Prevalence of inducible clindamycin resistance in Staphylococcus aureus isolated from clinical samples

Design

In vitro study

N= 305 isolates

Objective

To determine the prevalence of macrolide-lincosamide-streptogramin B resistance (MLSBi) in both hospital and community-associated S. aureus isolates, including MRSA (methicillin resistant S. aureus) and methicillin-susceptible S. aureus (MSSA)

Study Groups

MSSA (n= 165)

MRSA (n= 140)

Methods

Isolates of S. aureus were obtained from various clinical samples, and methicillin resistance was tested with a 1 mcg oxacillin disc and Mueller–Hinton agar plate inoculated with isolates and incubated at 35°C for 24 h. Clindamycin resistance was similarly tested using 15 mcg erythromycin and 2 mcg clindamycin discs and incubated overnight. A positive D test (i.e., flattening of zone of inhibition around clindamycin disc beside erythromycin disc) would be used to define inducible MLSBi resistance. Zone sizes ≤13 mm for erythromycin and ≤14 mm for clindamycin were considered resistant.

Strains resistant to both erythromycin and clindamycin were considered to have constitutive MLSB resistance; strains resistant to erythromycin but sensitive to clindamycin were considered the MS phenotype. Quality control was performed with S. aureus ATCC 25923 for both discs.

Outcome Measures

Presence of MLSBi

Results

MLSB resistance phenotype of S. aureus

Isolates

Constitutive MLSB resistance (ERY-R, CLI-R)

Inducible MLSB resistance (ERY-R, CLI-S, D+)

MS phenotype (ERY-R, CLI-S, D−)

MSSA (n= 165)

MRSA (n= 140)

ERY= Erythromycin, CLI= Clindamycin

Of the MRSA isolates, 37.5% had MLSBi presence, 16.6% had the constitutive phenotype, and 22.8% had the MS phenotype. Of the MLSBi detected, a significantly greater number were detected in hospital-associated MRSA (86.5%) versus community-associated MRSA (13.4%).

Susceptibilities to erythromycin and clindamycin were higher in MSSA vs. MRSA (93.94% versus 23.5%). Methicillin resistance, classification into health care or community associated and presence of comorbidity were significant factors associated with susceptibilities (p< 0.05).

Study Author Conclusions

Routine screening for inducible MLSBi resistance by double disc test can screen for potential treatment failures such that clindamycin can be used effectively and judiciously when indicated for staphylococcal infections especially for treating skin and soft tissue infections (SSTIs) in CA-MRSA due to low prevalence of MLSBi among CA-MRSA.

InpharmD Researcher Critique

Data obtained in vitro are not wholly extrapolatable to a human patient population. Additionally, there is a lack of discussion on baseline incidence of clindamycin resistance, although a higher prevalence of MLSBi in health care-associated MRSA provides implications of clindamycin as a potentially viable agent in community-associated MRSA infections still.

Incidence of constitutive and inducible clindamycin resistance among hospital-associated Staphylococcus aureus

Design

In vitro study

N= 153 isolates

Objective

To distinguish different resistance phenotypes in erythromycin-resistant S. aureus by a simple double-disc diffusion test (D test)

Study Groups

MRSA (n= 42)

MSSA (n= 111)

Methods

Samples were obtained from Sri Bhagawan Mahaveer Jain hospital in Bangalore and tested for susceptibility by Kirby Bauer disc diffusion method on Mueller-Hinton agar plates. Clindamycin 2 mcg plates were utilized. Methicillin resistance was detected via cefoxitin disc diffusion method and oxacillin screen agar, if present. In erythromycin-resistant isolates, erythromycin discs were placed edge-to-edge (i.e., 15 mm) with clindamycin discs and incubated at 37°C. After 18 hours, results were interpreted as inducible resistant (D test positive, iMLSB phenotype; erythromycin resistant and clindamycin susceptible with a D-shaped inhibition zone around the clindamycin disc), non-inducible resistant (D test negative, MS phenotype; erythromycin resistant and clindamycin susceptible with both zones of inhibition circular), or macrolide–lincosamide–Streptogramin B constitutive (cMLSB phenotype; erythromycin resistant and clindamycin resistant). Quality control was performed with S. aureus ATCC 25923 for both discs.

