Shooting up: the interface of microbial infections and drug abuse

S. aureus.

S. aureus is the most common pathogen causing skin and soft tissue infections in IDUs with community-associated MRSA accounting for a high proportion (Lowy & Miller, 2002; Lloyd-Smith et al., 2010). Infections are usually minor in nature; however, severe forms such as osteomyelitis, bacteraemia, septic deep vein thrombosis and endocarditis are not uncommon (Cooke et al., 2010; Fäh et al., 2002).

Genetic analysis of strains from drug users in the UK demonstrated the polyclonal nature of S. aureus in the lesions of the IDUs with marked variability in toxin gene content (Monk et al., 2004). The relatively high frequency of the sequence type (ST) 59 genotype suggests that it could be a common clone among IDUs in the region. In a more recent study from Brighton, UK, this ST59 clone appears to have disappeared from the local IDU population to be replaced by the single MRSA clone ST1 (Atkinson et al., 2009). This shift in the population structure of MRSA in IDUs from epidemic hospital-acquired clones to single MRSA clones suggests that IDUs form a unique group for S. aureus transmission.

Investigation of an outbreak in Alberta, Canada, identified the USA 300 strain of community-associated MRSA to be increasingly linked with infections in drug users and homeless populations (Gilbert et al., 2006). The strain possessed the staphylococcal cassette chromosome mec type-IV genetic element, which contains the mecA resistance gene, the PVL determinant and the spa type 008. The majority of the infections in the outbreak were community acquired and severe in nature, with a high proportion requiring intravenous antimicrobial therapy.

Nosocomial infections caused by S. aureus are particularly relevant to hospitalized IDUs since many of them need central vascular access (Petrosillo et al., 2002). IDUs may also use the central access to inject illicit drugs; thus, furthering the risk of catheter infection (Bassetti & Battegay, 2004).

Group A streptococci (GAS).

IDUs represent an increasing proportion of patients with invasive group A streptococcal disease (Léchot et al., 2001; Lamagni et al., 2008). In 2000, the UK witnessed a sudden increase in GAS infections in IDUs, sparking off a nationwide investigation (Efstratiou et al., 2003). Cases were reported throughout England and Wales, and the majority of them presented with skin sepsis and bacteraemia. A total of 12 different M serotypes were detected, which included M1, M4, M11 and M22, predominating early in the outbreak, and the ‘higher types’, M78, M82, M83, M87 and M89, emerging during the later years. Based on emm typing, GAS strains from IDUs in the UK were found to be predominantly emm82 and emm83 types, which were uncommon in the non-IDU population, and furthermore, emm82 strains also appear to be clonal (Curtis et al., 2007). An outbreak of soft tissue infections among cocaine users in Switzerland caused by the clonal GAS strain M type 25 was reported and the majority of the infected drug users obtained their drugs from a common source (Böhlen et al., 2000). Drug dealers often hide cocaine in their mouths to avoid the attention of the police. GAS may have spread to drug users by contamination of the plastic bags containing the cocaine or via respiratory droplets from a colonized drug dealer. Thus, GAS invasive soft-tissue infections may present in an epidemic fashion among IDUs even in the absence of shared paraphernalia.

P. aeruginosa.

Outbreaks of endocarditis caused by P. aeruginosa serotype 011 were reported from Chicago in the 1980s in drug users injecting the pentazocine–tripelennamine combination (Shekar et al., 1985). Contamination of drug paraphernalia during elaborate drug preparation techniques prior to self-injection is likely to have initiated the outbreak. In one method of drug preparation, drug tablets were placed in a match book, crushed by chewing, suspended in tap water or toilet water in a small unsterile container, filtered through a piece of cotton or a cigarette filter and injected using shared syringes. In addition, pentazocine–tripelennamine is usually not boiled prior to use (in contrast to heroin), leading perhaps to a greater chance of survival for the contaminating bacteria. Botsford et al. (1985) studied microbiological growth in pentazocine–tripelennamine and found that P. aeruginosa strains survived in the drug combination as opposed to the complete inhibition of strains of S. aureus (used as controls). A resurgence of P. aeruginosa endocarditis in IDUs, was noted in Detroit between 2006 and 2008 and though pentazocine–tripelennamine were no longer available in the streets, drug users did admit to using syringes cleaned with unboiled tap water (Reyes et al., 2009). P. aeruginosa has also been associated with other infections in IDUs including septic arthritis (typically affecting the sternoclavicular joint) (Brancós et al., 1991), spinal and disc space infections (Chuo et al., 2007; Kaplan, 1974) and osteomyelitis (Boll & Jurik, 1990).

