Detection and Identification of Gonococci Resistance to Cephalosporin and Determination the Most Effective Empirical Treatment for Gonococcal Urethritis in Male Human in Egypt ()
1. Introduction
Gonorrhoea is an ancient disease mentioned in the third book of Moses in the Bible, also in the 18th dynasty of Luxor in Egypt [1] [2] [3]. Gonorrhoea is the second prevalent sexually transmitted disease [4] [5]. WHO considered gonorrhoea as a major health problem, Center of Disease Control and prevention (CDC) mentioned gonorrhoea as a Super Pug [6] [7] [8] [9] [10], since gonorrhoea has remarkable ability to cause repeated infection in the same host and has extraordinary ability to develop resistance to all clinically used antibiotics [11] [12] [13]. However, Cephalosporins especially 3rd generation Ceftriaxone is still considered the first line empirical treatment for gonorrhoea worldwide, but resistance is reported globally in many countries [14] - [20].
In 2010, WHO GASP Program (WHO Global Gonococcal Antimicrobial Surveillance Program) proposed to monitor (AMR) Anti-Microbial Resistance of gonococci [6] [21] [22]; also in 2012 WHO published a global action plan to control the spread and impact of AMR in Niesseria gonorrhoeae which is in line with WHO’s global action plan on AMR; then in 2015 WHO supported Global Antimicrobial resistance Surveillance System (GLASS) [19] [23] [24]. WHO recommended GASP, GLASS and Global Action Plan on AMR of gonococci to expand nationally and internationally to collect data from countries all over the world to monitor AMR of gonococci [19] [23] [24]. Egypt has no data about gonorrhoea according to GASP map [19] as shown in (Figure 1); this study is to report some data in EGYPT.
2. Materials and Methods
During three years 2017-2020 33 clinical isolates were collected (urethral
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Figure 1. GASP map for Ceftriaxone resistance that shows EGYPT from region with data not available (Magus et al., 2021).
discharge swab) from male patients in varying ages diagnosed as uncomplicated gonococcal urethritis (UGU) obtained from National Institute of Urology and Nephrology in Cairo with disease diagnostic sheet and full history to each patient. Urethral discharge collected by the physician after cleaning urethral meatus with gauze soaked in physiological saline (0.9% w/v), at least one hour before voiding [25] [26]. Sample taken by inserting Rayon swab gently 2 - 3 cm into the anterior urethra and rotated from side to side [25], the purulent discharge expressed out by pressing at the base of the penis before inserting swab [24] [26] [27]; kept swab in Amies transport medium equipped in medical center [25] [28]; transporting to microbiology lab within 24 hours [27] [28] [29]; Make a fresh smear of urethral discharge specimens for Identification of polymorphic intraleuckocytes kidney shape diplococci by microscopic examination and Gram staining so Gram staining is very high specific & diagnostic tool for symptomatic male urethritis, the sensitivity of gram stain is up to (95%) and specifity is up to (97%) [12] [25] [26] [28] [30]; urethral discharge isolates was cultivated on selective media (Modified Thyer Martine medium with (VCNT) supplement)at optimal conditions, Bacterial culture is still considered the gold standard to diagnosis Neisseria gonorrhoeae especially in urogenital specimens, bacterial culture is high sensitive and high specific, sensitivity may reach (85% - 95%) undergo optimal conditions, and specifty up to (100%) considered diagnostic test [12] [19] [25] [26] [28] [30] [31]; Identification of tested organism by Colonies morphological features, biochemical tests of gonococci (Oxidase test, Catalase test and Carbohydrate fermentation test) and Gram staining of bacterial colonies to detect Gram-negative kidney shape diplococci [25] [28] [32]; then by disc diffusion method applied Antimicrobial susceptibility testing according to (Clinical Laboratory Standard Institute, CLSI) using antibiotics with MIC according to international standards and measuring IZD according to antimicrobial susceptibility testing reference ranges in international standards [12] [25] [26] [28] [31] [32] [33]; selected anti-biotic discs represent all functional anti-biotic groups as: Penicillins (first generation): Penicillin G, 10 IU, Aminopenicillins (3 red generation of penicillins): Amoxycillin, 10 µg; Amoxicillin/clavulanic acid, 30 µg; Ampicillin 10 µg/sulbactam 10 µg, 20 µg, Uredopencillins (4th generation of pencillins): pipracillin, 100 µg, Cephalosporins (1st generation): Cephradine, 30 µg, Cephalosporins (2nd generation): Cefaclor, 30 µg; Cefoxitin, 30 µg, Cephalosporins (3rd generation): Ceftriaxone, 30 µg, Cephalosporins (4th generation): Cefepime, 30 µg, Fluroquinolones (2nd generation): Ofloxacin, 5 µg; Ciprofloxacin, 5 µg, Fluroquinolones (3rd generation): Levofloxacin, 5 µg, Aminoglycosides: Amikacin, 30 µg; Tobramycin, 10 µg; Gentamicin, 10 µg, Oxazolidinone: Linezolid, 30 µg, Sulphonamides: Trimethoprim 1.25 µg/sulphamethoxazol 23.75 µg, 25 µg, Lincosamide: Clindamycin, 2 µg, Vancomycin: Vancomycin, 30 µg, Carbapenems: Imipenem, 10 U; Meropenem, 10 U, Tetracyclines: Doxycline, 30 µg, Macrolides: Azithromycin, 15 µg [12] [25] [26] [28] [31] [32] [33].
