1. Introduction {#sec1-1}
===============

*Staphylococcus aureus* and *Escherichia coli* frequently cause superficial and systemic infections \[[@ref1]\]. Further, both species are among the most frequent causes of bacteremia and sepsis in Western industrialized countries \[[@ref11]\], with observed proportions of 16.3% to 21.6% for *S. aureus* and 5.6% to 24.2% for *E. coli* among all causes of sepsis, associated with considerable morbidity and mortality \[[@ref17], [@ref18]\]. Prolonged antibiotic therapy is recommended for *S. aureus*-associated bacteremia due to high risk of secondary foci of infection and particularly high mortality \[[@ref19], [@ref20]\], both for methicillin-susceptible and for methicillin-resistant strains \[[@ref17]\]. Along with systemic infections, both species can play a role in superficial infections such as wound infections \[[@ref21]\] or in urinary tract infections \[[@ref24], [@ref25]\].

While the etiological relevance of both of these facultatively pathogenic species under the conditions described can be considered as well documented, the pathogenic potential of individual strains depends on the presence or absence of pathogenic factors and toxins \[[@ref26], [@ref27]\] and may vary. The pathogenic factors of *E. coli* comprise adhesins (fimbrial as well as afimbrial ones and outer membrane proteins), curli, flagella, fimbriae, invasins, iron acquisition factors (siderophores), lipopolysaccharides, pili, polysaccharide capsules, secreted serine proteases, and metalloproteases, and toxins like oligopeptides, AB (alpha and beta subunit)-toxins, and RTX (repeats in toxin) pore-forming toxins \[[@ref25], [@ref26], [@ref28]\]. For *S. aureus*, agglutinins, coagulases and staphylokinases, exoenzymes like nucleases and proteases, secreted toxins such as host protease modulators, pore-forming toxins, and superantigens, as well as the ability of forming biofilms due to cell surface-associated proteins, are among the described pathogenic factors \[[@ref33]\]. As recently discussed elsewhere \[[@ref42], [@ref43]\], resistance against bactericidal first-line drugs like beta-lactam antibiotics, caused by enzymes like, e.g., extended spectrum beta-lactamases (ESBL) or carbapenems for *E. coli*, as well as by penicillin-binding proteins for methicillin-resistant *S. aureus* (MRSA), can become a severe problem for medical care.

However, previous studies have suggested a trade-off between resistance and pathogenicity \[[@ref44], [@ref45]\], assuming that expressing resistance determinants may cost additional energy and could thus decrease the fitness and competitiveness of the strain. Highly varying resistance rates have been observed in *S. aureus* and *E. coli* strains in previous assessments \[[@ref2], [@ref6], [@ref7]\].

This study was conducted to provide hypotheses to be proven by future prospective studies, focusing on two questions. Firstly, we have performed a comparative head-to-head assessment of various systemic or superficial infections exclusively associated either with *S. aureus* or with *E. coli* to get hints on potentially differing disease severity as measured by the outcome parameters, namely, death during hospital stay, duration of hospital stay, and infectious disease as the main diagnosis. Secondly, associations of resistance with the clinical course of documented infections have been assessed to discern hints supporting the above-mentioned fitness cost hypothesis.

2. Patients and Methods {#sec1-2}
=======================

2.1. Study Design {#sec2-1}
-----------------

The assessment was conducted as a single-center retrospective observational study over 5 years at a German university hospital. Inclusion criteria will be discussed in detail later under the respective heading. Data were obtained from a laboratory information system (LIS) of the DIN EN ISO 15189-accredited Institute for Medical Microbiology, Virology, and Hygiene of the University Medicine Rostock, Germany. In detail, cases were identified by screening for the search terms: *Staphylococcus aureus* and *Escherichia coli.*

For the identification of the bacterial isolates assessed in this study, VITEK 2 identification cards (bioMérieux, Marcyl'Étoile, France) or matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) with a Shimadzu/Kratos "AXIMA Assurance" MALDI-TOF mass spectrometer (Shimadzu Germany Ltd., Duisburg, Germany) were used. As described by the manufacturer (bioMérieux), alpha-cyano-4-hydroxycinnamic acid preparation was carried out for all strains prior to MALDI-TOF assessment. The spectral fingerprints obtained were interpreted using the Vitek MSID IVD-mode database version 3.2.0.-6. (bioMérieux). The equivalence of these methods regarding their diagnostic reliability has repeatedly been confirmed in the literature \[[@ref46]\]. Antibiotic resistance was analyzed applying Clinical and Laboratory Standards Institute ((CLSI), CLSI M100-S17/M2-A9, M7-A7 January 2007; CLSI M100-S19, M2-A8, M7-A8 January 2009) and European Committee on Antimicrobial

