Ciprofloxacin (Page 10 of 14)

12.4 Microbiology

Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.

Mechanism of Resistance

The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10 -9 to 1×10 -6 .

Cross Resistance

There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.
Ciprofloxacin 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

Bacillus anthracis
Enterococcus faecalis
Staphylococcus aureus (methicillin-susceptible isolates only)
Staphylococcus epidermidis (methicillin-susceptible isolates only)
Staphylococcus saprophyticus
Streptococcus pneumoniae
Streptococcus pyogenes

Gram-negative bacteria
Campylobacter jejuni
Citrobacter koseri
Citrobacter freundii
Enterobacter cloacae
Escherichia coli
Haemophilus influenzae
Haemophilus parainfluenzae
Klebsiella pneumoniae
Moraxella catarrhalis
Morganella morganii
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Providencia rettgeri
Providencia stuartii
Pseudomonas aeruginosa
Salmonella typhi
Serratia marcescens
Shigella boydii
Shigella dysenteriae
Shigella flexneri
Shigella sonnei
Yersinia pestis

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 ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Gram-positive bacteria

Staphylococcus haemolyticus (methicillin-susceptible isolates only)

Staphylococcus hominis (methicillin-susceptible isolates only)

Gram-negative bacteria

Acinetobacter lwoffi
Aeromonas hydrophila
Edwardsiella tarda
Enterobacter aerogenes
Klebsiella oxytoca
Legionella pneumophila
Pasteurella multocida
Salmonella enteritidis
Vibrio cholerae
Vibrio parahaemolyticus
Vibrio vulnificus
Yersinia enterocolitica

Susceptibility Test 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 test method (broth and/or agar). 5,6,7 The MIC values should be interpreted according to criteria provided in Table 14.

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 should be determined using a standardized test method. 6,7,8 This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 14.

Table 14: Susceptibility Test Interpretive Criteria for Ciprofloxacin
1. The current absence of data on resistant isolates precludes defining any results other than “Susceptible.” If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing. 2. MIC is determined by the agar dilution method
MIC (mcg/mL) Zone Diameter (mm)
Bacteria S I R S I R
Enterobacteriaceae ≤1 2 ≥4 ≥21 16 to 20 ≤15
Enterococcus faecalis ≤1 2 ≥4 ≥21 16 to 20 ≤15
Staphylococcus aureus ≤1 2 ≥4 ≥21 16 to 20 ≤15
Staphylococcus epidermidis ≤1 2 ≥4 ≥21 16 to 20 ≤15
Staphylococcus saprophyticus ≤1 2 ≥4 ≥21 16 to 20 ≤15
Pseudomonas aeruginosa ≤1 2 ≥4 ≥21 16 to 20 ≤15
Haemophilus influenzae 1 ≤1 - - ≥21 - -
Haemophilus parainfluenzae 1 ≤1 - - ≥21 - -
Salmonella typhi ≤0.06 0.12 to 0.5 ≥1 ≥31 21 to 30 ≤20
Streptococcus pneumoniae ≤1 2 ≥4 ≥21 16 to 20 ≤15
Streptococcus pyogenes ≤1 2 ≥4 ≥21 16 to 20 ≤15
Neisseria gonorrhoeae 2 ≤0.06 0.12 to 0.5 ≥1 ≥41 28 to 40 ≤27
Bacillus anthracis 1 ≤0.25 - - - - -
Yersinia pestis 1 ≤0.25 - - - - -
S=Susceptible, I=Intermediate, and R=Resistant.

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 site of infection 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 high dosage of drug 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 the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. 5,6,7,8 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 15. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 15 should be achieved.

Table 15: Acceptable Quality Control Ranges for Ciprofloxacin
1 MIC is determined by the agar dilution method
Bacteria MIC range (mcg/mL) Zone Diameter (mm)
Enterococcus faecalis ATCC 29212 0.25 to 2 -
Escherichia coli ATCC 25922 0.004 to 0.015 30 to 40
Haemophilus influenzae ATCC 49247 0.004 to 0.03 34 to 42
Pseudomonas aeruginosa ATCC 27853 0.25 to 1 25 to 33
Staphylococcus aureus ATCC 29213 0.12 to 0.5 -
Staphylococcus aureus ATCC 25923 - 22 to 30
Neisseria gonorrhoeae ATCC 49226 1 0.001 to 0.008 48 to 58
Campylobacter jejuni ATCC 33560 0.06 to 0.25 and 0.03 to 0.12 -

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