George Sakoulas, MD

The activities of antibiotics against bacteria have traditionally been considered only in terms of their direct inhibition and killing properties in isolation. However, growing evidence suggests that antimicrobials also interact with host innate immunity to provide potent indirect effects which enhance bacterial clearance and may result in more rapid and complete effects, thereby reducing the likelihood of emergence of resistance among residual bacteria, and other positive clinical outcomes. Innate endogenous host defense peptides, evolved to protect the host by preventing establishment of infection from pathogenic organisms and have similar antimicrobial mechanisms of action to peptide antimicrobials delivered to patients such as daptomycin and colistin.

Scientific literature abounds with research examining the pharmacodynamics relationship of antibiotics, defining synergy, additivity, indifference, and antagonism, but studies of the pharmacodynamics of innate immune components with antibiotics are scarce. The monotherapy versus combination therapy debates for the treatment of infections fail to consider the potential additional value of the patient immune system on antibiotic pharmacotherapy (

The recommendations for antimicrobial susceptibly testing from Clinical Laboratory Standards Institute include the use of standard bacterial medium to establish the minimum inhibitory concentration.

 This is commonly defined by the lowest level of drug that inhibits bacterial growth, juxtaposed by the fact that it is determined in media designed to optimize bacterial growth. Therefore, the interpretation of the “true” MIC and its translation to the patient treated with an antimicrobial can be a controversial and moving target.

More recent research has explored the effect of different media types, commonly more host-mimicking media such as cell culture media (RPMI) and bacterial media buffered in more host physiologic ions such as bicarbonate.

 These media types may offer other advantages in that these are preferred for analyzing the antimicrobial effects of host defense peptides as well. These studies have found significant discrepancies in the antibiotic susceptibility between host-mimicking media and bacterial growth media. Strikingly, some antibiotics showing resistance in standard bacterial growth media (Mueller-Hinton) are susceptible in RPMI and other host-mimicking media. This includes azithromycin activity against 

 and recently nafcillin and cefazolin susceptibility against select MRSA strains.

 This has translated to in vivo efficacy in animal models and has demonstrated successful approaches in patients when there are discordant susceptibility results between standard and alternative media types.

There remains much debate over the clinical benefit of bactericidal versus bacteriostatic antibiotics.

 The occasionally observed similar efficacy of bacteriostatic antibiotics, as determined by traditional medium, may be because some are in fact bactericidal in the host environment.

 Since some bacteria use elements of traditional bacterial growth media to counteract antibiotics, there has been exploration of specific media types to better test individual antibiotics. Recently, carbapenems were shown to be active against metallo-beta-lactamase producing gram-negative organisms when studied in zinc-depleted Muller-Hinton broth, and susceptible strains in this media correlated with in vivo efficacy.

 This approach has now been translated into clinic testing for the new antibiotic cefiderocol, which requires iron-depleted media to prevent bacteria from artificially overcoming the antibiotic mechanism of siderophore-mimetic uptake of the cephalosporin molecule.

 There is a clear need for further studies to screen antibiotics in alternative media to improve the translation of pharmacodynamics to the bedside.  Increasingly, studies suggest that this may be a unique screening approach tailored to individual organism and antibiotic types.

While we might consider the direct, in vitro mechanism of action of an antibiotic to drive its antimicrobial efficacy, additional effects of antibiotics on bacteria have shown improved host clearance and immune optimization. This includes the ability for antibiotics to alter virulence factors and other mechanisms, which can modify host response. Clinical practice guidelines already recognize the benefit of affecting virulence factor production in the treatment of severe necrotizing fasciitis.

 Recently the influence on host immune responses with antibiotics was found with increased IL-1β and lower IL-10 production in patients treated with β-lactam adjunctive therapy combined with standard antibiotics in MRSA bacteremia.

 Although previous vaccine attempts against 

 have failed, new immunologic-based therapies show promise when combining virulence factor antibodies with traditional therapeutics.

 Each of these approaches for antibiotic- immune synergy would be missed with standard media.