Susceptibility Testing ((EUCAST), Clinical Break Point Version 2 January 2012 and Version 3 January 2013) clinical breakpoints using the appropriate VITEK 2 AST cards in the course of the study. No adjustment for breakpoint changes was performed. Assessed antimicrobials comprised penicillins (ampicillin, ampicillin-sulbactam, oxacillin, and piperacillin--tazobactam), cephalosporins (3rd and 4th generation cephalosporins, as well as cefuroxime and cefoxitin), the carbapenem imipenem, fluoroquinolones (norfloxacin, ciprofloxacin, levofloxacin, and moxifloxacin), aminoglycosides (gentamicin and tobramycin), glycopeptides (vancomycin and teicoplanin), the macrolide erythromycin, the lincosamide clindamycin, the streptogramin quinupristin, tetracycline, the glycylcycline tigecycline, the drug combination co-trimoxazole, fosfomycin, fusidic acid, rifampicin, the oxazolidinone linezolid, the lipopeptide daptomycin, and mupirocin.

After the removal of copy strains, except for the first isolate of each case, inpatient cases were assessed anonymously. Each patient was counted only once. Data were anonymously extracted from the patients' case files and collected in Microsoft Excel worksheets for statistical analysis.

2.2. Outcome Parameters {#sec2-2}
-----------------------

Primary and secondary outcome parameters were defined, with death during hospital stay as the primary outcome parameter and the duration of hospital stay, as well as presence or absence of an infectious disease as main diagnosis (localized or systemic infections) versus a non-infectious disease-related main diagnosis (from the fields of cardiovascular diseases, endocrinology, gastroenterology, neurology, orthopedics and trauma surgery, pneumology, rheumatology and tumors, urology, and others) as secondary outcome parameters.

The outcome parameters were assessed for patients with infections due to either *S. aureus* or *E. coli* with additional focus on superficial and systemic infections. Superficial infections assessed comprised skin and urinary tract infections, while lower respiratory tract infections, bacteremia, and infections of primary sterile compartments were defined as systemic infections.

Association of antibiotic resistance with the assessed outcome-parameter was also investigated.

2.3. Factors Potentially Affecting the Outcome {#sec2-3}
----------------------------------------------

In addition to the outcome parameters described above, a number of factors were documented to assess potential effects on the outcome parameters. These variables comprised continuous parameters, such as age, and also noncontinuous parameters, such as gender; isolation site of the strain; non-surgical ward vs. surgical and intensive care ward; main diagnoses from the fields of cardiovascular disease, endocrinology/metabolic disorders, gastroenterology, local infections or systemic infections, neurology, orthopedics/traumatology, pulmonology, rheumatology, neoplasia, urology and others; peak values of leukocytes; procalcitonin (PCT) and C-reactive protein (CRP); and the presence or absence of antibiotic treatment at the time of hospital admission. Leukocytes, CRP, and PCT were semiquantitatively categorized as shown in [Table 1](#table001){ref-type="table"}. Sample materials in which *S. aureus* or *E. coli* were identified were grouped as abscess materials, ascites, aspirates, biopsies and invasive foreign material, blood cultures, bronchial lavage, respiratory secretions, wound swabs, and urine. Antibiotic susceptibility or resistance as defined by EUCAST was recorded for comparison within the species.

The distribution of both the outcome parameters and potentially confounding variables is presented in [Table 2](#table002){ref-type="table"} for both *S. aureus* and *E. coli.*

2.4. Inclusion and Exclusion Criteria {#sec2-4}
-------------------------------------

Patients were included if either *S. aureus* or *E. coli* was identified in the microbiological laboratory in any clinical sample material and if clinical information from the case files was available.

Incompleteness of the assessable dataset alone was not considered as exclusion criterion, although it led to a reduction in the number of interpretable cases.

2.5. Statistical Assessment {#sec2-5}
---------------------------

Statistical assessment was done using STATA 15.1 (StataCorp, USA) with an exploratory aim. Binary logistic regression was used for the binary endpoint parameters, namely, death and infectious disease as main diagnosis. Linear regression was used for the endpoint parameter duration of hospital stay. All models were implemented as backward selection models with a significance level of 0.1 to exclude parameters from the model. Modeling was performed for the whole dataset (global modeling), as well as for patients with either *S. aureus* or *E. coli* (local modeling). Comparisons between disjoint subpopulations generally refer to their complement. As there have been no defined references in this study, for practical reasons, the category with the lowest score or the first appearance in each group has been used as a reference for the calculations. Parameters with insufficient numbers for regression analysis were excluded from the modeling. For the endpoint-parameter infectious disease as a main diagnosis, the parameters of main diagnoses were not included into the model due to lack of independence.

2.6. Ethics {#sec2-6}
-----------

Ethical clearance for the assessment was obtained from the Ethics Committee of the University Medicine Rostock (Registration number A 2014--0054). The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Do to the retrospective design of the study, the assessment was allowed by the ethics committee in an anonymous way without consent to participate.

