Co-Infections, Secondary Infections, and Antimicrobial Use in Patients Hospitalized with COVID-19 during the First Five Waves of the Pandemic in Pakistan; Findings and Implications
Abstract
:1. Introduction
2. Results
2.1. Demographic Characteristics of COVID-19 Patients
2.2. Clinical Characteristics of COVID-19 Patients
2.3. Antimicrobials Prescribed to COVID-19 Patients during Different Waves
2.4. Association between Antibiotic Use and Demographics as Well as Clinical Characteristics
2.5. Bacterial Agents Identified as Co-Infection and Secondary Infection
2.6. Prescribed Antibiotics during the Different Waves according to the ATC Classification
2.7. Antibiotics Prescribed during the Different Waves according to WHO AWaRe Classification
3. Discussion
4. Materials and Methods
4.1. Study Settings and Design
4.2. Study Variables
- Demographic characteristics include the patients’ ages, their sex, residence and presence or absence of any comorbidities, including diabetes mellitus, hypertension and other respiratory diseases. The age distribution categories, i.e., 10–30 years, 31–50 and >50 years, were based on previous studies by the co-authors.
- Clinical symptoms include a fever, cough, sore throat or headache.
- Laboratory findings, including X-rays, white blood cell counts (WBC) and C-reactive protein (CRP) were documented. The X-ray findings were reviewed by medical doctors and the treating physician was consulted in case of any confusion. Normal ranges of WBCs and CRP were taken from the reference mentioned on the testing kits.
- Whether hospitalized COVID-19 patients were on oxygen therapy or not.
- Ward subspecialty, including medical wards or intensive care units (ICU) on admission.
- Duration of hospital stay in days.
- Status of COVID-19 severity, categorized as asymptomatic, mild, moderate, severe or critical. These were categorized as per the guidelines issued by the Ministry of National Health Services, Regulation and Coordination, Government of Pakistan.
- Outcomes include whether patients were discharged from a hospital or died.
- Details about the antibiotics prescribed. This includes how many hospitalized COVID-19 patients were prescribed antibiotics during their stay in hospitals, as well as the presence of bacterial co-infection and bacterial secondary infections. Antibiotics were further classified according to the ATC classification as well as the WHO AWaRe classification.
- Bacterial co-infection was identified as those bacterial infections identified in ≤2 days after hospital admission due to COVID-19, and bacterial secondary infection as bacterial infections identified in >2 days after admission, microbiologically.
- The total number of antibiotics, the average number of antibiotics per patient, the duration of antibiotic therapy and the consumption of other antimicrobials, including antivirals, antifungal and antiprotozoal antimicrobials.
4.3. Data Collection Procedures