Outcome Measures

Presence of resistance phenotypes

Results

Endpoint

MRSA (n= 42)

MSSA (n= 111)

Phenotypes

E-S, CL-S

E-R, CL-R (constitutive MLSB)

E-R, CL-S, D test positive (inducible MLSB)

E-R, CL-S, D test negative (MS)

26 (16.99%)

8 (5.22%)

1 (0.65%)

9 (5.88%)

64 (41.83%)

12 (7.84%)

13 (8.49%)

20 (13.07%)

Abbreviations: E= erythromycin, CL= clindamycin, S= sensitive, R= resistant, constitutive MLSB= constitutive resistance to clindamycin, inducible MLSB= inducible resistance to clindamycin, MS= ms phenotype, OR= odds ratio, CI= confidence interval

The constitutive CL-R phenotype and the inducible resistance phenotype were both significantly greater in methicillin-sensitive Staphylococcal isolates than methicillin-resistant Staphylococcal isolates (OR 14.38; 95% CI 5.33–21.49; p= 0.002 and OR 18.30; 95% CI 8.72–25.77; p= 0.0002, respectively).

Study Author Conclusions

In the light of the restricted range of antibiotics available for the treatment of methicillin-resistant Staphylococcal infections and the known limitations of vancomycin, clindamycin should be considered for the management of serious soft tissue infections. Further, using clindamycin use of vancomycin can be avoided. In addition, such testing can provide information about resistant to MLS phenotype group of antibiotics and can be useful for surveillance studies related to MLS resistance in Staphylococci.

InpharmD Researcher Critique

Data obtained in vitro are not wholly extrapolatable to a human patient population. Additionally, there is a lack of discussion on baseline incidence of clindamycin resistance, although inducible resistance and MS phenotype were notably higher in MSSA versus MRSA, and based on these results, patients with erythromycin-resistant Staphylococcal isolates may still be treated with clindamycin without risk of resistance emergence.

Cefdinir vs cephalexin for the treatment of urinary tract infections: A retrospective evaluation

Design

Retrospective, multicenter, observational chart review

N= 242

Objective

To determine whether there is a difference in the rate of treatment failure between cefdinir and cephalexin in urinary tract infections (UTIs)

Study Groups

Cefdinir (n= 121)

Cephalexin (n= 121)

Inclusion Criteria

Patients with an International Classification of Diseases, 10th Revision (ICD-10) code for UTI, site unspecified, or cystitis without hematuria, and a corresponding prescription for either cefdinir or cephalexin

Exclusion Criteria

Patients with pyelonephritis, fungal UTI, bacteremia, or multiple infectious diagnoses, if they received more than one antibiotic prescription on discharge or if they had a documented UTI or had received antibiotics within the last 2 weeks 

Methods

The chart of patients discharged from the emergency department at one of the 11 hospitals within the health system was reviewed. All adult patients in the cefdinir group were administered a dosage of 300 mg twice daily, with the exception of two patients who received 250 mg twice daily. Of 18 pediatric patients treated with cefdinir, 17 received appropriate dosing based on age and weight. In contrast, there was more variability in the dosages of cephalexin used, with the most common being 500 mg administered two, three, or four times daily in 53, 25, and 35 adult patients, respectively. All 13 pediatric patients in the cephalexin group received appropriate dosages for their age and weight.

Infections were deemed complicated if they manifested in males or immunocompromised patients, or in the presence of renal calculi or obstructions, urinary catheters, or instrumentation. Uncomplicated UTIs were defined as those occurring in otherwise healthy, nonpregnant females without the features of a complicated infection.

Duration

July 31, 2021 to July 31, 2022

Outcome Measures

Primary: rate of treatment failure within 7 days of discharge from the emergency department, defined as a return to the emergency department for UTI or antibiotic switching, among patients treated with cefdinir compared to those treated with cephalexin

Secondary: rate of treatment failure at 14 days after discharge and subgroup analyses of treatment failure at 7 and 14 days after discharge in subgroups of uncomplicated and complicated UTIs

Baseline Characteristics

Cefdinir (n= 121)

Cephalexin (n= 121)

Age, years

Female

UTI classification

Uncomplicated

Complicated

72.7%

27.3% 

77.7%

22.3% 

Organisms isolated from urine cultures

Organism identified

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Susceptible isolate*

52.9%

56.2%

10.9%

10.9%

87.5%

42.1%

52.9%

22.2%

18.5%

88.2%

* Cefazolin was used as a surrogate to predict susceptibility results for cefdinir and cephalexin. Susceptibility was determined using minimum inhibitory concentration breakpoints from the Clinical and Laboratory Standards Institute guideline in circulation at the time of culture collection.