3. Results {#sec1-3}
==========

3.1. Study Population {#sec2-7}
---------------------

After removal of copy strains, the study population comprised 2015 cases: 1040 isolations of *S. aureus* and 975 isolations of *E. coli.* These isolations were associated with systemic infections in 758 cases, with superficial infections in 1039 cases, and with combined systemic and superficial infections in 218 cases.

3.2. Assessed Parameters {#sec2-8}
------------------------

Detailed information on the distribution of assessed patient and strain characteristics is provided in [Table 2](#table002){ref-type="table"}. Thereby, parameters are presented as distributed by either species of the bacterial isolates *(S. aureus* or *E. coli)*, as well as for the whole assessed population. Based on those data, global modeling for the whole dataset, as well as local modeling for patients with either S. *aureus* or *E. coli* with a focus on the study endpoints, was performed; the results are presented in the following sections.

3.3. Assessment of the Study Endpoints {#sec2-9}
--------------------------------------

Neither isolation of *S. aureus* nor that of *E. coli* was associated with any of the endpoint parameters in the global modeling. However, superficial infection with *S. aureus* was negatively associated with the primary outcome parameter death (P \< 0.001), but it was positively associated with infectious disease as the main diagnosis (P = 0.013). Superficial infection with *E. coli*, in contrast, was associated with shorter duration of hospital stay *(P* \< 0.001) and negatively associated with infectious disease as main diagnosis *(P* \< 0.001). Several variables potentially affected the primary and secondary outcome parameters as shown in [Tables 3--5](#table003 table004 table005){ref-type="table"}.

3.4. Associations between Resistance and Superficial or Systemic Infections {#sec2-10}
---------------------------------------------------------------------------

Enhanced resistance, i.e., resistance to 3 or more antibiotic substance classes, was not generally positively or negatively associated with invasive infections.

Resistance against tetracycline *(P* = 0.027) and fusidic acid *(P* \< 0.001) in patients with *S. aureus* and against third-generation cephalosporins *(P* \< 0.001) and ciprofloxacin *(P* = 0.097) in patients with *E. coli* was associated with increased duration of hospital stay. Also, there was a tendency for an increased risk of death in patients with clindamycinresistant *S. aureus (P* = 0.083) ([Tables 3](#table003){ref-type="table"} and [4](#table004){ref-type="table"}).

4. Discussion {#sec1-4}
=============

The study was conducted to analyze any differences in the etiological relevance of *S. aureus* and *E. coli* over a study period of 5 years with inpatients at a German university hospital with superficial or systemic infections. The focus was on the primary endpoint death during hospital stay, and the two secondary endpoints, duration of hospital stay and a main diagnosis of infectious disease. Potential associations between resistance and severity of the infectious diseases were also assessed.

The results of the assessment differed for the different cases. First of all, neither *S. aureus* nor *E. coli* as individual species alone were associated with any of the outcome parameters. As expected, superficial infections with *S. aureus* were associated with reduced risk of death compared with systemic infections; most interestingly, this association was not seen for superficial *E. coli* infections. The high relevance of *E. coli* for urinary tract infections \[[@ref30]\] (which were classed in the superficial infection group in this study) and their specific complications is a likely reason for this. Pathogenic factors associated with uropathogenic *E. coli* comprise fimbriae, curli, pili, capsules, iron scavenger receptors, flagella, toxins, and lipopolysaccharides \[[@ref25], [@ref26], [@ref30]\]. In contrast, superficial *E. coli* infections were associated with a decrease of duration of hospital stay and the likelihood of infectious disease as the main diagnosis compared with systemic infections. Also in contrast, the prominence of *S. aureus*-associated skin and soft-tissue infections \[[@ref50]\] allowed an association of superficial *S. aureus* infections and infectious disease as main diagnosis. Clumping factor B, Panton--Valentine leukocidin, and bi-component pore-forming toxins are prominent virulence factors that have been associated with skin and soft tissue infections due to *S. aureus* \[[@ref51]\]. Admittedly, molecular screening for virulence factors was beyond the scope of this study.

Antibiotic drug resistance was only weakly associated with disease severity as measured by the chosen outcome parameters. Potential resistance factors associated with the observed disease severity-associated resistance patterns comprise ribosomal methylases or efflux pumps causing clindamycin resistance \[[@ref55]\], tetracycline resistance genes of the *tet* gene family associated with tetracycline resistance \[[@ref56]\], or fusidic acid resistance genes of the *fus* gen family associated with fusidic acid resistance \[[@ref57]\] in *S. aureus*, as well as beta-lactamases associated with 3rd generation cephalosporin resistance in *E. coli* \[[@ref55]\]. In all observed cases, higher levels of resistance were associated with increased disease severity. Accordingly, this hypothesis-forming assessment provided no indications supporting the trade-off theory of fitness cost and antibiotic resistance, as suggested in the literature \[[@ref44], [@ref45]\]. Admittedly, the study was only an explorative assessment, and pathogenic factors of the isolates were not assessed, an undeniable limitation of the study. Further, applied interpretation standards of resistance testing have been changed in the course of the study, which interferes with interpretability, although major discrepancies are nevertheless unlikely.

