Oral antibiotic therapy in people who inject drugs (PWID) with bacteraemia

DOI: https://doi.org/10.4414/smw.2020.20259

Introduction

Infections are a leading cause of morbidity and hospitalisation in people who inject drugs (PWID) [1–6]. Among the most frequent infections in PWID are soft tissue infections, suppurative thrombophlebitis and endocarditis, which can all cause bacteraemia. In many cases, bacteraemia is treated with intravenous (IV) antibiotics for two or more weeks. IV antibiotic therapy requires a vascular catheter, with the potential risk of catheter-associated complications, and usually leads to higher costs and a longer hospital stay compared with oral therapy [7–9]. Prolonged IV treatment can be particularly challenging in some PWID due to difficult venous access and motivational problems. Many PWID need a central venous catheter (CVC) for adequate IV antibiotic treatment, but CVCs are prone to being manipulated and misused by PWID, who inject recreational drugs into them. This can lead to complications like central line thrombosis, secondary CVC-related infections, and de novo suppurative thrombophlebitis with nosocomial bacteria or fungi which are sometimes difficult to treat, as seen in our clinical practice and described in the literature [10, 11]. In some PWID, the rigid continuation of IV antibiotic therapy can endanger the patient’s health, and treatment alternatives, e.g., oral antibiotic treatment, must be evaluated.

This review aims to give an overview of the available evidence on oral antibiotic treatment options for bacteraemia in PWID. Oral treatment should only be considered in patients in which standard IV antimicrobial therapy presents an unacceptably high risk to the patient’s health. In our experience, this applies mainly to patients who have a history of multiple CVC-related complications. We emphasise that most bacteraemia in PWID can be treated with IV antibiotics [12], and that even outpatient parenteral antibiotic therapy can be a valid option in PWID [13, 14]. Whenever possible, a course of IV treatment should precede the switch to an oral regimen in cases where full-length IV treatment is not feasible.

Table 1 shows important aspects to consider when using oral antibiotics to treat bloodstream infections in PWID.

General management considerations

Bacteraemia in PWID is most often caused by S. aureus, followed by Streptococcus spp., Enterobacterales, Enterococci, Pseudomonas spp., yeasts, and others [1, 2, 11, 12]. Like all patients with bacteraemia, PWID must be evaluated for persistent infectious foci. Particular attention must be paid to infectious complications such as endocarditis, suppurative thrombophlebitis, septic arthritis and vertebral osteomyelitis, which must be excluded by appropriate diagnostic measures. This is especially true for S. aureus, which is the leading pathogen of skin and soft tissue infections [15], endocarditis [11, 16], septic deep venous thrombosis [17] and septic arthritis [18] in PWID. Source control must be achieved, e.g., by incision and drainage of deep or superficial cutaneous abscesses.

Our review focuses on the most frequently detected microorganisms in PWID: S. aureus, Streptococcus spp. and gram-negative bacteria.

The antimicrobial treatment should target the detected pathogen according to susceptibility testing and should achieve adequate drug concentrations in the blood and in the tissue at the site of infection (tables 2 and 3 ).

Treatment decisions in PWID with a severe infectious disease should be made by a multidisciplinary team, including specialists in internal medicine, infectious diseases, addiction medicine, psychiatry and nursing [35]. In PWID within a drug substitution program, adjustment of the substitution therapy may lower withdrawal symptoms and help to provide state-of-the-art IV antibiotic therapy.

Pharmacological considerations

Important factors to consider for oral antimicrobial therapy are (1) the susceptibility of the pathogen to the drug (measured by the minimum inhibitory concentration [MIC]), (2) antimicrobial pattern of activity (e.g., time-dependent killing, concentration-dependent killing), (3) oral bioavailability, (4) gastrointestinal tolerability, (5) distribution (blood and tissue concentration), (6) patient's adherence and (7) drug-drug interactions. In severe infections, adequate serum antibiotic drug concentrations are reached most reliably through parenteral application of antibiotics, as poor perfusion of the gut and liver limit the absorption of oral drugs [36].

Oral therapy requires antimicrobial agents with high oral bioavailability and few gastrointestinal side effects.

Among the penicillins, only amoxicillin has a high oral bioavailability (80–90%) [9] (table 2). Gastrointestinal side effects and a saturable absorption usually limit the maximal oral dose to 3–4 × 1 g per day [37, 38]. However, for some pathogens with low MICs, e.g., some Streptococcus spp., oral amoxicillin may reach serum drug levels which are sufficient to allow the successful treatment of bacteraemia with those pathogens. As an example, with an estimated peak concentration of 10 mg/l and a plasma half-life of 1.5 hours (see table 2), the amoxicillin blood concentration usually remains above the Streptococcus spp. EUCAST MIC breakpoint of 0.5 mg/l for more than 6 hours. Many Streptococcus spp. strains show even lower MICs [19]. The oral bioavailabilities of other oral beta-lactam antibiotics, such as penicillin V, anti-staphylococcal penicillins (e.g., flucloxacillin) and cephalosporins (e.g., cefuroxime), are too low for them to be used as reliable treatments for patients with bacteraemia.