4.4. Inclusion and Exclusion Criteria
4.5. Statistical Analysis
4.6. Ethical Considerations
5. Conclusions and Next Steps
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Variables | Number (%) of Patients | |||||
---|---|---|---|---|---|---|
Wave 1 | Wave 2 | Wave 3 | Wave 4 | Wave 5 | Total | |
Hospitals | ||||||
H1 | 217 (27.2) | 181 (25.8) | 163 (19.4) | 87 (22.8) | 162 (32.5) | 810 (25.14) |
H2 | 163 (20.4) | 165 (23.5) | 190 (22.6) | 123 (32.2) | 92 (18.5) | 733 (22.75) |
H3 | 171 (21.4) | 134 (19.1) | 221 (26.2) | 42 (11.0) | 124 (24.9) | 692 (21.48) |
H4 | 93 (11.6) | 151 (21.5) | 156 (18.5) | 93 (24.3) | 52 (10.4) | 545 (16.92) |
H5 | 154 (19.3) | 70 (10.0) | 112 (13.3) | 37 (9.7) | 68 (13.7) | 441 (13.69) |
Sex | ||||||
Male | 467 (58.5) | 327 (46.6) | 457 (54.3) | 182 (47.6) | 227 (45.6) | 1660 (51.53) |
Female | 331 (41.5) | 374 (53.4) | 385 (45.7) | 200 (52.4) | 271 (54.4) | 1561 (48.47) |
Residence | ||||||
Rural | 346 (43.4) | 274 (39.1) | 393 (46.7) | 179 (46.9) | 214 (43.0) | 1406 (43.65) |
Urban | 452 (56.6) | 427 (60.9) | 449 (53.3) | 203 (53.1) | 284 (57.0) | 1815 (56.35) |
Age (years) | ||||||
10–30 | 137 (17.2) | 96 (13.7) | 123 (14.6) | 52 (13.6) | 97 (19.5) | 505 (15.67) |
31–50 | 304 (38.1) | 275 (39.2) | 238 (28.3) | 108 (28.3) | 114 (22.9) | 1039 (32.25) |
>50 | 357 (44.7) | 330 (47.1) | 481 (57.1) | 222 (58.1) | 287 (57.6) | 1677 (52.06) |
Comorbidities | ||||||
None | 501 (62.8) | 484 (69.0) | 422 (50.1) | 277 (72.5) | 374 (75.1) | 2058 (63.89) |
Diabetes mellitus | 109 (13.7) | 56 (8.0) | 127 (15.1) | 34 (8.9) | 26 (5.2) | 352 (10.92) |
Hypertension | 79 (9.9) | 87 (12.4) | 161 (19.1) | 58 (15.2) | 74 (14.9) | 459 (14.25) |
Heart diseases | 31 (3.9) | 22 (3.1) | 68 (8.1) | 09 (2.4) | 13 (2.6) | 143 (4.43) |
Respiratory diseases | 52 (6.5) | 14 (2.0) | 33 (3.9) | - | 08 (1.6) | 107 (3.32) |
Others | 26 (3.3) | 38 (5.4) | 31 (3.7) | 04 (1.0) | 03 (0.6) | 102 (3.13) |
Variables | Number (%) of Patients | |||||
---|---|---|---|---|---|---|
Wave 1 | Wave 2 | Wave 3 | Wave 4 | Wave 5 | Total | |
Common symptoms | ||||||
Cough | 153 (19.2) | 156 (22.3) | 189 (22.4) | 56 (14.7) | 87 (17.5) | 657 (20.39) |
Fever | 109 (13.7) | 98 (14.0) | 110 (13.1) | 72 (18.8) | 48 (9.6) | 418 (12.97) |
Sore throat | 104 (13.0) | 74 (10.6) | 90 (10.7) | 51 (13.4) | 14 (2.8) | 306 (9.50) |
Headache | 73 (9.1) | 107 (15.3) | 133 (15.8) | 28 (7.3) | 59 (11.8) | 338 (10.49) |
Dyspnea | 68 (8.5) | 56 (8.0) | 68 (8.1) | 15 (3.9) | 27 (5.4) | 223 (6.92) |
Others | 163 (20.4) | 87 (12.4) | 110 (13.1) | 86 (22.5) | 159 (31.9) | 620 (18.99) |
Multiple symptoms | 91 (11.4) | 57 (8.1) | 67 (8.0) | 74 (19.4) | 104 (20.9) | 444 (13.78) |
No symptoms | 37 (4.6) | 66 (9.4) | 72 (8.9) | - | - | 215 (6.67) |
Laboratory findings | ||||||
Abnormal x-ray | 287 (36.0) | 177 (25.2) | 213 (25.3) | 93 (24.3) | 57 (11.4) | 967 (30.02) |
Out of range WBCs | 267 (33.5) | 321 (45.8) | 387 (46.0) | 132 (34.6) | 126 (25.3) | 1099 (34.11) |