Looking towards the future, it appears that our focus of antimicrobial pharmacology to the exclusion of host immunology has resulted in an outdated understanding of antimicrobial therapy. More objective examinations of immune system and antibiotic cooperativity through use of alternative media types, analysis of host cytokine responses, mathematical modeling and computer simulation will hopefully help transition this field into a more tangible science. Steps must be taken to reunite the understanding of innate immunity-antibiotic relationships in order to improve treatments, better appreciate antibiotic therapy, slow the development of resistance, and discover new therapeutic approaches.

Rose is an associate professor of pharmacy at the University of Wisconsin-Madison. His translational research interests and expertise in acute bacterial infections include antimicrobial pharmacology, resistance and virulence, and host-pathogen interactions. 

Berti is an assistant professor of pharmacy and medicine at Wayne State University in Detroit, Michigan. His research investigates how combining antibiotics in a deliberate and rational manner can improve outcomes for patients with challenging bacterial infections. By integrating pharmacokinetics, bacteriology, molecular biology and recombinant genetics, his group examines when therapies are appropriate, why they provide benefit and how best to administer them.

Sakoulas is a clinical infectious disease physician at Sharp Rees-Stealy Medical Group in San Diego, California. He also is an associate adjunct professor at the University of California San Diego School of Medicine, where he participates in the Collaborative to Halt Antibiotic-Resistant Microbes. 

Hancock REW, Haney EF, Gill EE. 2016. The immunology of host defence peptides: beyond antimicrobial activity. 

Clinical and Laboratory Standards Institute. 2019. Performance standards for antimicrobial susceptibility testing. CLSI document M100-ED29; Clinical and Laboratory Standards Institute, Wayne, PA.

. 2017. Correcting a fundamental flaw in the paradigm for antimicrobial susceptibility testing. 

Ersoy SC, Abdelhady W, Li L, Chambers HF, Xiong YQ, Bayer AS. 2019. Bicarbonate resensitization of methicillin-resistant 

. 2015. Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens. 

Wald-Dickler N, Holtom P, Spellberg B. 2018. Busting the myth of “static vs cidal”: a systemic literature review. 

Asempa TE, Abdelraouf K, Nicolau DP. 2020. Metallo-β-lactamase resistance in Enterobacteriaceae is an artefact of currently utilized antimicrobial susceptibility testing methods. 

Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant gram-negative bacilli. 

. 2014. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. 

Volk CF, Burgdorf S, Edwerdson G, Nizet V, Sakoulas G, Rose WE. 2019. Interleukin (IL)-1β and IL-10 host responses in patients with 

bacteremia determined by antimicrobial therapy. 

Miller LS, Fowler VG, Shukla SK, Rose WE, Proctor RA. 2020. Development of a vaccine against 

invasive infections: Evidence based on human immunity, genetics and bacterial evasion mechanisms. 

Articles

Growing evidence suggests that antimicrobials also interact with host innate immunity to provide potent indirect effects which enhance bacterial clearance and may result in more rapid and complete effects

Synergy Between Antibiotics and The Innate Immune System

 is a major cause of both hospital- and community-acquired infections, ranging from minor skin infections to invasive diseases such as osteomyelitis, infective endocarditis, and septicemia.

 bloodstream infections is the pathogen’s ability to simultaneously co-evolve resistance to both administered antibiotics and innate immune defense mechanisms.

 Consequently, serious infections are associated with high rates of treatment failure and mortality.

 In 2017, in the United States, there were an estimated 120,000 cases of Staphylococcus aureus bacteremia, resulting in 20,000 deaths. Although the mortality rate from methicillin-resistant 

 (MRSA) has been about double that of methicillin-susceptible 

 (MSSA), this article focuses on optimal antibiotic therapy for MSSA infections.

The timely administration of appropriate antibiotic therapy is associated with improved clinical outcomes in serious systemic infections. Initial sepsis empiric regimens most often consist of vancomycin with either ceftriaxone, cefepime, or a carbapenem, depending on the site of infection and risk of health care—associated infection. Use of piperacillin/tazobactam with vancomycin carries a relative risk of acute kidney injury of approximately 3, so its use is discouraged.