Abbreviation: IM, intramuscular; IV, intravenous; UTI, urinary tract infection

Results

Endpoint

Cefdinir 

Cephalexin 

Difference (95% CI)

p-value

Treatment failure at 7 days

Treatment failure at 7 days

Uncomplicated UTI

Complicated UTI

10/88 (11.4%)

4/33 (12.1%)

6/94 (6.4%)

4/27 (14.8) 

5 (–3.3 to 13.3) 

–2.7 (–20.1 to 14.7)

0.238

1.000

Treatment failure at 14 days

Overall

Uncomplicated UTI

Complicated UTI

25/121 (20.7%)

16/88 (18.2%)

9/33 (27.3%)

14/121 (11.6%)

9/94 (9.6%)

5/27 (18.5%)

9.1 (–0.1 to 18.3)

8.6 (–1.4 to 18.6)

8.8 (–12.4 to 29.9)

0.053

0.092

0.054

Abbreviation: CI= confidence interval; UTI, urinary tract infection

Adverse Events

Not disclosed

Study Author Conclusions

The results of this study suggest that cefdinir and cephalexin have comparable efficacy for the treatment of lower UTIs. While there was a numerically higher rate of treatment failure with cefdinir, there were no significant differences in treatment failure between the agents.

InpharmD Researcher Critique

This study has limitations including the reliance on ICD-10 codes to identify UTI-related emergency department visits, potentially leading to overestimation of treatment failure. Incomplete prescription data, particularly for uninsured patients, affects the assessment of treatment adherence and failure rates. The inability to track subsequent care outside the health system could underestimate treatment failure. Additionally, the study lacks assessment of nonadherence to prescribed antibiotics and includes febrile patients without exclusion criteria, possibly confounding results by including cases of pyelonephritis rather than lower UTIs, thereby highlighting the need for cautious interpretation of the findings.

Cefdinir Versus Cefaclor in the Treatment of Uncomplicated Urinary Tract Infection

Design

Prospective, multicenter, double-blind, randomized, parallel-group study

N= 661

Objective

To compare the clinical and microbiologic efficacy and the tolerability of a cephalosporin antibiotic, cefdinir, with those of cefaclor in the treatment of uncomplicated urinary tract infection (UTI)

Study Groups

Cefdinir (n= 196)

Cefaclor (n= 187)

Inclusion Criteria

Aged ≥ 13 years; two of the following symptoms at admission: dysuria, frequency, urgency, suprapubit pain, low back pain, or gross hematuria

Exclusion Criteria

Male patients with a history of UTI or an underlying urinary tract abnormality; hospitalized or had an indwelling urinary catheter; hepatic or renal impairment; known hypersensitivity to beta-lactam agents; admission pathogen known to be resistant to either study medication before randomization

Methods

Patients in in Europe, South Africa, and Australia were randomized (1:1) to cefdinir 100 mg BID or cefaclor 250 mg TID for 5 days. Concomitant treatment with other antibiotics were not allowed during the trial. A UTI diagnosis was confirmed with a positive midstream urine sample (≥10⁵ colony forming units [CFU]/mL) and a positive urine culture.

Duration

5 days

Follow-up: 4 to 6 weeks

Outcome Measures

Treatment cure, recurrence, or failure

Baseline Characteristics

Cefdinir (n= 196)

Cefaclor (n= 187)

Age, years

Female

White

Only 383 patients were considered assessable for efficacy due to negative admission urine cultures and clinical follow-up outside the time limits specified by the protocol.

E. coli was the most frequent pathogen isolated from admission urine cultures; of the pathogens, significantly fewer were cefdinir-resistant (3.7%) vs. cefaclor (6.7%; p< 0.003). For E. coli in particular, significantly fewer were cefdinir-resistant (2.0%) vs. cefaclor (5.1%; p< 0.007).

Results

Endpoint

Cefdinir

Cefaclor

p-value

Microbiologic response rate by pathogen

Microbiologic response rate by patient

Clinical cure rate by patient

Adverse Events

Common Adverse Events: Diarrhea (9.4% cefdinir vs. 2.1% cefaclor), headache (3.0% vs. 4.2%), nausea (1.5% vs. 3.6%).

All diarrhea adverse events were considered to be related to the study drug by the investigator; significantly more diarrhea events occurred in cefdinir (p< 0.001).