Tetanus.

Tetanus in IDUs appears to be the case of a re-emergence of an old disease in a new setting. First described in subcutaneous morphine users, tetanus is arguably the oldest infection associated with the IDU (Anon, 1876; Levinson et al., 1955). Subcutaneous or intramuscular injection (‘skin popping’) of contaminated heroin is the most common implicated factor (Bartlett, 1991). Though limited data are available on anti-tetanus antibody levels in IDUs, a study from Guipuzcoa, Spain (Gilla et al., 1994), showed that more than half of the subjects lacked protective antibodies (50.8 %) − indicating the existence of a large pool of unprotected and highly susceptible drug users.

Tetanus outbreaks among IDUs have been reported worldwide and are often associated with poor outcome and high mortality (Beeching & Crowcroft, 2005; Hahné et al., 2006; Pascual et al., 2003). An increase in the incidence of tetanus among IDUs may be attributed to an alteration in the adulterants or bacteriological profile of circulating street heroin. The powdered form of heroin is poorly soluble in water and is often dissolved in mild acids followed by heating in a spoon prior to use. The mild acid (pH ∼2.5) kills the non-spore-bearing bacteria, which serve as a source of competition to the surviving spore-bearers and the heat treatment stimulates the spores to germinate (Brazier et al., 2003). Simultaneous injection of heroin and cocaine (‘speed balls’) may induce soft tissue ischaemia making conditions favourable for anaerobic growth (Murphy et al., 2001). To improve laboratory detection, Akbulut et al. (2005) developed an efficient real-time PCR assay to amplify the C. tetani neurotoxin (TeNT) gene in wound specimens from IDUs.

Other clostridial infections.

Outbreaks of wound botulism among IDUs have increased in conjunction with the use of black tar heroin (Passaro et al., 1998; Brett et al., 2004; Kalka-Moll et al., 2007; Werner et al., 2000; Barry et al., 2009). Though most commonly associated with heroin use, botulism has also been reported following intranasal cocaine abuse (Kudrow et al., 1988). An unprecedented outbreak of severe soft tissue infection among heroin IDUs was reported from Glasgow, Scotland (CDC, 2000). The most frequently isolated pathogen was Clostridium novyi type A and findings pointed to contaminated heroin as the source of infection. The occurrence of similar contemporaneous outbreaks in Ireland and England reflected specific recognized routes of heroin distribution along which the infection had been spread (Jones et al., 2002; McGuigan et al., 2002). Other pathogenic clostridia such as Clostridium histolyticum, Clostridium sordellii, Clostridium perfringens, Clostridium septicum and Clostridium bifermentans have also been reported following ‘muscle popping’ in IDUs (Brazier et al., 2002).

In the setting of IDUs, diagnostic microbiology departments should be alert to the possibility of isolating unusual clostridia. The origins of street heroin in most parts of the world are found in South-West Asia, particularly Afghanistan. Given the turmoil in the region and non-sterile methods of production and transport, contamination is possible at virtually any stage in the process.

Anthrax.