3. Results
Our results according to statistical analysis provide the most effective antibiotic group and the most effective antibiotic drug, the most effective group were as follows:
Flouroquinolones ranks first effective followed by Tetracyclin, Macrolides, Carbapenemes, Aminoglcosides, and oxazolidinon in sixth rank, followed by Cephalosporin, Sulphonamides, Penicillins, Vancomycin and Lincosamide was the least effective, show ranks mean and st. deviation values as in (Table 1 and Figure 2).
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Figure 2. Diagrams show the ranking of the most effective antibiotic group gradually from the most effective to the least.
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(N: Number of cases; the minimum value = 1 compensation for resistant cases; maximum value = 3 compensation for susceptible cases; Std. Deviation: standard deviation; C.V: coefficient of variation; 1 ≤ Mean = Weighted average ≤ 3)
Table 1. Final ranking of antibiotic groups.
The most effective antibiotic drug inside Flouroquinolones group is Levofloxacin, so ranking of drugs both overall ranking and internal ranking inside each group, which provide homogeneity and heterogeneity inside each group were as show in (Table 2 and Figure 3).
From statistical studies there are two groups, less resistant group represented by 11 cases and more resistant group represented by 22 cases show in cluster analysis in (Figure 4); this table provides Frequencies and percent of susceptibility to each group and to total cases show in (Table 3).
4. Discussion
Drug resistance in Neisseria gonorroeae is considered according WHO collected data a major health concern [6] [7] [8] [9] [10], the AMR of gonococcal isolates reported to WHO by 73 countries in 2017-2018 is that each country collects at least 100 gonococcal isolates per year. WHO, findings was decreased susceptibility or resistance to Ceftriaxone was (31%) of 68 reporting countries and to Cefixime (47%) of 51 reporting countries.
Resistance to Azithromycin was reported by (84%) of 61 countries. Interpretation in many countries showed exceedingly high resistance to Ciprofloxacin (100%) of 70 reporting countries [6] [7] [12] [19] [23] [24].
In 2016 WHO estimated that: 6.9 million incident cases of gonorrohoeae occurred in adults, while in 2020 was 82.4 million, the first line empirical treatment was Ceftriaxone as monotherapy in most countries. However resistance to Ceftriaxone has been spread and continues to emerge globally [6] [7] [12] [19] [23] [24].
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(N: Number of cases; the minimum value = 1 compensation for resistant cases; maximum value = 3 compensation for susceptible cases; Std. Deviation: standard deviation; C.V: coefficient of variation; 1 ≤ Mean = Weighted average ≤ 3)
Table 2. Final ranking of antibiotic drugs.
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(PG: Penicillin G, AML: Amoxicillin, AMC: Amoxicillin/clavulanic, SAM: Ampicillin 10 µg/sulbactam 10 µg, PRL: pipracillin CE: Cephradine, CEC: Cefaclor, FOX: Cefoxitin, CRO: Ceftriaxone, FEP: Cefepime, OFX: ofloxacin, CIP: ciprofloxacin, LEV: levofloxaic, AK: Amikacin, TOB: Tobramycin, CN: Gentamicin, LZD: Linezolid, SXT: Trimethoprim 1.25 µg/sulphamethoxazol 23.75 µg, DA: Clindamycin, VA: Vancomycin, IPM: Imipenem, MEM: Meropenem, DO: Doxycycline, AZM: Azithromycin)
Table 3. Frequencies and percent of susceptibility to each group and to total cases.
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Figure 3. Diagrams show the ranking of the most effective antibiotic drug gradually from the most to the least.
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Figure 4. Dendrogram using average linkage (within groups).
In UK and Australia the first strain with resistance to Ceftriaxone was isolated in 2010. In Asia several Ceftriaxone resistance strains appeared [6] [7] [12] [19] [23] [24].