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: 4 cefdinir patients (1.2%) discontinued therapy due to diarrhea.

Study Author Conclusions

Empiric therapy with cefdinir appears to be a reasonable choice for patients with uncomplicated urinary tract infection in whom cephalosporin treatment is indicated.

InpharmD Researcher Critique

As the study was conducted internationally, treatment practices may differ in a domestic U.S. patient population. This study was also published in 2000, and clinical practices have changed in tandem with increasing resistance rates since its published date.

Retrospective Comparison of Cefdinir, Cephalexin, and Sulfamethoxazole-Trimethoprim in the Treatment of Outpatient Pediatric Urinary Tract Infections

Design

Retrospective, observational, single-center study

N= 2,685

Objective

To compare the outcomes and adverse effects of the most commonly used enteral antibiotics for the treatment of pediatric urinary tract infections (UTIs) in the outpatient setting

Study Groups

Cefdinir (n= 1,564)

Cephalexin (n= 126)

Trimethoprim-sulfamethoxazole (TMP-SMX; n= 656)

Other (n= 309)

Inclusion Criteria

Children aged 2 months to 18 years, prescribed an oral antibiotic within 48 hours of urine culture collection for UTI

Exclusion Criteria

Children requiring hospital admission within 24 hours of urine collection, receiving antibiotics, had urine culture within prior 30 days, congenital genitourinary tract abnormalities, indwelling catheter, neurogenic bladder, spina bifida, bladder stone, vesicoureteral-reflux, history of kidney transplant, urine sample collected within 30 days of cystoscopy procedure

Methods

Patient data were compiled via retrospective chart review of patients admitted to primary care, urgent care, or emergency department from a single health center. 

Duration

Treated between January 1, 2014 to August 31, 2019

Outcome Measures

Primary: rate of re-encounters (included re-encounters to hospital, emergency department, or urgent care) within 30 days of initial urine culture; modification of the antibiotic regimen within 14 days of initial prescription

Secondary: C. difficile infection within 90 days of the initial urine culture, documented new allergic reaction to the antibiotic prescribed within 30 days following the initial prescription

Baseline Characteristics

Cefdinir (n= 1,564)

Cephalexin (n= 126)

TMP-SMX (n= 656)

Age, years

Female

Weight, kg

Febrile

Duration of therapy, days

Children receiving TMP-SMX were significantly older and weighed more (p≤ 0.001, respectively). More children were febrile receiving cefdinir, with a longer duration on average of therapy (p≤ 0.001, respectively).

Results

Endpoint

Cefdinir (n= 1,594)

Cephalexin (n= 126)

TMP-SMX (n= 656)

Other (n= 309)

p-value

Re-encounter

Median days to re-encounter (IQR)

246 (15%)

15 (7 to 22)

19 (15%)

12 (6 to 24)

109 (17%)

16 (9 to 21)

46 (15%)

14 (6 to 23)

0.88

0.91

Change in antibiotic*

Median hours to drug change (IQR)**

79 (5%)

49 (40 to 73) (n= 77)

18 (14%)

42 (29 to 68) (n= 18)

97 (15%)

49 (42 to 71) (n= 95)

43 (14%)

50 (38 to 71) (n= 42)

≤ 0.001

0.37

New C. difficile infection

New allergy

Median days to new allergy (IQR)

7 (0.4%)

6 (3 to 9)

0

-

11 (1.7%)

9 (8 to 11)

1 (0.3%)

10

0.018

-

A subgroup analysis was conducted for febrile patients, finding no difference in re-encounter rates between medications.

* Significant pairwise comparisons: cefdinir vs. cephalexin (p≤ 0.001), cefdinir vs TMP-SMX (p≤ 0.001), cefdinir vs. other (p≤ 0.001).

** Limited to patients with available data.

IQR, interquartile range

Adverse Events

Study Author Conclusions

In summary, TMP-SMX and cephalexin were associated with a higher rate of medication changes compared with cefdinir, largely due to susceptibility interpretation. Re-encounters for acute care were similar for the 3 antibiotics. Given its low side-effect profile and narrow spectrum compared with the alternatives, cephalexin appears to be a reasonable choice as first-line therapy for the treatment of uncomplicated pediatric UTI in the out-patient setting.

InpharmD Researcher Critique

Due to its retrospective study design, results may not be free of bias. Similarly, as this study was conducted at a single-center, results may not be readily generalizable to broader patient samples. Data or changes in treatment from outside of the health system would not be accounted for. Several data points, like compliance with medication, were not accounted for. 