Since December 2009, 31 cases of anthrax, including 11 deaths, have been confirmed among drug users in Scotland (Booth et al., 2010; Ramsay et al., 2010). Contamination of heroin or a cutting agent along the supply chain is considered to be the vehicle of infection. Patients presented with a new pattern of infection, previously described as injectional anthrax, characterized by inflammation and abscesses at sites of heroin injection (Ringertz et al., 2000; Lalitha et al., 1988). A fatal case of anthrax also occurred in a heroin user in Germany in December 2009 (Radun et al., 2010). It is unclear whether there is a link between this case and the anthrax outbreak among IDUs in Scotland. If the hypothesis of a potential link to the Scottish cases proves true, it might well be that several countries worldwide have been supplied with the same contaminated batch of heroin.

Tuberculosis.

Drug use has been associated with a higher prevalence of latent and active tuberculosis and HIV-infected drug users are at particularly high risk (Reichman et al., 1979; Perlman et al., 1995; Markowitz et al., 1993; Friedman et al., 1996; Oeltmann et al., 2009). A cluster of tuberculosis cases was identified in Seattle, USA, among East-African immigrants with a history of illicit marijuana use (Oeltmann et al., 2006). Isolates shared identical genotyping patterns, which in the state of Washington was exclusive to this outbreak. Patients reported frequent ‘hotboxing’, the practice of group smoking of marijuana in a vehicle with the windows closed so that exhaled smoke is repeatedly inhaled. Indigenous practices such as the sharing of a marijuana water pipe (‘bong’) in Australia and using a common ‘chilam’ or earthen tubular pot filled with tobacco and burning coal among opium users in India have been reported to favour tuberculosis transmission (Munckhof et al., 2003; Mathur & Chaudhary, 1996). ‘Shotgunning’ or inhaling smoke from illicit drugs and exhaling it directly into another's mouth has been associated with M. tuberculosis transmission among a group of exotic dancers and their contacts (McElroy et al., 2003).

In March 1992, a cluster of tuberculosis cases among drug users was identified in San Mateo County, California (Leonhardt et al., 1994). All patients gave a history of cocaine abuse that included visiting one of the two crack houses of the neighbourhood. The index case contributed to the transmission as a transient resident of several dwellings. Crack use has been associated with impairment of pulmonary function and exacerbation of coughing, which could facilitate tuberculosis transmission (CDC, 1991). Because of delays in diagnosis and treatment, cocaine users with tuberculosis might remain contagious for longer periods. In addition, crack is often used in dwellings with limited ventilation to minimize detection, which may favour transmission.

Diphtheria.

Sporadic outbreaks of non-toxigenic Corynebacterium diphtheriae strains have been reported in population subgroups such as homosexuals in Great Britain (Wilson, 1995), Aboriginals in Australia (Hogg et al., 1996) and IDUs in Switzerland (Zuber et al., 1992). The site of infection is often the skin rather than the pharynx and toxic manifestations are rare. A study from Zurich established a high carrier rate in drug users, with all C. diphtheriae isolates identified as biotype mitis and displaying the same restriction pattern by ribotyping (Gruner et al., 1994). Gubler et al. (1998) reported a cluster of infections by nontoxigenic C. diphtheriae mitis among a group of Swiss drug users. Patients frequented the open drug scene (‘needle parks’) prevalent in Zurich at the time, which allowed easy access to drugs and the congregation of drug users from all over Europe. This clone and closely related ones have been recovered from cases of endocarditis and orthopaedic infections in IDUs from parts of Western Europe as well (Funke et al., 1999). Given that migration and contacts are not uncommon among IDUs, it is possible that the strains may have spread through the use of common drug paraphernalia or through drugs themselves. Populations of IDUs can serve as a reservoir for C. diphtheriae, and given the propensity of non-toxigenic strains to cause invasive infections and acquire the toxin expressing lysogenic phage (McGregor, 2005); this reservoir could pose a serious public-health problem.

HIV.

Drug use-related transmission accounts for at least 10 % of HIV infections globally, but this may have risen up to 40 % in recent times (Strathdee & Stockman, 2010), with injecting drug use taking over as the primary mode of HIV transmission in several countries. The sharing of needles/syringes and other drug-injection equipment is a well-known route of HIV transmission (Thompson et al., 2003). However, injection drug use contributes to the spread of HIV even in non-drug user populations such as from IDU husbands to their non-injecting wives (Panda et al., 2000). In Dar E Salaam, Tanzania, local practices such as ‘flashblood’ (i.e. deliberate sharing of blood with drug preparations) may be fuelling HIV transmission, but the extent to which this or similar practices exist elsewhere is unknown (McCurdy et al., 2010).