According to our results in the study done in EGYPT to detect the antimicrobial resistance to Neisseria gonorrhoeae and the most effective empirical treatment for non-complicated gonococcal urethritis in adult males, Flouroquinolones ranks first effective followed by Tetracyclin, Macrolides, Carbapenemes, Aminoglcosides, and oxazolidinon in sixth rank, followed by Cephalosporin, Sulphonamides, Penicillins, Vancomycin and Lincosamide was the least effective, show ranks as in previous (Table 1).
Inside Flouroquinolones Group Levofloxacin was the most effective followed by Ciprofloxacin, and Ofloxacin represented ranks as in (Table 4).
The mean level of Ciprofloxacin resistance in WHO regions ranged from 49% (European region) to 93% (South East Asia region), overall 12 countries in five WHO regions reporting more than 90% resistance to Ciprofloxacin [7] [12] [19] [23] [24]. This shows resistance to Ciprofloxacin is higher than EGYPT that equals 15.2% according to our results shows as in (Table 5).
From GASP Mapfor Ciprofloxacin resistance that shows EGYPT from region with data not available as shows in (Figure 5).
Resistance to Chephalosporins in our results were reported as 90.9% for Ceftriaxone, Cefoxitine 97%, Cefaclor 87.9%, Cefradine 97%, while Cefepime 42.4% Which mean heterogeneous resistance in the Chephalosporin group show as in (Table 6).
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Figure 5. GASP Map for Ciprofloxacin. (Magus et al., 2021).
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(N: Number of cases; the minimum value = 1 compensation for resistant cases; maximum value = 3 compensation for susceptible cases; Std. Deviation: standard deviation; C.V: coefficient of variation; 1 ≤ Mean = Weighted average ≤ 3)
Table 4. Internal ranking of Fluroquinolones.
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(OFX: Ofloxacin, CIP: Ciprofloxacin, LEV: Levofloxaic)
Table 5. Frequencies and percent of susceptibility to each drug in Fluroquinolones.
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(CE: Cephradine, CEC: Cefaclor, FOX: Cefoxitin, CRO: Ceftriaxone, FEP: Cefepime)
Table 6. Frequencies and percent of susceptibility to each drug in Cephalosporins.
These results is different, according to WHO (GASP) resistance to Ceftriaxone in Africa 40%, Americas 22%, Estern Mediterranean 14%, Europe 10%, South-East Asia 50%, Western Pacific 38%, with total Resistance 22% Resistance to Ceftriaxone in EGYPT we were recorded 90.9% which is much higher [6] [7] [12] [19] [23] [24].
From GASP Mapfor Ceftriaxone resistance that shows EGYPT from region with data not available as shows in (previous Figure 1).
Ceftriaxone in EGYPT is shelf medicine given by pharmacist and given in an-inappropriate dose and short course; this attributes the high incidence of resistance, while Flouroquinolons are usually prescribed by physician, also most patients asked medical advice late after chronicity. Ceftriaxone is in injection form and non-compliant patients discontinue the injection once they improve and do not complete the treatment, while most of Flourquinolons are in tablet form this will encourage the patient to complete the course of treatment, moreover in EGYPT sexually transmitted diseases are considered shameful and the patient easy ask advice from friend or colleague and Ceftriaxone injection is given, so our result in EGYPT is slightly different due to regulations of medicine administration and socioeconomic habits.
5. Conclusion
The most effective empirical treatment for uncomplicated gonococcal urethritis in male in EGYPT is Fluoroquinolones; especially Levofloxacin ranks first susceptibility as 78.8% and 15.2% resistance followed by Ciprofloxacin susceptibility as 69.7% and 15.2% resistance, finally Ofloxacin susceptibility as 66.7% and 24.2% resistance. Ceftriaxone not more recommended in EGYPT as empirical treatment for uncomplicated gonococcal urethritis, susceptibility as 6.1% and 90.9% resistance. We can use combination therapy of Fluoroquinolones with Azithromycin or Doxycycline, which is susceptibility as 30.3% for Azithromycin and 42.4% for Doxycycycline, while resistance as 39.4% for Azithromycin and 27.3% for Doxycycline. It is worth noting that: only Cefepime in Cephalosporins group whose susceptibility represents as 42.4% and 42.4% resistance, in addition to the Carbapenems group (represented by Imipenem and Meropenem) whose susceptibility represents as 42.4% for Imipenem and 45.5% resistance, then 42.2% susceptibility for Meropenem and 48.5% resistance. Those can play role in combination therapy.