The study has a number of further limitations. Since the study is a retrospective exploration, conclusions regarding associative relationships can only provide hypotheses. In addition, especially in the global model of both groups with either *S. aureus* or *E. coli* and in the local model for patients with *S. aureus*, the models account for only a small part of the total dispersion, so it must be assumed that a considerable amount of information that could have been explanatory was not collected. However, the hypotheses derived from this study can be used to guide future prospective studies.

5. Conclusion {#sec1-5}
=============

In conclusion, the study did not show specific association of disease severity, as defined by the endpoint parameters with the isolation of either *S. aureus or E. coli*, while, as expected, superficial infections were generally associated with milder diseases in comparison to systemic infections, as suggested by the outcome parameters. Interestingly, a reduced risk of death was shown for superficial infections due to *S. aureus* but not for those due *to E. coli*, in comparison to systemic infections. As far as can be determined despite the limitations of the study, resistance was associated with increased disease severity as defined by the endpoint parameters, so the phenomenon of trade-off between resistance and pathogenicity was not supported.

**Funding Sources**

No financial support was received for this study.

**Authors\' Contributions**

JU, SB, and UJ conducted the collection and assessments of the data. AP and PW performed the laboratory assessments. AH and NGS were in charge of the statistical assessment. AH, AP, HF, and PW planned the design of the retrospective study. All authors jointly wrote and optimized the manuscript.

**Conflict of Interest**

Nothing to declare.

###### 

Algorithm of semi-quantification of leukocyte counts as well as CRP and PCT concentrations

  ---------------------------------------------------------------------------------------------------------------------------------
  Parameter         Unit      Reference value   Category 1        Category 2           Category 3             Category 4
  ----------------- --------- ----------------- ----------------- -------------------- ---------------------- ---------------------
  Leukocyte count   10^9^/L   4--9              Reduced (\<4)     Normal (4--9)\       Increased (\>9)\       
                                                                  Slightly increased   Moderately increased   

  CRP               mg/L      \<5               Normal (\<5)      (5--50)\             (\>50--100)\           Severely increased\
                                                                  Slightly increased   Moderately increased   (\>100)

  PCT               ng/L      \<0.06            Normal (\<0.06)   (\>0.06--10)         (\>10--100)            Severely increased\
                                                                                                              (\>100)
  ---------------------------------------------------------------------------------------------------------------------------------

###### 

Overview on the distribution of individually assessed parameters in patients with *S. aureus* or *E. coli* infections

  -----------------------------------------------------------------------------------------
  Parameter                                     *S. aureus*\   *E. coli*\    Overall\
                                                *n* = 1040     *n* = 975     *n* = 2015
  --------------------------------------------- -------------- ------------- --------------
  **Death** *n* (%)                             128 (12.4%)    91 (9.3%)     219 (10.9%)

  **Gender**                                                                 

  Male                                          648 (62.3%)    423 (43.4%)   1071 (53.2%)

  Female                                        392 (37.7%)    552 (56.6%)   944 (46.9%)

  **Patient group**                                                          

  Systemic infection                            405 (38.9%)    353 (36.2%)   758 (37.6%)

  Superficial infection                         557 (53.6%)    482 (49.4%)   1039 (51.6%)

  Combined superficial and systemic infection   78 (5.5%)      140 (14.4%)   218 (10.8%)

  **Sample materials**                                                       

  Ascites                                       3 (0.3%)       10 (1.0%)     13 (0.7%)

  Biopsies and invasive foreign material        47 (4.5%)      428 (43.9%)   475 (23.6%)

  Blood cultures                                234 (22.5%)    245 (25.1%)   479 (23.8%)

  Bronchial lavage                              17 (1.6%)      19 (2.0%)     36 (1.8%)

  Respiratory secretions                        127 (12.2%)    37 (3.8%)     164 (8.1%)

  Aspirates                                     14 (1.4%)      35 (3.6%)     49 (2.4%)

  Abscess materials                             70 (6.7%)      73 (7.5%)     143 (7.1%)

  Wound swabs                                   501 (48.2%)    27 (2.8%)     528 (26.2%)

  Urine                                         27 (2.6%)      101 (10.4%)   128 (6.4%)

  **Main diagnoses**                                                         

  Endocrinology/metabolic disorders             16 (1.5%)      4 (0.4%)      20 (1.0%)

  Gastroenterology                              56 (5.4%)      175 (17.8%)   231 (11.5%)