Non-injection drug use also contributes to the spread of HIV when users engage in risky behaviour such as trading sex for drugs or money. HIV prevalence estimates are similar for non-IDUs and IDUs across countries (Des Jarlais et al., 2007; Bassols et al., 2007; Strathdee et al., 2008b) with several proposed explanations for the high prevalence in non-IDU populations (Strathdee & Stockman, 2010). Sharing of non-injection drug paraphernalia (straws, dollar bills used for snorting cocaine, inhalers and crack pipes) may play a role as drug users often have sores and cracks on their noses/mouths, which could facilitate viral transmission. The high degree of mixing or ‘bridging’ between IDU and non-IDU populations can lead to transmission of HIV through overlapping social and sexual networks.

The molecular epidemiology of HIV strains circulating among IDU populations is seen to correlate strongly with the prevalent regional subtype. However, a variety of recombinant forms have been seen to enter circulation leading to a growing complexity of HIV-1 strains (Sanders-Buell et al., 2010; Mullick et al., 2010; Ma et al., 2009). Once introduced into IDU networks, these recombinant strains lead to an explosive rise in new HIV-1 infection, fuelled principally by needle sharing. In Manipur, the north-eastern state of India that borders Myanmar, rapid transmission of HIV infection among its vast drug-injecting population has been witnessed (Sarkar et al., 1993). The seroprevalence among IDUs increased from 0 to 50 % within 6 months and the infection quickly spread to the population at large. Drug users continue to bear a substantial burden of HIV infection globally and interventions such as needle-exchange programs could reduce the likelihood of HIV transmission.

HBV and hepatitis D virus (HDV).

Parenterally exposed groups such as drug users can easily contract and transmit HBV infection due to high-risk practices and the high HBV prevalence in this group (van Houdt et al., 2009). Recent injecting is the main transmission route for HBV infection and though sexual transmission has become more important over time, it plays a minor role for transmission among IDUs (Levine et al., 1995). Non-injecting drug users, on the other hand, are probably infected with HBV via unsafe sexual contacts and the sharing of crack-use equipment (Neaigus et al., 2007). The majority of the drug users are infected with the identical genotype D strain, serotype ayw3 (Panessa et al., 2009), which appears to be specific to this population. Sporadic spillover of HBV infection from the general population to the drug users via drug-injecting commercial sex workers and the reverse spillover from IDUs to the general population, via the heterosexual clients of drug-injecting commercial sex workers have been reported (van Houdt et al., 2007, 2009). Combined HBV and HDV infection has been associated with hepatitis outbreaks with an unusually high mortality in drug users (Christensen et al., 2001; Stevenson et al., 2001). Though other routes of HDV acquisition such as intrafamilial transmission have been reported, injecting drug use still remains the common route of transmission (Cross et al., 2008).

HCV.

Hepatitis C is the most common infection among IDUs, and at present IDUs form the major risk group for acquiring this infection. HCV prevalence rates in IDUs range from 40 to 90 % in different studies, and comprise up to 90 % hepatitis C notifications in certain countries (Thomas et al., 1995; Jittiwutikarn et al., 2006; Basu, 2010; Zamani et al., 2010). Genotypes 1a and 3a predominate among IDUs, with genotype 3a being far more frequent in IDUs than the general population (Webster et al., 2000; Silva et al., 2010; Mahfoud et al., 2010). A positive HCV status in IDUs is associated with the sharing of injection paraphernalia, frequency and years of drug use, HBV co-infection and alternate injecting practices, such as drawing blood into the syringe prior to injection (booting) (Hahn et al., 2002; Stark et al., 1997; Villano et al., 1997). Drug abuse not only promotes HCV transmission but also plays a vital role as a cofactor in promoting HCV replication in host cells (Li et al., 2003). In addition, primary HCV infection does not confer protective immunity against subsequent infection with viruses of other genotypes. Proust et al. (2000) report a case of two successive HCV infections in an IDU caused by two different HCV strains of genotypes 1a (first episode) and 3a (second episode). Even after clearance of the primary infection, IDUs are still at risk of acquiring a secondary HCV infection with a different viral genotype.