Out of range CRP | 151 (18.9) | 136 (19.4) | 157 (18.6) | 53 (13.9) | 31 (6.2) | 552 (17.13) |
Oxygen therapy | ||||||
Yes | 187 (23.4) | 114 (16.3) | 126 (15.0) | 79 (20.7) | 152 (30.5) | 779 (24.18) |
No | 611 (76.6) | 587 (83.7) | 716 (85.0) | 303 (79.3) | 346 (69.5) | 2442 (75.82) |
COVID severity | ||||||
Asymptomatic | 37 (4.6) | 66 (9.4) | 72 (8.6) | - | - | 215 (6.67) |
Mild | 146 (18.3) | 192 (27.4) | 234 (27.8) | 140 (36.6) | 19 (3.8) | 761 (23.62) |
Moderate | 464 (58.1) | 259 (36.9) | 285 (33.8) | 133 (34.8) | 316 (63.5) | 1465 (45.48) |
Severe | 105 (13.2) | 125 (17.8) | 172 (20.2) | 82 (21.5) | 106 (21.3) | 537 (16.67) |
Critical | 46 (5.8) | 59 (8.4) | 79 (9.4) | 27 (7.1) | 57 (11.4) | 243 (7.54) |
Ward Subspecialty | ||||||
Medical ward | 701 (87.8) | 565 (80.6) | 683 (81.1) | 324 (84.8) | 417 (83.7) | 2636 (81.83) |
Intensive care unit (ICU) | 97 (12.2) | 136 (19.4) | 159 (18.9) | 58 (15.2) | 81 (16.3) | 585 (18.16) |
Duration of hospital stay | ||||||
<7 days | 113 (14.1) | 139 (19.8) | 193 (22.9) | 26 (6.8) | 98 (19.7) | 569 (17.66) |
7–14 days | 528 (66.2) | 479 (68.3) | 566 (67.2) | 239 (62.6) | 278 (55.8) | 2090 (64.88) |
≥15 days | 157 (19.7) | 83 (11.8) | 83 (9.9) | 117 (30.6) | 122 (24.5) | 562 (17.44) |
Outcomes | ||||||
Discharged | 772 (96.7) | 682 (97.3) | 809 (96.1) | 376 (98.4) | 485 (97.4) | 3124 (97.0) |
Deceased | 26 (3.3) | 19 (2.7) | 33 (3.9) | 06 (1.6) | 13 (2.6) | 97 (3.0) |
Variables | Wave 1 | Wave 2 | Wave 3 | Wave 4 | Wave 5 | Total N (%) |
---|---|---|---|---|---|---|
Patients prescribed antibiotics | ||||||
Yes | 717 (89.8) | 656 (93.5) | 769 (91.3) | 328 (85.8) | 419 (84.13) | 2889 (89.7) |
No | 81 (10.1) | 45 (6.4) | 73 (8.6) | 54 (14.1) | 79 (15.8) | 332 (10.3) |
Presence of bacterial co-infection * | ||||||
Yes | 3 | 7 | 17 | 2 | 4 | 33 (1.14) |
No | 21 | 45 | 29 | 9 | 13 | 117 (4.04) |
Test not availed | 693 | 604 | 723 | 317 | 402 | 2739 (94.80) |
Presence of bacterial secondary infection * | ||||||
Yes | 13 | 9 | 31 | 17 | 21 | 91 (3.14) |
No | 34 | 18 | 56 | 32 | 16 | 156 (5.39) |
Test not availed | 670 | 629 | 682 | 279 | 382 | 2642 (91.45) |
Total number of antibiotics for all patients prescribed antibiotics (2889 patients) | 1618 | 1454 | 1369 | 513 | 611 | 5565 |
Average number of prescribed antibiotics per patient (Mean ± SD) | 2.03 ± 1.01 | 2.07 ± 0.87 | 1.63 ± 0.95 | 1.35 ± 0.64 | 1.23 ± 0.81 | 1.66 ± 0.85 |
Initiation time of prescribed antibiotics | ||||||
On admission (day 1) | 1359 (83.9) | 1222 (84.0) | 1182 (86.3) | 426 (83.0) | 510 (83.4) | 4699 (84.43) |
After 2–5 days | 198 (12.2) | 212 (14.58) | 108 (7.8) | 56 (10.9) | 58 (9.4) | 632 (11.35) |
≥6 days | 61 (3.7) | 20 (1.3) | 79 (5.7) | 31 (6.0) | 43 (7.0) | 234 (4.20) |
Number of antibiotics per patient * | ||||||
One antibiotic | 127 (18.1) | 104 (15.8) | 361 (46.9) | 202 (61.5) | 264 (63.0) | 1058 (36.62) |