  Cardiovascular disease                        99 (9.5%)      82 (8.4%)     181 (9.0%)

  Local infection                               333 (32.0%)    35 (3.6%)     368 (18.3%)

  Systemic infection                            103 (9.9%)     183 (18.8%)   286 (14.2%)

  Rheumatology and neoplasia                    108 (10.4%)    131 (13.4%)   239 (11.7%)

  Neurological disorder                         116 (11.2%)    24 (2.5%)     140 (7.0%)

  Orthopedics/Traumatology                      79 (7.6%)      24 (2.4%)     103 (5.1%)

  Pulmonary disease                             60 (5.8%)      80 (8.2%)     140 (7.0%)

  Other diseases                                37 (3.6%)      50 (5.1%)     87 (4.3%)

  Urologic disease                              33 (3.2%)      187 (19.2%)   220 (10.9%)

  **Ward**                                                                   

  Surgical                                      422 (40.6%)    394 (40.4%)   816 (40.5%)

  Medical                                       618 (59.4%)    581 (59.6%)   1199 (59.5%)

  **Previous antibiotic therapy**                                            

  Not documented                                594 (57.1%)    665 (68.2%)   1259 (62.5%)

  Documented                                    446 (42.9%)    310 (31.8%)   756 (37.5%)

  **Ampicillin**                                                             

  Susceptible                                   40 (37.7%)     462 (47.7%)   502 (46.7%)

  Resistant                                     66 (62.3%)     507 (52.3%)   573 (53.3%)

  **Levofloxacin**                                                           

  Susceptible                                   841 (85.8%)    n.a.          841 (85.8%)

  Resistant                                     139 (14.2%)    n.a.          139 (14.2%)

  **Norfloxacin**                                                            

  Susceptible                                   220 (85.9%)    n.a.          220 (85.9%)

  Resistant                                     36 (14.1%)     n.a.          36 (14.1%)

  **Ciprofloxacin**                                                          

  Susceptible                                   221 (86.0%)    728 (75.2%)   949 (77.5%)

  Resistant                                     36 (14.0%)     240 (24.8%)   276 (22.5%)

  **Moxifloxacin**                                                           

  Susceptible                                   860 (87.8%)    n.a.          860 (87.8%)

  Resistant                                     119 (12.2%)    n.a.          119 (12.2%)

  Erythromycin                                                               

  Susceptible                                   880 (89.8%)    n.a.          880 (89.8%)

  Resistant                                     100 (10.2%)    n.a.          100 (10.2%)

  **Clindamycin**                                                            

  Susceptible                                   885 (90.3%)    n.a.          885 (90.3%)

  Resistant                                     95 (9.7%)      n.a.          95 (9.7%)

  **Quinupristin**                                                           

  Susceptible                                   256 (100%)     n.a.          256 (100%)

  Resistant                                     0              n.a.          0

  **Gentamicin**                                                             

  Susceptible                                   957 (97.8%)    915 (94.3%)   1872 (96.1%)

  Resistant                                     22 (2.3%)      55 (5.7%)     77 (4.0%)

  **Tetracycline**                                                           

  Susceptible                                   905 (92.4%)    390 (61.2%)   1295 (80.1%)

  Resistant                                     74 (7.6%)      247 (38.8%)   321 (19.9%)

  **Tobramycin**                                                             

  Susceptible                                   822 (97.4%)    n.a.          822 (97.4%)

  Resistant                                     22 (2.6%)      n.a.          22 (2.6%)

  **Tigecycline**                                                            

  Susceptible                                   722 (100%)     426 (100%)    1148 (100%)

  Resistant                                     0              0             0

  **Co-trimoxazole**                                                         

  Susceptible                                   972 (99.3%)    686 (70.4%)   1658 (84.9%)

  Resistant                                     7 (0.7%)       289 (29.6%)   296 (15.2%)

  **Fosfomycin**                                                             

  Susceptible                                   972 (99.4%)    334 (99.4%)   1306 (99.4%)

  Resistant                                     6 (0.6%)       2 (0.6%)      8 (0.6%)

  **Fusidic acid**                                                           

  Susceptible                                   950 (97.5%)    n.a.          950 (97.5%)

  Resistant                                     24 (2.5%)      n.a.          24 (2.5%)

  **Rifampicin**                                                             

  Susceptible                                   976 (99.7%)    n.a.          976 (99.7%)

  Resistant                                     3 (0.3%)       n.a.          3 (0.3%)

  **Oxacillin**                                                              

  Susceptible                                   1035 (100%)    n.a.          1035 (100%)

  Resistant                                     0              n.a.          0

  **Ampicillin--Sulbactam**                                                  

  Susceptible                                   948 (100%)     580 (65.2%)   1528 (83.1%)

  Resistant                                     0              310 (84.8%)   310 (16.9%)