The decisions surrounding the transitioning of empiric appropriate therapy to optimal targeted therapy in 

 bacteremia involve the integration of patient risk stratification, assessing the rate of clinical response, and source control. Antimicrobial therapy for 

 bacteremia should be viewed as consisting of an intensive “induction” early phase to achieve clinical and microbiological stability followed by a less intensive “consolidative” stage for outpatient completion. 

During the early targeted therapy phase of treatment, once blood cultures identify “gram-positive cocci in clusters,” regimens should be focused on 

until cultures are processed by the clinical microbiology laboratory or, ideally, rapid diagnostic methods can discriminate MSSA from MRSA later that day. In cases of 

 bacteremia due to soft tissue infection or pneumonia, which are easily identified through initial physical exam and radiology, single-therapy regimens are likely adequate. However, great concern should arise with 

 bacteremia in the setting of an unclear source. Such patients usually present with protean symptoms, such as weakness, shortness of breath, and without fever. They may have nonspecific back and other joint pain, possibly as an acute exacerbation of previous long-standing chronic pain. Patients with end-stage renal disease and other immunocompromising comorbidities and bioprostheses, clinical instability, and a history of intravenous drug abuse should also be paid very close attention. We advocate early combination therapy with daptomycin plus ceftaroline until MRSA is ruled out microbiologically (either through rapid diagnostics or through standard susceptibility testing) based on a small but randomized prospective study showing reduced mortality in high-risk patients treated with this regimen compared with standard-of-care monotherapy.

 Vancomycin plus anti-staphylococcal β-lactam (ASBL) treatment has demonstrated more rapid S aureus bacteremia clearance but at the price of acute kidney injury, recapitulating the recommendation against vancomycin plus piperacillin/tazobactam.

 and vancomycin-plus-ceftaroline regimens may be considered, but improved outcomes with these regimens have not been demonstrated clinically. The combination of daptomycin plus fosfomycin has shown favorable data in Spain, but parental fosfomycin is not available in the United States.

In cases where combination therapy for “gram-positive cocci in clusters” has not been adopted and the patient has remained on vancomycin, strong clinical evidence supports rapid transition from empiric vancomycin to β-lactam therapy as soon as MSSA is identified.

 The ability of rapid diagnostics to shorten the empiric window between the initial “gram-positive cocci in clusters” reported by the laboratory to either MSSA or MRSA has been associated with more timely β-lactam therapy, decreased length of stay, and decreased hospitalization costs, driven largely by prompt initiation of β-lactam therapy for MSSA.14 Beyond the generally accepted need to switch from vancomycin to a β-lactam, other antibiotic choices afford the opportunity for interpretation. 

Optimal therapy for confirmed MSSA bacteremia has traditionally favored an ASBL (eg, nafcillin, oxacillin, flucloxacillin, cloxacillin) over cefazolin. One primary argument that favors ASBLs is that some MSSA strains exhibit a so-called cefazolin inoculum effect, whereby cefazolin is hydrolyzed when a dense inoculum of bacteria is present. Strains with an inoculum effect show cefazolin minimum inhibitory concentrations (MICs) that increase >3 dilutions when 107 cfu/mL of organisms is tested rather than the standard 10

 cfu/mL recommended by susceptibility testing guidelines, frequently pushing MICs out of susceptible range.

 Like selection of susceptibility testing media itself, susceptibility testing inocula standards were not designed for simulation of in vivo conditions or bacterial counts seen in clinical infection, so the translation of susceptibility testing differences based on inocula to clinical response is unknown. However, several cases of clinical failure in cases of severe invasive 

 infections have been documented in the literature.

One major limitation of ASBL therapy is the real-world concern of the tolerability for the weeks-long duration of therapy required for many invasive S aureus infections such as endocarditis, osteomyelitis, and other deep-space infections. Long-term administration of ASBLs has been associated with myelosuppression, hepatitis, phlebitis, and interstitial nephritis superimposed on an already cumbersome every-4-hour dosing regimen.

 These concerns have increased over the years due to the higher risk of complications among elderly patients and the increasing number of patients who are quickly discharged on outpatient parenteral antibiotic therapy (OPAT) with less supervision of adverse effects than would be available in a hospital setting. Recent retrospective data, while vulnerable to treatment selection bias, have shown similar outcomes in patients treated with cefazolin and ASBLs for MSSA bacteremia with better tolerability.