Fluoroquinolones (including ciprofloxacin, levofloxacin and moxifloxacin) have good oral bioavailability, are well tolerated when taken orally at standard doses [39], and reach similar pharmacokinetic parameters when taken orally as when given intravenously [40]. The same applies to rifampin, which should always be given in combination with other antibiotics to avoid the development of resistance. Trimethoprim-sulfamethoxazole (TMP-SMX), clindamycin and the oxazolidinone linezolid also have high bioavailabilities, but are bacteriostatic (except TMP-SMX for S. aureus) at standard doses compared to the bactericidal activity of the fluoroquinolones and rifampin. Linezolid has potentially serious side effects (mainly neurotoxicity and haematotoxicity), especially when taken for longer periods [39], and is expensive. Table 2 shows the basic pharmacokinetic characteristics, important side effects and potential interactions of antimicrobial agents used for oral treatment of bacteraemia.

Staphylococcus aureus

S. aureus is by far the most common pathogen detected in blood cultures from PWID [1, 2, 11, 12, 41]. S. aureus bacteraemia is traditionally classified as complicated or uncomplicated. The following criteria define uncomplicated S. aureus bacteraemia: (a) exclusion of endocarditis, (b) no implanted foreign body, (c) negative follow-up blood cultures 2–4 days after the initial set, (d) defervescence within 72 hours of initiating effective therapy and (e) no evidence of metastatic sites of infection (all criteria must be fulfilled) [42]. Uncomplicated S. aureus bacteraemia is typically treated with intravenous antibiotics for two weeks [43, 44]. Complicated S. aureus bacteraemia includes endocarditis, suppurative thrombophlebitis and metastatic infections. In these cases, the treatment is complex and frequently requires surgical intervention and prolonged IV antibiotic treatment, usually for 4–6 weeks [7, 45–47]. S. aureus is classified as methicillin-susceptible S. aureus (MSSA) if the isolate is susceptible to anti-staphylococcal beta-lactams like methicillin or oxacillin, and as methicillin-resistant S. aureus (MRSA) if it is resistant to these. MRSA cannot be treated with beta-lactams, except for the parenteral fifth generation cephalosporins (ceftaroline, ceftobibrole).

A recent propensity score-matched cohort study [27] investigated whether patients with uncomplicated S. aureus bacteraemia who were switched to oral linezolid after a mean of seven days of IV treatment had worse outcomes than patients who were treated with a standard IV regimen for a mean of 15 days. The study found no significant difference in the 90-day relapse rates in survivors, and no differences in the 14- and 30-day mortality rates. In this study, 15.8% of all S. aureus isolates were MRSA.

In a meta-analysis of five randomised controlled trials, Shorr et al. [25] found no significant differences in clinical cure rates between patients treated with IV vancomycin and patients switched to oral linezolid after a mean duration of IV treatment of 8.6 days and with a mean total duration of treatment of 12.1 days. Overall, 50.7% of the patients presented with MRSA infections. The most common sources of infection were pneumonia (41.7%) and skin and soft tissue infections (29.9%).

As for complicated S. aureus bacteraemia, only a few studies have investigated oral antibiotic treatment in patients with endocarditis or suppurative thrombophlebitis.

In a retrospective study of 36 PWID with suppurative thrombophlebitis due to S. aureus or Streptococcus spp., no relapse was observed if IV treatment was given for at least seven days before switching to the oral regimen [48].

A randomised controlled trial from 1996 compared oral treatment with ciprofloxacin (750 mg bid) and rifampin (300 mg bid) to standard IV treatment (oxacillin + gentamicin), both for 28 days, in PWID with right-sided endocarditis caused by S. aureus [16]. The authors found no significant difference in outcome between the two groups. Ever since, this study has been cited in various endocarditis guidelines [45, 46]. To our knowledge, it is the only study to have investigated the role and outcome of oral antibiotic treatment alone (i.e.,, without IV treatment) for S. aureus bacteraemia. However, the results should be interpreted with caution because of the high exclusion rate (only 44 out of 573 participants were included in the final analysis; most were excluded because they did not suffer from right-sided staphylococcal endocarditis or were lost to follow-up) and the questionable – espcecially from an ethical point of view – study protocol.