  **Cefoxitin**                                                              

  Susceptible                                   964 (100%)     n.a.          964 (100%)

  Resistant                                     0              n.a.          0

  **Cefuroxime**                                                             

  Susceptible                                   948 (100%)     n.a.          948 (100%)

  Resistant                                     0              n.a.          0

  **Imipenem**                                                               

  Susceptible                                   948 (100%)     974 (100%)    1922 (100%)

  Resistant                                     0              0             0

  **Teicoplanin**                                                            

  Susceptible                                   978 (100%)     n.a.          978 (100%)

  Resistant                                     0              n.a.          0

  **Vancomycin**                                                             

  Susceptible                                   978 (100%)     n.a.          978 (100%)

  Resistant                                     0              n.a.          0

  **Linezolid**                                                              

  Susceptible                                   980 (100%)     n.a.          980 (100%)

  Resistant                                     0              n.a.          0

  **Daptomycin**                                                             

  Susceptible                                   137 (99.3%)    n.a.          137 (99.3%)

  Resistant                                     1 (0.7%)       n.a.          1 (0.7%)

  **Mupirocin**                                                              

  Susceptible                                   963 (99.8%)    n.a.          963 (99.8%)

  Resistant                                     2 (0.2%)       n.a.          2 (0.2%)

  **Third-generation cephalosporins**                                        

  Susceptible                                   n.a.           835 (88.6%)   835 (88.6%)

  Resistant                                     n.a.           108 (11.5%)   108 (11.5%)

  **Fourth-generation cephalosporins**                                       

  Susceptible                                   n.a.           901 (92.6%)   901 (92.6%)

  Resistant                                     n.a.           72 (7.4%)     72 (7.4%)

  **Piperacillin--Tazobactam**                                               

  Susceptible                                   n.a.           747 (85.4%)   747 (85.4%)

  Resistant                                     n.a.           128 (14.6%)   128 (14.6%)

  **Days in hospital**                          1440           974           2014

  **(available for (*n*))**                                                  

  Mean (SD)                                     19.6 (19.2)    15.3 (16.3)   17.6 (18.0)

  Median                                        14.0           10.0          12.0

  **Days to sample**                            1040           975           2015

  **acquisition**                                                            

  **(available for (*n*))**                                                  

  Mean (SD)                                     4.7 (10.4)     3.8 (7.5)     4.3 (9.1)

  Median                                        1.0            1.0           1.0

  **Age (available for (*n*))**                 1040           975           2015

  Mean (SD)                                     58.3 (22.0)    69.3 (15.1)   63.6 (19.7)

  Median                                        63.0           72.0          69.0

  **CRP (available for (*n*))**                 1009           899           1908

  Mean (SD)                                     1.9(1.1)       2.1 (1.0)     2.0 (1.0)

  Median                                        2.0            2.0           2.0

  **PCT (available for (*n*))**                 242            157           399

  Mean (SD)                                     1.2 (0.5)      1.3 (0.2)     1.3 (0.5)

  Median                                        1.0            1.0           1.0

  **Leukocytes**                                998            975           1973

  **(available for (*n*))**                                                  

  Mean (SD)                                     2.5 (0.6)      2.5 (0.6)     2.5 (0.6)

  Median                                        3.0            3.0           3.0
  -----------------------------------------------------------------------------------------

###### 

Explorative binary logistic regression model with backward selection for the global model with patients with *S. aureus* and/or *E. coli* infections. Association with the outcome parameter death