Two antibiotics | 279 (39.8) | 306 (46.6) | 216 (28.0) | 67 (20.4) | 118 (28.1) | 986 (34.12) |
Three or more antibiotics | 311 (44.3) | 246 (37.5) | 192 (24.9) | 59 (17.9) | 37 (8.8) | 845 (29.24) |
Duration of prescribed antibiotic therapy | ||||||
1–5 days | 511 (31.5) | 368 (25.4) | 258 (18.8) | 179 (34.8) | 166 (27.1) | 1482 (26.63) |
6–10 days | 913 (56.4) | 1034 (71.5) | 941 (68.7) | 316 (61.5) | 403 (65.9) | 3607 (64.81) |
>11 days | 194 (11.9) | 52 (3.5) | 170 (12.4) | 18 (3.5) | 42 (6.8) | 476 (14.77) |
Other anti-infective agents | ||||||
Antiviral | 157 | 172 | 206 | 82 | 44 | 661 (10.28) |
Antifungal | 67 | 28 | 51 | 11 | 18 | 157 (2.44) |
Antiprotozoal | 19 | 7 | 17 | - | - | 43 (0.66) |
Variable | No. of Antibiotics (Mean ± SD) | p-Value | Post-Hoc Analysis |
---|---|---|---|
Age (years) | 0.183 * | -- | |
(a) 10–30 | 1.69 ± 0.94 | ||
(b) 31–50 | 1.77 ± 0.97 | ||
(c) >50 | 1.71 ± 0.93 | ||
Sex | 0.043 | -- | |
(a) Male | 1.76 ± 0.97 | ||
(b) Female | 1.69 ± 0.93 | ||
COVID-19 wave | <0.001 | ||
(a) First | 2.03 ± 1.01 | ||
(b) Second | 2.07 ± 0.87 | a > c (p < 0.001), a > d (p < 0.001), a > e (p < 0.001) | |
(c) Third | 1.63 ± 0.95 | b > c (p < 0.001), b > d (p < 0.001), b > e (p < 0.001) | |
(d) Fourth | 1.35 ± 0.64 | c > d (p < 0.001), c > e (p < 0.001) | |
(e) Fifth | 1.23 ± 0.81 | ||
COVID-19 severity | <0.001 | ||
(a) Asymptomatic | 1.43 ± 1.13 | ||
(b) Mild | 1.48 ± 0.97 | ||
(c) Moderate | 1.73 ± 0.96 | c > a (p = 0.009), c > b (p < 0.001) | |
(d) Severe | 1.98 ± 0.76 | d > a (p < 0.001), d > b (p < 0.001), d > c (p < 0.001) | |
(e) Critical | 2.03 ± 0.85 | e > a (p < 0.001), e > b (p < 0.001), e > c (p < 0.001) | |
Comorbidity | <0.001 | ||
(a) None | 1.71 ± 0.95 | ||
(b) Diabetes mellitus | 1.85 ± 0.97 | b > c (p = 0.001) | |
(c) Hypertension | 1.58 ± 0.90 | ||
(d) Heart diseases | 1.78 ± 0.89 | ||
(e) Respiratory diseases | 2.06 ± 1.05 | e > a (p = 0.012), e > c (p < 0.001) | |
(f) Others | 2.00 ± 0.92 | f > a (p = 0.026), f > c (p = 0.001) | |
X-Ray | 0.049 * | ||
(a) Abnormal | 1.80 ± 0.97 | -- | |
(b) Normal | 1.71 ± 0.93 | ||
(c) Not performed | 1.70 ± 0.96 | ||
WBCs | <0.001 | ||
(a) Elevated | 1.82 ± 0.94 | ||
(b) Not-elevated | 1.66 ± 1.01 | a > b (p = 0.003), a > c (p < 0.001) | |
(c) Test not performed | 1.67 ± 0.93 | ||
CRP | <0.001 | ||
(a) Elevated | 1.97 ± 0.87 | ||
(b) Not-elevated | 1.82 ± 1.05 | a > b (p = 0.041), a > c (p < 0.001) | |
(c) Test not performed | 1.65 ± 0.94 | ||
Oxygen therapy | <0.001 | -- | |
(a) Yes | 2.05 ± 0.78 | ||
(b) No | 1.64 ± 0.97 | ||
Ward Subspecialty | <0.001 | -- | |
(a) Medical ward | 1.67 ± 0.96 | ||
(b) Intensive care unit | 2.00 ± 0.85 | ||
Duration of hospital stay | <0.001 | ||
(a) <7 days | 1.21 ± 0.96 | ||
(b) 7–14 days | 1.75 ± 0.94 | b > a (p < 0.001) | |
(c) ≥15 days | 2.18 ± 0.72 | c > a (p < 0.001), c > b (p < 0.001) |
Bacterial Agent | Number (%) of Patients | ||
---|---|---|---|
Identified as Co-Infection (n = 33) | Identified as Secondary Infection (n = 91) | Total (n = 124) | |