In a French retrospective cohort study, the authors compared 212 patients (mostly non-PWID) with endocarditis receiving a full course of IV antimicrobial treatment to 214 patients who were switched to an oral regimen [28]. For S. aureus endocarditis, different oral regimens were used. Combination therapy. mainly one of (a) clindamycin + either rifampin, a fluoroquinolone or amoxicillin, (b) a fluoroquinolone + either rifampin or amoxicillin, or (c) amoxicillin + rifampin), was given in 72% of cases, and monotherapy (amoxicillin, fluoroquinolone, clindamycin or linezolid) was used in the remaining patients. After correcting for various risk factors, the authors found no significant difference in all-cause mortality between the IV and the oral groups with a mean follow-up of five months. However, the mean duration of IV treatment before switching to oral treatment was 21 days.

A two time periods (i.e., before/after) intervention study of patients with S. aureus endocarditis compared a standard intravenous protocol (oxacillin or vancomycin for six weeks combined with gentamycin for five days) with an early oral switch protocol (high dose (960 mg/4800 mg per day) oral TMP/SMX after seven days of IV treatment with a combination of TMP/SMX and clindamycin). Length of hospital stay and mortality rate were both reduced in the oral TMP/SMX group [49, 50]. This treatment regimen is included as an alternative therapy in the 2015 European Society of Cardiology Endocarditis guidelines [46]. However, two randomised trials that compared oral TMP/SMX to IV vancomycin for various S. aureus infections, including bacteraemia, showed inferior outcomes for patients treated with TMP/SMX [51, 52], although they used lower dosages (320 mg/1600 mg bid). One of these trials included only PWID [51].

Finally, the recent POET study randomised patients with endocarditis to standard IV treatment or a switch to dual oral treatment after a minimum of 10 days of IV treatment [29]. The authors used a multitude of different oral regimens for S. aureus bacteraemia, including (a) dicloxacillin combined with either rifampin or fusidic acid, (b) amoxicillin combined with either rifampin or fusidic acid, or (c) moxifloxacin combined with either rifampin or fusidic acid. Considering the composite primary outcome (all-cause mortality, unplanned cardiac surgery, embolic events or relapse of bacteraemia with the primary pathogen) six months after completion of treatment, non-inferiority criteria were met. Moreover, the authors showed that in almost all patients, oral regimens reached serum antibiotic drug levels which are considered effective for treating bacteraemia.

In conclusion, there is growing evidence that a switch from initial IV antimicrobial treatment to oral treatment can be an option in uncomplicated, and even in selected cases of complicated, S. aureus bacteraemia. Several studies have shown good results with linezolid or various (mainly rifampin-containing) dual regimens (table 3). Monotherapy with agents other than linezolid (e.g., TMP/SMX) seems to be less favorable. However, treatment with linezolid is problematic in PWID because of the high risks of serotonin syndrome in conjunction with opioids [53, 54] and of bone marrow toxicity. Another disadvantage is the high cost of linezolid. Rifampin interacts with a multitude of drugs, including methadone, and can therefore lead to withdrawal symptoms. Unfortunately, data on the treatment of S. aureus bacteraemia with oral antibiotics other than linezolid and rifampin are scarce. Other options may be considered in situations where rifampin and linezolid cannot be given (table 3).

The new lipoglycopeptide antibiotic dalbavancin, which is not yet available in Switzerland, might be an interesting treatment option in the future. Dalbavancin has a very long half-life (147–258 hours) and can be given intravenously once weekly. Dalbavancin is FDA approved for skin and soft-tissue infections (SSTI) and has in vitro activity against many gram-positive pathogens, including MSSA, MRSA and streptococci. A few studies, some of which included PWID, have shown promising results for patients with bacteraemia [55–57]. However, most of these studies were small, with a heterogeneous study population, and their findings should be confirmed by larger studies.

Streptococcoccus spp.

Among streptococcal bacteraemia in PWID, group A streptococcal (GAS) infections are particularly frequent [58]. In PWID, invasive GAS infections typically present as an SSTI, often with an abscess at the injection site [58]. There is no consensus, either among clinicians or in the literature, on the best management of GAS bacteraemia in SSTI [59]. At least one trial with oral treatment excluded patients with positive blood cultures [60]. However, guidelines do not recommend drawing blood cultures routinely in immunocompetent patients with cellulitis and erysipela [44]. Penicillin is the drug of choice to treat GAS infections. The switch to oral therapy must be discussed on a case-by-case basis once source control has been achieved. A potential candidate for oral therapy is amoxicillin – as GAS remain invariably susceptible to penicillin, usually with low MICs (see paragraph “pharmacological considerations”). Other highly bioavailable agents are levofloxacin, moxifloxacin, clindamycin and linezolid. However, supporting data for all oral options is lacking because, to the best of our knowledge, no clinical trials have compared these agents with IV therapy in bacteremic GAS infections.