Oral sitafloxacin vs intravenous ceftriaxone followed by oral cefdinir for acute pyelonephritis and complicated urinary tract infection: a randomized controlled trial

Design

Open-label, randomized, controlled, noninferiority clinical trial

N= 289

Objective

To compare the efficacy and safety of oral sitafloxacin (STFX) with that of intravenous ceftriaxone (CTRX) followed by oral cefdinir (CFDN) for the therapy of acute pyelonephritis (APN) and complicated urinary tract infection (cUTI)

Study Groups

STFX (n= 141)

CTRX/CFDN (n= 148)

Inclusion Criteria

Exclusion Criteria

Pregnancy/lactation, renal abscess requiring surgical intervention, ileal loop urinary diversion, renal transplantation, persistent indwelling urinary catheter, suspected or confirmed prostatitis or prostatic abscess, history of or current convulsive diseases, myasthenia gravis or other central nervous diseases, history of QT-interval prolongation, require additional systemic antibiotics, HIV, severe hepatic, heart, or renal disease

Methods

Patients were randomized (1:1) to receive either STFX 100 mg BID for 7 to 14 days or CTRX 2 g intravenous (IV) once a day for 2 to 3 days followed by CFDN PO 100 mg every 8 hours for an additional 4 to 12 days. Treatment duration typically lasts for 7 to 14 days depending on patient response. All patients required at least five days of hospitalization.

Duration

Outcome Measures

Primary: clinical success rate at the end of treatment defined as either cure of infection or improvement of infection

Secondary: clinical success at the end of study, safety

Baseline Characteristics

STFX (n= 141)

CTRX/CFDN (n= 148)

Age, years

Female

Type of urinary tract infection

Acute pyelonephritis

Complicated UTI

Diabetes mellitus

Obstructive uropathy

Systemic lupus erythematosus

Renal disease

72.3%

27.7%

17.7%

10.6%

0.7%

0

75.7%

24.3%

12.8%

10.1%

0%

0.7%

Urine culture

Total E. coli

Non-ESBL-producing E. Coli

ESBL-producing E. Coli

57.7%

39.2%

18.6%

58.0%

51.6%

6.5%

Resistance to study antibiotic

STFX

CTRX

CFDN

6.4%

16.3%

15.6%

5.4%

5.4%

8.8%

Median duration of antibiotic treatment (interquartile range[IQR]), days

10 (1 to 14)

3 (1 to 6)/7 (1 to 23)

Results

Endpoint

STFX (n= 141)

CTRX/CFDN (n= 148)

p-value

Clinical success at end of treatment

Overall

Acute pyelonephritis

Complicated UTI

122 (86.6%)

90/102 (88.2%)

32/39 (82.0%)

124 (83.8%)

97/112 (86.6%)

27/36 (86.6%)

-

< 0.001

0.009

Clinical success at the end of study

80.1%

74.3%

Any adverse event

Metabolic

Blood and lymphatic system

Gastrointestinal

Infection

Pulmonary

Neurologic

Skin

4.0%

4.7%

4.0%

3.3%

2.7%

1.3%

0.7%

8.4%

5.2%

3.9%

2.6%

2.6%

2.6%

1.3%

Adverse Events

Treatment-related adverse events: 17 (11.3%) occurred in the STFX group vs. 8 (5.2%) in the CTRX/CFDN group (p= 0.84)

Serious Adverse Events: 1 (0.7%) occured in the STFX group vs. 2 (1.3%) in the CTRX/CFDN group (p= 1.0)

Percentage that Discontinued due to Adverse Events: 2 (1.3%) in the STFX group discontinued vs. 1 (0.6%) in the CTRX/CFDN group (p= 0.62)

Study Author Conclusions

Oral STFX is non-inferior to intravenous CTRX followed by oral CFDN in adult patients with APN and cUTI. Lower rates of resistance compared to CTRX and/or CFDN and oral administration suggest STFX as a more attractive treatment option in this patient population.

InpharmD Researcher Critique

The majority of patients presented with acute pyelonephritis and were female. Despite treatment using cefdinir being accompanied by ceftriaxone, treatment seems to be comparable between the two investigational regimens. However, a lack of a control group leaves the possibility that safety with cefdinir may be worse than other renally-compatible antibiotics, especially since sitafloxacin is not a conventional agent available in the United States.