 Cefazolin also allows for placement of a midline rather than a peripherally inserted central catheter for treatments of 4 weeks or less, due to its reduced propensity to cause phlebitis. Midlines are less invasive, have reduced risk of thrombosis, and are less anxiety-provoking for some patients. Finally, in patients on hemodialysis, placement of a venous access can be avoided with cefazolin; the drug can be administered 3 times weekly after hemodialysis sessions. Some employ a regimen of 2 g, 2 g, 3 g, where the 3 g covers the longer 3-day gap between Friday—Monday or Saturday–Tuesday sessions, although data supporting that approach over standard 2 g dosing are lacking. 

We believe that both concerns are valid and need to be incorporated into the decision-making process of prescribing antibiotics to treat MSSA bacteremia. In cases of MSSA, we favor ASBL therapy while the patient is in the hospital to bridge them through bacteremia clearance, source control, and clinical stability. Use of ASBL therapy early on reduces risk of the inoculum effect in cases with high organism burden infections. The inpatient period also allows for placement of a venous midline catheter for cefazolin OPAT (

). On occasion, we have encountered persistent MSSA bacteremia on cefazolin or ASBL monotherapy (frequently due to endocarditis) that we have successfully cleared with cefazolin plus ertapenem.

 Again, once stability is achieved, monotherapy is employed, with a preference for ASBL for OPAT in these more challenging circumstances, especially if the patient is being discharged to a skilled nursing facility where closer monitoring is enabled and the 4-hour dosing interval of ASBLs imposes less inconvenience than in the case of a more mobile patient being discharged to their home. 

Although case reports describe successful use of ceftriaxone in MSSA bacteremia, a recent comparative study showed inferior outcomes of ceftriaxone compared with cefazolin.

 Given the pharmacokinetics (ie, protein binding) and MICs of MSSA to ceftriaxone, routine use of ceftriaxone in MSSA is not recommended. Finally, it is worth noting that discussions surrounding the use of combination therapy for the treatment of 

 infections, including MRSA, are sure to be controversial. We must consider the fact that combination therapy is employed in the treatment of many other infectious diseases, from mycobacterial and parasitic to viral (ie, HIV) and even fungal (ie, induction of cryptococcal meningitis therapy). The patients from initial case reports of penicillin use in the 1940s, which served as the foundation of current monotherapy paradigms, differed greatly from contemporary patients in terms of host innate immunity status and the complexity of their antecedent surgical interventions that led up to their infections, including the presence of bioprosthetic devices such as heart valves and pacemakers. To extrapolate antimicrobial monotherapy to all contemporary patients, some of whom are much more immunocompromised and with more complex infections, seems illogical. Considering that the net antimicrobial effect of a patient on antibiotic pharmacotherapy is the collective summation of exogenous pharmacotherapy and innate immunity points out that pure monotherapy does not actually exist; consequently, some patients may require exogenous pharmacotherapy to compensate for their attenuated innate immune-mediated killing or to overcome a large bacterial inoculum of infection. 

In summary, the last 2 decades have increased therapy options in the treatment of MRSA and MSSA infections, yet there is a dearth of guidance on how to best utilize these new antibiotics and how to integrate them with older ones. We hope this review helps readers consider important differences between adequate and optimal therapy when treating these challenging infections. 

Methicillin resistance in Staphylococcus aureus: mechanisms and modulation. 

 2002;85(Pt 1):57-72. doi: 10.3184/003685002783238870.

The importance of the development of antibiotic resistance in Staphylococcus aureus. 

. 2006;12(Suppl 1):3-8. doi: 10.1111/j.1469-0691.2006.01343.x.

. 2005;23:197-223. doi: 10.1146/annurev.imunol.23.021704.115653.

Treatment failure and costs in patients with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections: a South Texas Ambulatory Research Network (STARNet) study. 

. 2013;26(5):508-517. doi: 10.3122/jabfm.2013.05.120247.

