Antimicrobial Resistance


Antimicrobial Resistance in Russia

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Antimicrobial resistance in Russia


Community Pathogens

Streptococcus pneumoniae
Streptococcus pyogenes
Haemophilus influenzae
Neisseria gonorrhoeae
Escherichia coli
Shigella spp.
Salmonella spp.

Mycobacterium tuberculosis

Nosocomial Pathogens

Staphylococcus aureus
Enterococcus spp.
Enterobacteriaceae
Pseudomonas aeruginosa

For the recent years, the antimicrobial resistance of nosocomial and community-acquired pathogens considerably increased all over the world. Talking about the rise of antimicrobial resistance it is necessary to take into consideration a level of the problem: whether it is global, regional or a local one.

Above all, it is important to comprehend global tendencies in emerging of resistance. For instance, this is appearance and spread of strains of the methicillin-resistant S.aureus, penicillin-resistant S.pneumoniae and ESBL-producing K.pneumoniae.

However, antimicrobial resistance is not a total phenomenon involving all bacteria and drugs. S.pyogenes and T.pallidum are always susceptible to b-lactams and H.influenzae – to III generation cephalosporins.

In spite of great importance of global tendencies in antimicrobial resistance, it is crucial to rely on local data obtained from a particular country (i.e. regional data) for design and implementation of antibiotic policy.

Levels of resistance vary considerably in different regions of Russian Federation. Thereupon the significance of territorial resistance monitoring and applying its results into clinical practice is beyond any doubts.

In Russia, antimicrobial susceptibility testing (AST) faces many problems and the main is the absence of standardized testing methods. The only existing official recommendation "Notification of procedures of AST by disc diffusing method" published by the USSR Ministry of Health, in 1983 neither describes the methods of AST of fastidious microorganisms (S.pneumoniae, H.influenzae, N.gonorrhoeae) nor includes any interpretation criteria for modern, currently used antibiotics (cephalosporins, fluoroquinolones, carbapenems). Moreover, the expertise showed that recommended AGV medium was not suitable for AST for a number of antibiotics (e.g. antifolates).

Thus, the substantial susceptibility data obtained in bacteriological laboratories cannot be estimated and analyzed. As well as one should carefully consider publications that do not have the information about AST methods and interpretation criteria used in the study.

This chapter contains results of studies conducted accordingly to internationally recognized NCCLS standards. For proper perception and considering relevant clinical practice, discussed microorganisms are divided into community-acquired and nosocomial pathogens.



Community-acquired pathogens

Streptococcus pneumoniae

The last decade was noted for emergence and prevalence of penicillin-resistant pneumococci and strains resistant to macrolides, chloramphenicol and tetracycline have been registered in a number of countries. In some regions resistance to macrolides prevails over the resistance to penicillin. Among healthy children in day-care clinics in Moscow, Smolensk and Yartsevo about 7.5% nasopharyngeal pneumococci had intermediate resistance to penicillin (MIC 0,12-1 mg/l). At the same time, no strains with high level of resistance (MIC > 2 mg/l) were found.

All strains with intermediate resistance to penicillin were susceptible to amoxicillin/clavulanate. Resistance to macrolides was 4.6%. The highest rate of resistance (56.8%) was due to co-trimoxazole.

By preliminary data from multicenter study "PeGAS-1", the number of strains with intermediate resistance to penicillin was 9% and less than 1% of strains with MIC > 2 mg/l were found. The resistance rate to erythromycin was 3.6%.

For the time being, the resistance of S.pneumoniae to tetracycline (64.9%) and co-trimoxazole (62.2%) is the most important problem.



Streptococcus pyogenes

b-haemolythic group A streptococci possess universe susceptibility to b-lactams. Issue of the day is the macrolide resistance that exceeds 30% in some countries. Resistance to macrolides in Russia seems to be 12.6% (Table 1). The major clinical problem is the resistance to tetracyclines that in Russia exceeds 60%.


Table 1. Susceptibility of S.pyogenes to antimicrobials (Smolensk, 1997)

Antibiotic S, % IR, % R, % MIC90 MIC Range, mg/L
Penicillin 100.0 0.0 0 0.016 0.012-0.032
Amoxicillin 100.0 0.0 0 0.023 0.016-0.032
Cefuroxime 100.0 0.0 0 0.023 0.016-0.125
Tetracycline 38.8 1.0 60.2 128 0.125-256
Erythromycin 87.4 2.9 9.7 0.75 0.016-3
Clindamycin 98.1 1.9 0.0 0.125 0.047-0.38


Haemophilus influenzae

The main mechanism of H.influenzae resistance to aminopenicillins (ampicillin and amoxicillin) is the production of plasmid mediated b-lactamases.