  Association with the outcome parameter death            Global modeling with both patients with *S. aureus* and patients with *E. coli*   Modeling with patients with *S. aureus*   Modeling with patients with *E. coli*                                 
  ------------------------------------------------------- --------------------------------------------------------------------------------- ----------------------------------------- --------------------------------------- --------- ------------------- ---------
  Isolation from biopsies and invasive foreign material   0.52 (0.32, 0.85)                                                                 0.009                                     n.a.                                    n.a.      0.09 (0.04, 0.29)   \<0.001
  Isolation from blood cultures                           0.71 (0.47, 1.06)                                                                 0.091                                     n.a.                                    n.a.      0.13 (0.06, 0.29)   \<0.001
  Isolation from respiratory secretions                   n.a.                                                                              n.a.                                      n.a.                                    n.a.      0.31 (0.09, 1.11)   0.073
  Isolation from aspirates                                n.a.                                                                              n.a.                                      n.a.                                    n.a.      0.26 (0.07, 1.00)   0.050
  Isolation from abscess materials                        2.34 (1.47, 3.72)                                                                 \<0.001                                   n.a.                                    n.a.      n.a.                n.a.
  Isolation from urine                                    n.a.                                                                              n.a.                                      n.a.                                    n.a.      0.21 (0.08, 0.56)   0.002
  Gastroenterology                                        0.60 (0.36, 1.00)                                                                 0.051                                     n.a.                                    n.a.      n.a.                n.a.
  Cardiovascular disease                                  n.a.                                                                              n.a.                                      n.a.                                    n.a.      2.33 (1.00, 5.47)   0.050
  Local infection                                         0.61 (0.40, 0.91)                                                                 0.016                                     n.a.                                    n.a.      n.a.                n.a.
  Rheumatology and neoplasia                              0.56 (0.32, 0.97)                                                                 0.039                                     n.a.                                    n.a.      n.a.                n.a.
  Pulmonary disease                                       n.a.                                                                              n.a.                                      n.a.                                    n.a.      2.28 (1.04, 4.97)   0.039
  Urologic disease                                        0.04 (0.01, 0.30)                                                                 0.002                                     n.a.                                    n.a.      0.12 (0.02, 0.90)   0.039
  Documented previous antibiotic therapy                  1.39 (1.02, 1.89)                                                                 0.037                                     n.a.                                    n.a.      1.78 (0.99, 3.20)   0.055
  Leukocyte count                                         0.79 (0.62, 1.01)                                                                 0.063                                     n.a.                                    n.a.      n.a.                n.a.
  Age                                                     n.a.                                                                              n.a.                                      n.a.                                    n.a.      1.03 (1.00, 1.05)   0.019
  Superficial infections                                  n.a.                                                                              n.a.                                      0.27 (0.17, 0.41)                       \<0.001   n.a.                n.a.
  Clindamycin resistance                                  n.a.                                                                              n.a.                                      1.73 (0.93, 3.22)                       0.083     n.a.                n.a.
  *N* 1883, Pseudo *R*^2^ 0.0684                          *N* 851, Pseudo *R*^2^ 0.0604                                                     *N* 745, Pseudo *R*^2^ 0.1901                                                                                   

Odds ratios \>1 indicate a risk association with the outcome "death," but odds ratios \<1 indicate a protective association.

###### 

Explorative linear regression model with backward selection for the global model with patients with *S. aureus* and/or *E. coli* infections. Association with the outcome parameter duration of hospital stay

  Association with the outcome parameter duration of hospital stay   Global modeling with both patients with *S. aureus* and patients with *E. coli*   Modeling with patients with *S. aureus*   Modeling with patients with *E. coli*                                       
  ------------------------------------------------------------------ --------------------------------------------------------------------------------- ----------------------------------------- --------------------------------------- --------- ------------------------- ---------
  Biopsies and invasive foreign material                             --1.36 (--2.23, --0.49)                                                           0.002                                     n.a.                                    n.a.      --2.00 (--3.14, --0.88)   0.001
  Blood cultures                                                     n.a.                                                                              n.a.                                      1.40 (0.08, 2.71)                       0.037     --3.15 (--4.49, --1.81)   \<0.001
  Bronchial lavage                                                   n.a.                                                                              n.a.                                      n.a.                                    n.a.      --5.51 (--8.45, --2.56)   \<0.001
  Respiratory secretions                                             n.a.                                                                              n.a.                                      2.16 (0.52, 3.80)                       0.010     --2.89 (--5.48, --0.29)   0.029
  Aspirates                                                          n.a.                                                                              n.a.                                      n.a.                                    n.a.      --2.55 (--4.66, --0.44)   0.018
  Wound swabs                                                        --1.16 (--1.98, --0.34)                                                           0.005                                     n.a.                                    n.a.      n.a.                      n.a.
  Gastroenterology                                                   3.18 (2.11, 4.25)                                                                 \<0.001                                   5.18 (2.84, 7.52)                       \<0.001   2.57 (1.36, 3.79)         \<0.001
  Cardiovascular disease                                             1.68 (0.50, 2.85)                                                                 0.005                                     n.a.                                    n.a.      2.26 (0.70, 3.81)         0.005
  Rheumatology and neoplasia                                         2.90 (1.79, 4.01)                                                                 \<0.001                                   2.98 (1.01, 4.06)                       0.003     2.86 (1.54, 4.17)         \<0.001
  Pulmonary disease                                                  2.01 (0.72, 3.30)                                                                 0.002                                     n.a.                                    n.a.      2.83 (1.27, 4.38)         \<0.001
  Other diseases                                                     2.79 (1.14, 4.43)                                                                 0.001                                     3.15 (0.19, 6.19)                       0.037     2.39 (0.45, 4.32)         0.016
  Urologic disease                                                   1.99 (0.85, 3.13)                                                                 0.001                                     n.a.                                    n.a.      2.18 (0.99, 3.38)         \<0.001
  Previous antibiotic therapy                                        1.46 (0.79, 2.13)                                                                 \<0.001                                   2.10 (1.01, 3.20)                       \<0.001   n.a.                      n.a.
  CRP                                                                --0.47 (--0.80, --0.14)                                                           0.005                                     --0.73 (--1.28, --0.18)                 0.010     --0.44 (--0.83, --0.04)   0.032
  Age                                                                --0.036 (--0.05, --0.02)                                                          \<0.001                                   --0.04 (--0.06, --0.01)                 0.002     n.a.                      n.a.
  Third-generation cephalosporin resistance                          n.a.                                                                              n.a.                                      n.a.                                    n.a.      2.59 (1.38, 3.81)         \<0.001
  Tetracycline resistance                                            n.a.                                                                              n.a.                                      2.22 (0.25, 4.18)                       0.027     n.a.                      n.a.
  Fusidic acid resistance                                            n.a.                                                                              n.a.                                      5.67 (2.26, 9.08)                       0.001     n.a.                      n.a.
  Ciprofloxacin resistance                                           n.a.                                                                              n.a.                                      n.a.                                    n.a.      0.81 (--0.15, 1.76)       0.097
  Superficial infection                                              n.a.                                                                              n.a.                                      n.a.                                    n.a.      --2.46 (--3.71, --1.21)   \<0.001
  *N* 1883, adjusted R^2^ 0.3987                                     *N* 918, adjusted R^2^ 0.3863                                                     *N* 774, adjusted *R^2^* 0.5340                                                                                       