Kourtis AP, Hatfield K, Baggs J, et al. Vital signs: epidemiology and recent trends in methicillin-resistant and in methicillin-susceptible 

 bloodstream infections — United States. 

. 2019;68(9):214-219. doi: 10.15585/mmwr.mm6809e1.

Watkins RR, Deresinski S. Increasing evidence of the nephrotoxicity of piperacillin/tazobactam and vancomcyin combination therapy—what is the clinician to do? 

. 2017;65(12):2137-2143. doi: 10.1093/cid/cix675.

Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis. 

. 2018;46(1):12-20. doi: 10.1097/CCM.0000000000002769.

Clinical data on daptomycin plus ceftaroline versus standard of care monotherapy in the treatment of methicillin-resistant 

 bacteremia [published online April 25, 2019].

Davis J, Foo H, Lye D, et al. Combination antibiotic therapy for methicillin-resistant 

 bacteraemia: the CAMERA2 randomised controlled trial. Presented at: 29th European Congress on Clinical Microbiology and Infectious Diseases; April 13-16, 2019; Amsterdam, The Netherlands. Abstr L0014.

Trinh TD, Zasowski EJ, Lagnf AM, et al. Combination vancomycin/cefazolin (VAN/CFZ) for methicillin-resistant 

. 2017;4(Suppl 1):S281. doi: 10.1093/ofid/ofx163.631.

Pujol M, Miro JM, Shaw E, et al. Daptomycin plus fosfomycin versus daptomycin monotherapy for methicillin-resistant 

 bacteremia. a multicenter, randomized clinical trial. Presented at: ID Week 2019; October 4, 2018; San Francisco, CA. Abstract LB3. 

idsa.confex.com/idsa/2018/webprogram/Paper74232.html#

Holland TL, Arnold C, Fowler VG Jr. Clinical management of Staphylococcus aureus bacteremia: a review. 

. 2014;312(13):1330-1341. doi: 10.1001/jama.2014.9743.

Schweizer ML, Furuno JP, Harris AD, et al. Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible 

. 2011;11:279. doi: 10.1186/1471-2334-11-279.

Bauer KA, West JE, Balada-Llasat JM, Pancholi P, Stevenson KB, Goff DA. An antimicrobial stewardship program’s impact with rapid polymerase chain reaction methicillin-resistant Staphylococcus aureus/S. aureus blood culture test in patients with S. aureus bacteremia. 

. 2010;51(9):1074-1080. doi: 10.1086/656623.

Nannini EC, Singh KV, Murray BE. Relapse of type A beta-lactamase-producing Staphylococcus aureus native valve endocarditis during cefazolin therapy: revisiting the issue. 

. 2003;37(9):1194-1198. doi: 10.1086/379021.

Bryant RE, Alford RH. Unsuccessful treatment of staphylococcal endocarditis with cefazolin. 

Quinn EL, Pohlod D, Madhavan T, Burch K, Fisher E, Cox F. Clinical experiences with cefazolin and other cephalosporins in bacterial endocarditis. 

Fernández-Guerrero ML, de Górgolas M. Cefazolin therapy for Staphylococcus aureus bacteremia. 

. 2005;41(1):127. doi: 10.1016/j.cmi.2019.03.010.

Weis S, Kesselmeier M, Davis JS, et al. Cefazolin versus anti-staphylococcal penicillins for the treatment of patients with 

. 2019;25(7): 818-827. doi: 10.1016/j.cmi.2019.03.010.

Ulloa ER, Singh KV, Geriak M, et al. Cefazolin and ertapenem salvage therapy rapidly clears persistent methicillin-susceptible 

 bacteremia [published online November 27, 2019]. 

Carr DR, Stiefel U, Bonomo RA, Burant CJ, Sims SV. A comparison of cefazolin versus ceftriaxone for the treatment of methicillin-susceptible 

 bacteremia in a tertiary care VA medical center. 

. 2018;5(5):ofyS89. doi: 10.1093/ofid/ofy089.

Get Off the SOFA! Introducing the Quick Pitt Bacteremia Score

Therapy options have increased in recent decades, yet there is a lack of guidance. 

George Sakoulas, MD

Articles

Latest News