According to data from Moscow, Yartsevo and Smolensk (Table 2) production of b-lactamases does not present a serious problem. The resistance of H.influenzae to co-trimoxazole is the most troublesome – 20.3%.


Table 2. Susceptibility of H.influenzae to antimicrobials (1998)

Antibiotic S, % IR, % R, % MIC90 MIC Range, mg/L
Ampicillin 97.7 1.3 1.0 0.38 0.016-128
Amoxicillin/clavulanate 99.3 0 0.7 1 0.016-8
Cefaclor 97.7 1.3 1 3 0.25-32
Erythromycin 8 1-16
Co-trimoxazole 79.1 0.6 20.3 32 0.016-32


Neisseria gonorrhoeae

The AST of gonococci is a complex issue that demands special media and any reliable data concerning N.gonorrhoeae resistance are not available in Russia.

In pilot survey (Smolensk, 1999) the rate of penicillin resistance strains of N.gonorrhoeae were 77.9%, and 96.1% to doxicycline. About 1.3% of strains were intermediately resistant to ciprofloxacin. No strains resistant to ceftriaxone were found.



Escherichia coli

E.coli is the most frequent pathogen that causes community-acquired urinary tract infections. In 1998 the multicenter study of resistance of gram-negative pathogens of urinary tract infections in out-patient women was conducted in Moscow, Smolensk and Novosibirsk (Pict. 1)


Picture 1. Resistance of E.coli to antibiotics in Russia (1998)

Picture 1. Resistance of E.coli to antibiotics in Russia (1998)

Abbreviations:
AMP – ampicillin; GEN – gentamicin; SXT – co-trimoxazole; FUR – nitrofurantoin;
NAL – nalidixic acid; NOR – norfloxacin; CIP – ciprofloxacin.

The highest rates of resistance were observed to ampicillin (33.3%) and co-trimoxazole (18.4%). The lowest resistance was to fluoroquinolones, norfloxacin (2.6%) and ciprofloxacin (2.6%).



Shigella flexneri and Shigella sonnei

Antimicrobial susceptibility testing was perfomed for Shigella spp. isolated in Smolensk during 1998-1999. Almost all of the S.flexneri strains isolated in 1998 were resistant to ampicillin (95%), ampicillin-sulbactam (95%), co-trimoxazole (98%), cloramphenicol (98%) and tetracycline (98%). Isolated in the same survey S.sonnei possessed lower resistance to ampicillin (7%), however resistance to other antimicrobials did not differ significantly. The resistance to co-trimoxazole was 100%, chloramphenicol – 72% and tetracycline – 93%. All strains of Shigella spp. were susceptible to nalidixic acid and ciprofloxacin. Results of AST of shigellae isolated in 1999 in Moscow and Smolensk are presented in the Table 3.


Table 3. Resistance (%) of Shigella spp. to antimicrobials (Smolensk, Moscow, 1999)

Microorganism AMP AMS SXT CHL TET NAL CIP
S.flexneri 95.7 94.6 97.9 92.5 98.9 1.1 0
S.sonnei 34.7 34.7 95.1 38.6 93.1 0 0

Abbreviations:
AMP – ampicillin, AMS – ampicillin/sulbactam, SXT – co-trimoxazole, CHL – chloramphenicol, TET – tetracycline,
NAL – nalidixic acid, CIP – ciprofloxacin

As it is seen in Table 3, there were no considerable changes in resistance rates of S.flexneri with the exception to increased resistance of S.sonnei to ampicillin and ampicilin/sulbactam – from 7% in 1998 up to 35% in 1999.

Data on resistance of shigellae in Ekaterinburg presented in Table 4 also show that S.sonnei was lower resistant to penicillin and tetracycline as compared to S.flexneri. The exception is co-trimoxazole because of resistance of S.sonnei to it. The particular interest presents ciprofloxacin resistance of shigellae.


Table 4. Resistance (%) of Shigella spp. to antimicrobials (Ekaterinburg, 1999)

Microorganism AMP AMS SXT CRO TET CIP
S.flexneri 98.1 98.1 73.6 0 91,8 3.8
S.sonnei 7.3 7.3 97.6 0 66.7 4.9

Abbreviations:
AMP – ampicillin, AMS – ampicillin/sulbactam, SXT – co-trimoxazole, CRO – ceftriaxone,
TET – tetracycline, CIP – ciprofloxacin.