For Streptococcus pneumoniae, studies [61–63] of community-acquired pneumonia (CAP), including bacteraemia, did not show worse outcomes when patients were switched from IV to oral antimicrobial treatment (mostly beta-lactam antibiotics). This is reflected in the ATS/IDSA 2007 guidelines [64], which encourage a switch to oral treatment of pneumococcal bacteraemia in the setting of CAP once the patient has improved clinically. It is of note that the 2019 ATS/IDSA guidelines [65] do not recommend drawing blood cultures in CAP without specific risk factors.

Bacteraemia with streptococci from other groups (e.g., oral Streptococcus spp. and Streptococcus bovis group) are often associated with endocarditis. Some of these streptococci may show increased MICs to penicillin. To our knowledge, there are no studies that have investigated oral therapies for bacteraemia with these pathogens in diseases other than endocarditis. In streptococcal endocarditis (including different groups of streptococci), the switch to oral treatment (mostly amoxicillin monotherapy, and in a small proportion amoxicillin combined with either clindamycin or rifampin) was not associated with a significant difference in all-cause mortality or relapse in a retrospective French cohort [28]. In the POET study [29], streptococcal endocarditis was successfully treated with oral combination therapy (mostly amoxicillin and rifampin or amoxicillin and moxifloxacin) after an initial course of IV treatment.

In summary, we suggest that a switch to an oral treatment, especially with amoxicillin, is a reasonable option in PWID with streptococcal bacteraemiafor whom an alternative to IV treatment is warranted (table 3). In complicated infections such as endocarditis, combination oral therapy can be considered

Gram-negative bacteria

Several studies have shown that oral fluoroquinolones can be a valid option for the treatment of bacteraemia with susceptible gram-negative pathogens [30–33]. Although most evidence comes from studies of urogenital bacteraemia, there are also some studies from gram-negative bacteraemia of other origins [30, 32]. Fluoroquinolones have good bioavailability and usually reach adequate serum drug concentrations for successfully treating gram-negative bacteraemia.

The risk of cardiac QTc interval prolongation and torsade de pointes ventricular arrhythmias must be kept in mind when using fluoroquinolones in PWID, especially in combination with other QTc interval-prolonging drugs such as methadone [66].

Other oral treatment options, including oral beta-lactam antibiotics and TMP/SMX, are less convincing [32, 67] and seem to be inferior to fluoroquinolones, although reported cure rates were still above 85% for patients switched to an oral beta-lactam after initial IV treatment [32–34]. However, these trials were not powered to show non-inferiority in comparison to oral fluoroquinolones.

In patients with more resistant gram-negative infections, e.g., due to fluoroquinolone-resistant Pseudomonas aeruginosa or many ESBL-producing Enterobacterales, there are usually no good options for oral treatment. Although there is limited data for intramuscular or even subcutaneous treatment with broad-spectrum beta-lactam antibiotics [68–70], caregivers must balance the benefits of such therapy against its risks (soft tissue infection, haematoma, pain).

In summary, gram-negative bacteraemia can be treated successfully with oral fluoroquinolones if susceptible. Oral TMP/SMX is less favourable, but can be considered in fluoroquinolone-resistant gram-negative bacteraemia.

Conclusion

Data on oral antibiotic treatment of bacteraemia in PWID is scarce. Most data originate from retrospective studies and a non-PWID population. Only a few randomised controlled trials have investigated oral treatment options for bacteraemia.

The best existing evidence for oral antibiotic treatment in PWID is for gram-negative bacteraemia in the setting of urinary tract infections, which can be treated successfully with oral fluoroquinolones. Oral treatment options for fluoroquinolone-resistant gram-negative bacteraemia are very limited, with TMP/SMX a possible second choice.

In gram-positive bacteraemia, most clinical data on oral antimicrobial treatment comes from switch studies, in which antimicrobial therapy was started intravenously before a switch to oral treatment. The selection of an oral regimen in PWID with S. aureus bacteraemia seems particularly challenging, as the best-documented regimens, including fluoroquinolones, linezolid and rifampin, also have the highest risk of toxicity and interactions.

The very limited number of good and well-studied oral antimicrobial treatment options in this very complex patient population highlights the importance of adequate source control and an interdisciplinary approach, encompassing all persons involved in the treatment and care, to select the best therapy and to ensure follow-up.

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