Coefficients \>0 indicate a prolonging association with the endpoint days to discharge (parameter extends on average by the shown number of days), coefficients \<0 indicate a shortening association (parameter reduces on average by the shown number of days).

###### 

Explorative binary logistic regression model with backward selection for the global model with patients with *S. aureus* and/or *E. coli* infections. Association with the outcome parameter infectious disease as main diagnosis

  Association with the outcome parameter infectious disease as main diagnosis   Global modeling with both patients with *S. aureus* and patients with *E. coli*   Modeling with patients with *S. aureus*   Modeling with patients with *E. coli*                                        
  ----------------------------------------------------------------------------- --------------------------------------------------------------------------------- ----------------------------------------- --------------------------------------- --------- -------------------------- ---------
  Biopsies and invasive foreign material                                        n.a.                                                                              n.a.                                      n.a.                                    n.a.      4.26 (1.78, 10.19)         0.001
  Blood cultures                                                                5.53 (4.15, 7.38)                                                                 \<0.001                                   n.a.                                    n.a.      5.69 (2.78, 11.68)         \<0.001
  Bronchial lavage                                                              n.a.                                                                              n.a.                                      0.23 (0.05, 1.07)                       0.061     n.a.                       n.a.
  Respiratory secretions                                                        n.a.                                                                              n.a.                                      0.20 (0.11, 0.37)                       \<0.001   n.a.                       n.a.
  Aspirates                                                                     5.40 (2.92, 10.01)                                                                \<0.001                                   n.a.                                    n.a.      14.19 (5.24, 38.40)        \<0.001
  Abscess materials                                                             5.52 (3.61, 8.46)                                                                 \<0.001                                   4.88 (2.58, 9.25)                       \<0.001   n.a.                       n.a.
  Wound swabs                                                                   8.08 (6.06, 10.77)                                                                \<0.001                                   1.83 (1.33, 2.51)                       \<0.001   651.55 (157.87, 2689.04)   \<0.001
  Urine                                                                         n.a.                                                                              n.a.                                      0.13 (0.03, 0.60)                       0.008     18.99 (6.41, 56.22)        \<0.001
  Age                                                                           0.99 (0.98, 0.99)                                                                 \<0.001                                   0.99 (0.98, 0.99)                       0.001     1.01 (1.00, 1.03)          0.083
  Gender                                                                        1.25 (1.00, 1.54)                                                                 0.045                                     n.a.                                    n.a.      n.a.                       n.a.
  Leukocyte count                                                               1.47 (1.22, 1.75)                                                                 \<0.001                                   1.35 (1.06, 1.73)                       0.016     1.71 (1.22, 2.41)          0.002
  CRP                                                                           n.a.                                                                              n.a.                                      0.86 (0.74, 0.99)                       0.034     1.43 (1.12, 1.81)          0.004
  Superficial infections                                                        n.a.                                                                              n.a.                                      1.42 (1.08, 1.87)                       0.013     0.04 (0.02, 0.08)          \<0.001
  Surgical and intensive care wards                                             n.a.                                                                              n.a.                                      n.a.                                    n.a.      0.18 (0.11, 0.30)          \<0.001
  *N* 1885, Pseudo *R*^2^ 0.1385                                                *N* 986, Pseudo *R*^2^ 0.1292                                                     *N* 899, Pseudo *R*^2^ 0.3473,                                                                                         

Odds ratios \>1 indicate a risk association with the outcome infectious disease as main diagnosis, whereas odds ratios \<1 indicate a protective association.