Salmonella spp.

As shown in Table 5, resistance of Salmonella spp. remains comparatively low with no strains resistant to cefotaxime, ciprofloxacin and co-trimoxazole.

The highest resistance was observed to tetracycline (10.5%) and chloramphenicol (9.5%).


Table 5. Resistance (%) Salmonella spp. to antibiotics (Smolensk, 1999)

Microorganism AMP AMS FTX NAL CIP CHL TET SXT
S.enteritidis 2.7 2.7 0 2.7 0 6.7 4 0
Salmonella spp. 6.3 6.3 0 3.2 0 9.5 10.5 0

Abbreviations:
AMP – ampicillin, AMS – ampicillin/sulbactam, FTX – cefotaxime, NAL – nalidixic acid,
CIP – ciprofloxacin, CHL – chloramphenicol, TET – tetracycline, SXT – co-trimoxazole.

The presented data do not reveal the complete situation with antimicrobial resistance in Russia, yet. In 1996 in St-Petersburg clinical and environmental strains of S.typhimurium resistant to cefotaxime were found. In 1999 in Ekaterinburg 16.7% Salmonella strains were resistant to ampicillin and ampicillin/sulbactam, 13.8% – to tetracycline and 6.1% to co-trimoxazole. All examined strains were susceptible to fluoroquinolones. Moreover, one clinical strain manifested resistance to III generation cephalosporins and susceptibility to flouroquinolones and co-trimoxazole.



Mycobacterium tuberculosis

One of the leading reasons of failure of tuberculosis therapy is increased frequency of multi-drug resistant Mycobacterium tuberculosis, i.e. strains resistant at least to isoniazide and rifampicin.

In 1991-1994 in nine regions of North-Western Russia (Komi Republic, Pskov, Novgorod, Saint-Petersburg and Leningrad region, Karelia, Vologda, Arkhangel'sk, Murmansk) frequency of M.tuberculosis primary resistant to one or more antimycobacterial drugs increased from 17% to 24%. The rate of secondary resistance did not significantly changed and was about 50%.

In Leningrad region in 1992-1994 primary resistance was 29.2%, isolation frequency of multiresistance strains reached 5.1% without significant variations during whole survey period. Secondary resistance of extra-pulmonary isolates in 1989-1994 was 45.6% as compared to 69.5% in respiratory isolates.

The spread of secondary multidrug resistant respiratory strains increased significantly and made 33% as compared to 69.5% in extra-pulmonary isolates.

In Ivanovsk region primary multidrug resistance in 1998 was 3,8%. According to data of survey in Tomsk (1995-1996) primary resistance in mycobacteria reached 27.7%, multidrug resistance – 3.4%.

The survey has shown the marked tendency in growth of multidrug-resistance among M.tuberculosis during last years as a whole and especially to two basic drugs – isoniasid and rifampin.



Nosocomial pathogens

S.aureus and coagulase-negative staphylococci (CNS)

In multicenter survey of staphylococci susceptibility in Moscow and St-Petersburg (1998), considerable differences in emerging of MRSA in some hospitals were revealed. The resistance to oxacillin was more frequent in CNS (0-65,9%) than among S.aureus (0-40%). Generally in Moscow the isolation of MRSA was 33,4% and 4,1% in St-Petersburg.

All staphylococci resistant to oxacillin were susceptible to vancomycin and 95%, 84% and 70% of MRSA were susceptible to fusidic acid, rifampin and ciprofloxacin, respectively (as compared with 80%, 85% 61% for CNS respectively).



Enterococcus spp.

Sixteen percent of E.faecalis strains resistant to ampicillin were revealed in survey conducted in Moscow and St-Petersburg, and considerable variations of resistance frequency were observed among hospitals. Level of aminoglycoside resistance to strepromycin was 44% and and 25% to gentamicin. Neither intermediate nor resistant strains were observed to vancomycin. Unlike to E.faecalis 75% strains of E.faecium were resistant to ampicillin, when its susceptibility to other antimicrobials didn't differ noticeably.

With epidemiological purpose susceptibility testing of enterococci strains isolated from of premature new-born feces were conducted. Results of antimicrobial activity in vitro are presented in Table 6.