HTLV.

Infection with proliferative HTLV I/II and cytopathic HTLV-III are known to be rare in the general population; however, IDUs engaging in practices such as needle sharing and ‘booting’ provide a setting highly favourable for transmission. IDUs are exposed to considerable antigen load due to the direct invasion of noxious chemicals, toxins and pathogens directly into their bloodstream. This predisposes them to rapid clinical progression to neurological (HTLV-I/II) or haematological (HTLV-I) disease.

The prevalence of HTLV infection in IDUs reveals a high degree of geographical variability. Robert-Guroff et al. (1986) reported seropositivity among IDUs in Queens, New York, to be 9 % for HTLV-I, 18 % for HTLV-II and 41 % for HTLV-III, which was significantly higher than that in the general population (less than 1 %). However, a study from South Scandinavia, which screened 693 IDUs, reported a prevalence rate as low as 0.7 % (Blomberg et al., 1994). Prevalence rates also appear to vary considerably in the same country as well, ranging from 8.3 % in Brooklyn to 24.3 % in New Orleans in the USA (Lee et al., 1990). While HTLV-II is the predominant strain among IDUs in the USA and Europe, a study from Israel reports predominant HTLV-I seropositivity among IDUs pointing to the possibility of an endemic focus of infection (Maayan et al., 1992).

Candida species.

Endogenous Candida albicans endophthalmitis in IDUs has been extensively documented in the literature (Aguilar et al., 1979; Keyashian & Malani, 2007) and is one of the most common ocular complications of drug use. Culture recovery of Candida from the vitreous specimen is difficult and diagnosis largely relies on direct smear examination. Fruit juice is often used to dissolve drugs prior to injection and serves as a good culture medium for Candida (Albini et al., 2007; Scheidegger et al., 1993). Drug contamination by Candida is also associated with a distinct syndrome of disseminated infection characterized by chorioretinitis, folliculitis and costochondral arthritis (Odds et al., 1987; Bisbe et al., 1992).

Aspergillus species.

Though not as frequent as Candida species, fungal endophthalmitis caused by Aspergillus species is a recognized complication of drug use (Elliott et al., 1979; Hirst et al., 2005). Cases of Aspergillus flavus endophthalmitis among IDUs associated with unsterile injection practices, such as diluting drugs in tap water and filtering the mix through cigarette filters, have been reported (CDC, 1990). Because Aspergillus species are ubiquitous moulds, the source of infection is difficult to determine. Other forms of Aspergillus spp. infection such as osteomyelitis, endocarditis and brain abscess have also been associated with drug use (Salloum et al., 2004; Petrosillo et al., 2001; Morrow et al., 1983).

Mucormycosis.

Although isolated cerebral mucormycosis is uncommon, intravenous drug use is considered to be the most important risk factor associated with the infection. IDUs typically develop a form of primary cerebral mucormycosis affecting the basal ganglia and the Rhizopus species is most often isolated (Micozzi & Wetli, 1985; Verma et al., 2006; Hopkins et al., 1994). The infection probably results from parenteral inoculation of spores contained in the drugs or drug paraphernalia (Blázquez et al., 1996). This entity differs from rhinocerebral zygomycosis commonly associated with diabetes mellitus with no external signs of involvement and deep CNS localization. In the presence of basal ganglia lesions in an IDU, the possibility of mucormycosis should be considered, regardless of the patient's HIV status (Gaing et al., 1992).

Penicillium marneffei.