Staphylococcus aureus | 14 (42.42) | 16 (17.58) | 30 (24.19) |
Streptococcus pneumoniae | 9 (27.27) | 17 (18.68) | 26 (20.96) |
Pseudomonas aeruginosa | - | 24 (26.37) | 24 (19.35) |
Haemophilus influenzae | 8 (24.24) | 11 (12.08) | 19 (15.32) |
E. coli | 1 (3.03) | 13 (14.28) | 14 (11.29) |
Klebsiella species | 1 (3.03) | 7 (7.69) | 8 (6.45) |
Other | - | 3 (3.29) | 3 (2.41) |
ATC Class | Name of Antibiotics (ATC Code) | Wave 1 | Wave 2 | Wave 3 | Wave 4 | Wave5 | Total (%) (n = 5566) |
---|---|---|---|---|---|---|---|
Third-generation cephalosporin | Ceftriaxone (J01DD04) | 255 | 274 | 146 | 33 | 71 | 779 (13.99) |
Cephoperazone+ beta-lactamase inhibitor (J01DD12) | 183 | 78 | 37 | 86 | 123 | 507 (9.11) | |
Piperacillin and enzyme inhibitor | Piperacillin + enzyme inhibitor (J01CR05) | 397 | 248 | 311 | 68 | 126 | 1150 (20.66) |
Macrolides | Azithromycin (J01FA10) | 361 | 212 | 271 | 77 | 46 | 967 (17.37) |
Carbapenems | Meropenem (J01DH02) | 238 | 279 | 206 | 64 | 73 | 860 (15.45) |
Fluoroquinolones | Ciprofloxacin (J01MA02) | 47 | 77 | 57 | 23 | 24 | 228 (4.09) |
Levofloxacin (J01MA12) | - | 17 | 12 | 18 | - | 47 (0.84) | |
Moxifloxacin (J01MA14) | 63 | 156 | 176 | 71 | 57 | 523 (9.39) | |
Other antibacterials | Linezolid (J01XX08) | 28 | 83 | 52 | 41 | 36 | 240 (4.31) |
Fourth-generation cephalosporins | Cefepime (J01DE01) | 09 | 15 | 34 | 12 | 22 | 92 (1.65) |
Amoxicillin and beta-lactamase inhibitor | Amoxicillin+ Beta-lactamase inhibitors (J01CR02) | 03 | - | 41 | 13 | 28 | 85 (1.52) |
Glycopeptide antibacterials | Vancomycin (J01XA01) | 17 | - | 13 | 07 | 05 | 42 (0.75) |
Penicillins with extended spectrum | Amoxicillin (J01CA04) | 11 | 07 | 09 | - | - | 27 (0.48) |
Other | - | 06 | 08 | 04 | - | 18 (0.32) |
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Ramzan, K.; Shafiq, S.; Raees, I.; Mustafa, Z.U.; Salman, M.; Khan, A.H.; Meyer, J.C.; Godman, B. Co-Infections, Secondary Infections, and Antimicrobial Use in Patients Hospitalized with COVID-19 during the First Five Waves of the Pandemic in Pakistan; Findings and Implications. Antibiotics 2022, 11, 789. https://doi.org/10.3390/antibiotics11060789
Ramzan K, Shafiq S, Raees I, Mustafa ZU, Salman M, Khan AH, Meyer JC, Godman B. Co-Infections, Secondary Infections, and Antimicrobial Use in Patients Hospitalized with COVID-19 during the First Five Waves of the Pandemic in Pakistan; Findings and Implications. Antibiotics. 2022; 11(6):789. https://doi.org/10.3390/antibiotics11060789
Chicago/Turabian StyleRamzan, Kiran, Sameen Shafiq, Iqra Raees, Zia Ul Mustafa, Muhammad Salman, Amer Hayat Khan, Johanna C. Meyer, and Brian Godman. 2022. "Co-Infections, Secondary Infections, and Antimicrobial Use in Patients Hospitalized with COVID-19 during the First Five Waves of the Pandemic in Pakistan; Findings and Implications" Antibiotics 11, no. 6: 789. https://doi.org/10.3390/antibiotics11060789