However, the efficacy of moxifloxacin hydrochloride in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.

Gram-positive bacteria

Staphylococcus epidermidis

Streptococcus agalactiae

Streptococcus viridans group

Gram-negative bacteria

Citrobacter freundii

Klebsiella oxytoca

Legionella pneumophila

Anaerobic bacteria

Fusobacterium species

Prevotella species

Susceptibility Tests Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth and/or agar). ^1,2,4 The MIC values should be interpreted according to the criteria in Table 10.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size prove should be determined using a standardized test method.^2,3 This procedure uses paper disks impregnated with 5 mcg moxifloxacin to test the susceptibility of bacteria to moxifloxacin.

The disc diffusion interpretive criteria are provided in Table 10.

Anaerobic Techniques

For anaerobic bacteria, the susceptibility to moxifloxacin can be determined by a standardized test method.^2,5 The MIC values obtained should be interpreted according to the criteria provided in Table 10.

Table 10: Susceptibility Test Interpretive Criteria for Moxifloxacin

	MIC ( mcg / mL )			Zone Diameter ( mm )
Species	S	I	R	S	I	R
Enterobacteriaceae	≤2	4	≥8	≥19	16–18	≤15
Enterococcus faecalis	≤1	2	≥4	≥18	15–17	≤14
Staphylococcus aureus	≤0.5	1	≥2	≥24	21-23	≤20
Haemophilus influenzae	≤1	a	a	≥18	a	a
Haemophilus parainfluenzae	≤1	a	a	≥18	a	a
Streptococcus pneumoniae	≤1	2	≥4	≥18	15–17	≤14
Streptococcus species	≤1	2	≥4	≥18	15–17	≤14
Anaerobic bacteria	≤2	4	≥8	–	–	–
Yersinia pestis	≤0.25	a	a	–	–	–
S=susceptible, I=Intermediate, and R=resistant.a) The current absence of data on moxifloxacin-resistant isolates precludes defining any results other than “Susceptible”. Isolates yielding test results (MIC or zone diameter) other than susceptible, should be submitted to a reference laboratory for additional testing.

A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug product can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay and the techniques of the individuals performing the test.^1,2,3,4,5 Standard moxifloxacin powder should provide the following range of MIC values noted in Table 11. For the diffusion technique using the 5 mcg moxifloxacin disk, the criteria in Table 11 should be achieved.

Table 11: Acceptable Quality Control Ranges for Moxifloxacin

Strains	MIC range ( mcg / mL )	Zone Diameter ( mm )
Enterococcus faecalis ATCC 29212	0.06–0.5	–
Escherichia coli ATCC 25922	0.008–0.06	28–35
Haemophilus influenzae ATCC 49247	0.008–0.03	31–39
Staphylococcus aureus ATCC 29213	0.015–0.12	–
Staphylococcus aureus ATCC 25923	–	28–35
Streptococcus pneumoniae ATCC 49619	0.06–0.25	25–31
Bacteroides fragilis ATCC 25285	0.125–0.5	–
Bacteroides thetaiotaomicron ATCC 29741	1–4	–
Eubacterium lentum ATCC 43055	0.125–0.5	–