Penicillium marneffei is an emerging fungal pathogen causing fatal systemic mycoses in immunocompromised patients. Endemic in tropical Asia, its importance as a human disease was recognized only after the arrival of the HIV pandemic. A report from Manipur, India, describes 36 cases of Penicillium marneffei infection in HIV infected individuals of which 31 (86 %) were IDUs (Ranjana et al., 2002). Since the spread of HIV infection is closely linked to drug abuse, there is an increasing trend of Penicillium marneffei infection among IDUs. Drug abusers with a history of travel may serve as carriers of the infection and thus Penicillium marneffei infection should be considered in narcotic users even in non-endemic areas (Julander & Petrini, 1997; Viviani et al., 1993).

Malaria.

The earliest outbreak of malaria among IDUs was reported from the University of Cairo among heroin users linked with the communal use of syringes (Biggam, 1929). Since then there have been several reports describing epidemic outbreaks of malaria caused by Plasmodium falciparum and Plasmodium vivax traced to the sharing of needles among IDUs (Gonzalez Garcia et al., 1986; Baker & Crawford, 1978; Brown & Khoa, 1975; Friedmann et al., 1973; Bick & Anhalt, 1971). In fact, the mixing of quinine with heroin was a practice introduced by drug dealers in Chicago in the 1940s to halt an outbreak of malaria among IDUs (Platt & Labate, 1976).

The influence of narcotic addiction on the outcome of malaria in IDUs has been extensively studied (Chau et al., 2002). Inoculation of 0.05 ml blood from a ‘donor’ with parasitaemia (∼ 5000 parasites μl⁻¹) via an infected needle would exceed the number of parasites usually transmitted by a single mosquito bite. The consequences of a larger inoculum would be a shorter prepatent period and less time for specific host defences to be mobilized. This has led to the impression that malaria in IDUs is associated with a poor outcome. However, in the above study, the outcome of malaria in IDUs did not differ significantly from those who had acquired the infection via mosquito bite. Several factors such as malnutrition, iron deficiency and increased splenic function due to repeated infections may attenuate severe malaria in IDUs. The disadvantage of a large inoculum and short incubation period may be balanced by pre-existing immune defences. However, IDUs also potentially concentrate factors involved in the emergence and spread of drug-resistant strains such as treatment delay, immunosuppression and social marginalization (Bastos et al., 1999).

Leishmaniasis.

Needle sharing by IDUs has been proposed as providing an alternative, artificial and anthroponotic cycle for leishmania transmission. The prevalence of markers of leishmania infection (leishmanin skin test and serum leishmania antibodies) was reported to be higher among IDUs than among a similar cohort of individuals who were without a history of drug use (Pineda et al., 2001). Arguments put forth in support of needle transmission of leishmania include the quantity of blood contained in a shared needle (∼0.3 ml), which far exceeds the amount transmitted by the Phlebotomus bite (∼0.3–0.5 μl), the patient's blood sample is capable of being infective to sand-flies and that certain zymodemes are found almost exclusively in infected IDUs. Further, shared RFLP patterns were found in blood samples tested from discarded syringes in an outbreak of leishmaniasis in north-east Spain, suggesting the spread of certain leishmania clones among IDUs with shared needles as the vector (Cruz et al., 2002).

Toxoplasmosis.

The decline in Th1 and increase in Th2 activity, as a result of drug-induced immunomodulation, predisposes drug users to infection with intracellular pathogens such as Toxoplasma gondii (Buchy et al., 2003; Li et al., 2010). Cytokine investigations revealed reduced levels of phytohaemagglutinin-induced IFN-γ, serum IFN-γ and IL-12, but levels of IL-4, IL-6, IL-10 and TNF-α had concomitantly increased. IL-12 and IFN-γ production are essential for controlling infections caused by intracellular organisms, and IL-6 and TNF-α confer anti-Toxoplasma activity. The increase in IL-6 levels may provide a protective effect for the host by controlling the number of T. gondii parasites and also serve as a marker to assess infections with intracellular pathogens in IDUs.