Table 6. Resistance (%) of Enterococcus spp. to antimicorbials (Smolensk)

Antibiotic E.faecalis (N=33) E.faecium (N=61)
Ampicillin 3 77
Gentamicin 0 64
Streptomyicin 3 56
Vancomycin    9 *    10 *
Chloramphenicol 39 54
Rifampicin 88 93
Quinupristin/dalfopristin 15 3

* Intermediate resistant strains

Generally, E.faecium demonstrated higher resistance rate to tested antimicrobials with the exception of vancomycin, its activity was equal to all enterococci, and quinopristin/dalfopristin (3% resistant of E.faecium against 15% of E.faecalis). Only 3% of E.faecalis were resistant to ampicillin unlike 77% of E.faecium. Majority of E.faecium strains showed high level of resistance to aminoglycosides (64% to gentamicin and 56% to streptomycin).



Enterobacteriaceae

The resistance of Enterobacteriaceae varies widely among hospitals, which presents the reflection of the antibiotic policy. Data on antimicrobial resistance of most gram(-) nosocomial pathogens were obtained in multiceneter NPRS-1997 survey. The centers that participated in the study were Moscow, St-Petersburg, Smolensk, Krasnodar, Kazan, Nizhnij Novgorod, Ekaterinburg, Novosibirsk, Krasnoyarsk). The results are presented in Table 7.


Table 7. Resistance to antimicrobials (%) of gram-negative bacteria isolated in ICUs in Russia (NPRS-1997)

Antibiotic E.coli K.pneumoniae P.mirabilis Enterobacter spp. Acinetobacter spp.
Piperacillin 44 85 59 70 88
Piperacillin/tazobactam 11 51 22 63 82
Amoxicillin/clavulanate 27 52 20 88 73
Cefuroxime 19 52 32 82 96
Cefotaxime 6 32 20 60 88
Ceftriaxone 5 33 17 57 94
Ceftazidime 3 26 1 56 78
Imipenem 0 0 0 0 0
Gentamicin 13 58 56 42 91
Amikacin 1 0 1 4 7
Ciprofloxacin 1 2 5 5 53
Co-trimoxazole 27 51 62 12 88

Resistance to piperacillin varies from 44% for E.coli to 88% for Acinetobacter spp, to piperacillin/tazobactam from 11% for E.coli to 82% for Acinetobacter spp. High resistance of K.pneumoniae to III generation cephalosporins (26-33%) is due to ESBL-producing and Enterobacter spp. (56-60%).

It is necessary to notice high frequency of resistance to gentamicin, which varies from 13% for E.coli up to 91% for Acinetobacter spp. The lowest resistance was observed to ciprofloxacin, amikacin and imipenem.

In "Micromax" survey (Table 8) conducted in 1998 in 8 hospitals of Moscow, Smolensk, Ekaterinburg, low resistance of E.coli and Proteus spp to b-lactams was noticed with slight differences among participating centers. At the same time Klebsiella spp showed high resistance to III generation of cephalosporins (average 40% to ceftiaxone and 31% to ceftazidime). Resistance to cefepime was almost two times lower – 16%.


Table 8. Resistance to antimicrobials (%) of nosocomial gram(-) bacteria, ("Micromax" study, 1999)

Antibiotic E.coli Proteus spp. Klebsiella spp.
Piperacillin/tazobactam 3 1 17
Ceftriaxone 13 10 40
Ceftazidime 5 3 31
Cefepime 3 3 16
Imipenem 0 0 0
Ciprofloxacin 12 15 14

No strains of E.coli, Proteus spp. and Klebsiella spp resistant to imipenem were detected.



Pseudomonas aeruginosa

In NPRS-1997 multicenter study up to 50% of .aeruginosa strains were resistant to piperacillin, 41% to piperacillin/tazobactam and more than 10% to ceftazidime. Resistance to imipenem was relatively low (0-11%) in all participating centers. Resistance to gentamicin was 75% as compared to 7% to amikacin. From 6% up to 42% (average 15%) of P.aeruginosa strains were resistant to ciprofloxacin.

Moscow study showed high resistance frequency of P.aeruginosa to antipseudomonal b-lactams: 45% for piperacillin/tazobactam, 55% to ceftazidime, 47% to cefepime.

The lowest resistance was found to carbapenems (imipenem – 18%, meropenem – 19%). Notice high frequency of resistance of P.aeruginosa to ciprofloxacin (45%).

Among aminoglycosides the most active was amikacin (11% of resistant strains), while more than 60% of the strains were resistant to gentamicin.

In conclusion, it is necessary to notice that information mentioned in this chapter certainly can not be considered as exhaustive and it does not reflect the state of antibiotic resistance in Russia. That is why it is extremely important to conduct permanent monitoring of resistance with summarizing corrected data.


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